IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

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

Landau, David B., E-mail: david.landau@kcl.ac.uk; Hughes, Laura; Baker, Angela

2016-08-01

Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumormore » doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.« less

SU-F-J-25: Position Monitoring for Intracranial SRS Using BrainLAB ExacTrac Snap Verification

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

Jang, S; McCaw, T; Huq, M

2016-06-15

Purpose: To determine the accuracy of position monitoring with BrainLAB ExacTrac snap verification following couch rotations during intracranial SRS. Methods: A CT scan of an anthropomorphic head phantom was acquired using 1.25mm slices. The isocenter was positioned near the centroid of the frontal lobe. The head phantom was initially aligned on the treatment couch using cone-beam CT, then repositioned using ExacTrac x-ray verification with residual errors less than 0.2mm and 0.2°. Snap verification was performed over the full range of couch angles in 15° increments with known positioning offsets of 0–3mm applied to the phantom along each axis. At eachmore » couch angle, the smallest tolerance was determined for which no positioning deviation was detected. Results: For couch angles 30°–60° from the center position, where the longitudinal axis of the phantom is approximately aligned with the beam axis of one x-ray tube, snap verification consistently detected positioning errors exceeding the maximum 8mm tolerance. Defining localization error as the difference between the known offset and the minimum tolerance for which no deviation was detected, the RMS error is mostly less than 1mm outside of couch angles 30°–60° from the central couch position. Given separate measurements of patient position from the two imagers, whether to proceed with treatment can be determined by the criterion of a reading within tolerance from just one (OR criterion) or both (AND criterion) imagers. Using a positioning tolerance of 1.5mm, snap verification has sensitivity and specificity of 94% and 75%, respectively, with the AND criterion, and 67% and 93%, respectively, with the OR criterion. If readings exceeding maximum tolerance are excluded, the sensitivity and specificity are 88% and 86%, respectively, with the AND criterion. Conclusion: With a positioning tolerance of 1.5mm, ExacTrac snap verification can be used during intracranial SRS with sensitivity and specificity between 85% and 90%.« less

Pilot-scale verification of maximum tolerable hydrodynamic stress for mammalian cell culture.

PubMed

Neunstoecklin, Benjamin; Villiger, Thomas K; Lucas, Eric; Stettler, Matthieu; Broly, Hervé; Morbidelli, Massimo; Soos, Miroslav

2016-04-01

Although several scaling bioreactor models of mammalian cell cultures are suggested and described in the literature, they mostly lack a significant validation at pilot or manufacturing scale. The aim of this study is to validate an oscillating hydrodynamic stress loop system developed earlier by our group for the evaluation of the maximum operating range for stirring, based on a maximum tolerable hydrodynamic stress. A 300-L pilot-scale bioreactor for cultivation of a Sp2/0 cell line was used for this purpose. Prior to cultivations, a stress-sensitive particulate system was applied to determine the stress values generated by stirring and sparging. Pilot-scale data, collected from 7- to 28-Pa maximum stress conditions, were compared with data from classical 3-L cultivations and cultivations from the oscillating stress loop system. Results for the growth behavior, analyzed metabolites, productivity, and product quality showed a dependency on the different environmental stress conditions but not on reactor size. Pilot-scale conditions were very similar to those generated in the oscillating stress loop model confirming its predictive capability, including conditions at the edge of failure.

Strategies to reduce exposure of fumonisins from complementary foods in rural Tanzania.

PubMed

Kimanya, Martin E; De Meulenaer, Bruno; Van Camp, John; Baert, Katleen; Kolsteren, Patrick

2012-10-01

Feeding infants with maize can expose them to fumonisin mycotoxins. We assessed fumonisin exposure from complementary foods in rural Tanzania and determined strategies to reduce the exposure. We conducted a cross-sectional study in four villages of Tarakea division, Northern Tanzania. We used a repeat 24-hour dietary recall to collect data of maize consumption as complementary food for 254 infants aged 6-8 months. Fumonisin concentrations in the maize were also estimated. Fumonisin exposure was assessed using @risk analysis software. With the software, several maximum fumonisin contamination and maize consumption patterns were combined in order to determine effective strategies for minimizing fumonisin exposure. Of the infants, 89% consumed maize at amounts up to 158g/person/day (mean; 43g/person/day±28). The maize was contaminated with fumonisins at levels up to 3201µgkg(-1) . Risk of fumonisin intake above the provisional maximum tolerable daily limit of 2µgkg(-1) body weight was 15% (95% confidence interval; 10-19). The risk was minimized when the maximum contamination was set at 150µgkg(-1) . The risk was also minimized when the maximum consumption was set at 20g/child/day while keeping the maximum contamination at the European Union (EU) maximum tolerated limit (MTL) of 1000µgkg(-1) . Considering the economical and technological limitations of adopting good agricultural practices in rural Tanzania, it is practically difficult to reduce contamination in maize to 150µgkg(-1) . We suggest adoption of the EU MTL of 1000µgkg(-1) for fumonisins in maize and reduction, by replacement with another cereal, of the maize component in complementary foods to a maximum intake of 20g/child/day. © 2011 Blackwell Publishing Ltd.

Assessment of toxic impact of metals on proline, antioxidant enzymes, and biological characteristics of Pseudomonas aeruginosa inoculated Cicer arietinum grown in chromium and nickel-stressed sandy clay loam soils.

PubMed

Saif, Saima; Khan, Mohammad Saghir

2018-04-17

Considering the heavy metal risk to soil microbiota and agro-ecosystems, the study was designed to determine metal toxicity to bacteria and to find metal tolerant bacteria carrying multifarious plant growth promoting activities and to assess their impact on chickpea cultivated in stressed soils. Metal tolerant strain SFP1 recognized as Pseudomonas aeruginosa employing 16S rRNA gene sequence determination showed maximum tolerance to Cr (400 μg/ml) and Ni (800 μg/ml) and produced variable amounts of indole acetic acid, HCN, NH 3 , and ACC deaminase and could solubilize insoluble phosphates even under Cr (VI) and Ni stress. Metal tolerant P. aeruginosa reduced toxicity of Cr (VI) and Ni and concomitantly enhanced the performance of chickpea grown under stressed and conventional soils. At 144 mg Cr kg -1 , the measured parameters of a bacterial strain was significantly enhanced, but it was lower compared to those recorded at 660 mg Ni kg -1 . The strain SFP1 demonstrated maximum increase in seed yield (81%) and grain protein (16%) at 660 mg Ni kg -1 over uninoculated and untreated control. Stressed plants had more proline, antioxidant enzymes, and metal concentrations in plant tissues. P. aeruginosa, however, remarkably declined the level of stress markers (proline and APX, SOD, CAT, and GR), as well as with Cr (VI) and Ni uptake by chickpea. Conclusively, P. aeruginosa strain SFP1 due to its dual metal tolerant ability, capacity to secrete plant growth promoting regulators even under metal stress and potential to mitigate metal toxicity, could be developed as microbial inoculant for enhancing chickpea production in Cr and Ni contaminated soils.

Fault Tree Handbook

DTIC Science & Technology

1981-01-01

are applied to determine what system states (usually failed states) are possible; deductive methods are applied to determine how a given system state...Similar considerations apply to the single failures of CVA, BVB and CVB and this important additional information has been displayed in the principal...way. The point "maximum tolerable failure" corresponds to the survival point of the company building the aircraft. Above that point, only intolerable

Phase I Study of Daily Irinotecan as a Radiation Sensitizer for Locally Advanced Pancreatic Cancer

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

Fouchardiere, Christelle de la, E-mail: delafo@lyon.fnclcc.f; Negrier, Sylvie; Labrosse, Hugues

2010-06-01

Purpose: The study aimed to determine the maximum tolerated dose of daily irinotecan given with concomitant radiotherapy in patients with locally advanced adenocarcinoma of the pancreas. Methods and Materials: Between September 2000 and March 2008, 36 patients with histologically proven unresectable pancreas adenocarcinoma were studied prospectively. Irinotecan was administered daily, 1 to 2 h before irradiation. Doses were started at 6 mg/m{sup 2} per day and then escalated by increments of 2 mg/m{sup 2} every 3 patients. Radiotherapy was administered in 2-Gy fractions, 5 fractions per week, up to a total dose of 50 Gy to the tumor volume. Inoperabilitymore » was confirmed by a surgeon involved in a multidisciplinary team. All images and responses were centrally reviewed by radiologists. Results: Thirty-six patients were enrolled over a period of 8 years through eight dose levels (6 mg/m{sup 2} to 20 mg/m{sup 2} per day). The maximum tolerated dose was determined to be 18 mg/m{sup 2} per day. The dose-limiting toxicities were nausea/vomiting, diarrhea, anorexia, dehydration, and hypokalemia. The median survival time was 12.6 months with a median follow-up of 53.8 months. The median progression-free survival time was 6.5 months, and 4 patients (11.4%) with very good responses could undergo surgery. Conclusions: The maximum tolerated dose of irinotecan is 18 mg/m{sup 2} per day for 5 weeks. Dose-limiting toxicities are mainly gastrointestinal. Even though efficacy was not the aim of this study, the results are very promising, with a median survival time of 12.6 months.« less

Heavy metals in aromatic spices by inductively coupled plasma-mass spectrometry.

PubMed

Bua, Daniel Giuseppe; Annuario, Giovanni; Albergamo, Ambrogina; Cicero, Nicola; Dugo, Giacomo

2016-09-01

Objective of this study was to determine the content of Cd, Hg, As and Pb in common spices traded in the Italian market, using inductively coupled plasma-mass spectrometry (ICP-MS). The results were compared with the maximum limits established by the national Legislative Decree (LD) no. 107 implementing the Council Directive 88/388/EEC and by international organisations, such as Food and Agriculture Organization (FAO) and World Health Organization (WHO). Food safety for spices was assessed considering the tolerable weekly intake (TWI) and the provisional tolerable weekly intake (PTWI), respectively, for Cd and Hg and the 95% lower confidence limit of the benchmark dose of 1% extra risk (BMDL01) for As and Pb. Investigated elements in all samples were within the maximum limits as set by the national and international normative institutions. Nevertheless, the heavy metal content of some spices exceeded the PTWI, TWI and BMDL01, which needs attention when considering consumer's health.

The relation between tilt table and acceleration-tolerance and their dependence on stature and physical fitness

NASA Technical Reports Server (NTRS)

Klein, K. E.; Backhausen, F.; Bruner, H.; Eichhorn, J.; Jovy, D.; Schotte, J.; Vogt, L.; Wegman, H. M.

1980-01-01

A group of 12 highly trained athletes and a group of 12untrained students were subjected to passive changes of position on a tilt table and positive accelerations in a centrifuge. During a 20 min tilt, including two additional respiratory maneuvers, the number of faints and average cardiovascular responses did not differ significantly between the groups. During linear increase of acceleration, the average blackout level was almost identical in both groups. Statistically significant coefficients of product-moment correlation for various relations were obtained. The coefficient of multiple determination computed for the dependence of acceleration tolerance on heart-eye distance and systolic blood pressure at rest allows the explanation of almost 50% of the variation of acceleration tolerance. The maximum oxygen uptake showed the expected significant correlation to the heart rate at rest, but not the acceleration tolerance, or to the cardiovascular responses to tilting.

High lenticular tolerance to ultraviolet radiation-B by pigmented guinea-pig; application of a safety limit strategy for UVR-induced cataract.

PubMed

Mody, Vino C; Kakar, Manoj; Söderberg, Per G; Löfgren, Stefan

2012-05-01

The purpose of this study was to determine a threshold measure, maximum tolerable dose (MTD), for avoidance of UVR-B-induced cataract in the pigmented guinea-pig. Thirty pupil-dilated anesthetized young female guinea-pigs, divided into five equal groups, received between 0 and 84.9 kJ/m(2) unilateral UVR-B. Lens extraction and in vitro lens photography occurred 24 hr after exposure. Measurement of intensity of lens light scattering served as quantifying tool for the degree of cataract. Data analysis included regression, using a second order polynomial model. The applied MTD concept was based on the UVR-B dose-response curve obtained for the pigmented guinea-pig. A smaller number of pigmented guinea-pigs, pigmented rats and albino rats underwent morphometric analysis of the anterior segment geometry. All eyes exposed to UVR-B developed cataract in the anterior subcapsular region. MTD for avoidance of UVR-B-induced cataract was 69.0 kJ/m(2) in the pigmented guinea-pig. Iris was considerably thicker in the guinea-pig than in the rats. Lens blockage by the dilated iris was lowest in the guinea-pig. Maximum tolerable dose for avoidance of UVR-B-induced cataract in the pigmented guinea-pig was 69.0 kJ/m(2), over 10-fold higher than the threshold 5 kJ/m(2) obtained by Pitts et al. in the pigmented rabbit. Maximum tolerable dose is an appropriate method for estimation of toxicity for UVR-B-induced cataract in the guinea-pig. The pigmented guinea-pig is significantly less sensitive to UVR-B exposure than the pigmented rabbit and pigmented rat. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

PubMed

Mark, Tomer M; Guarneri, Danielle; Forsberg, Peter; Rossi, Adriana; Pearse, Roger; Perry, Arthur; Pekle, Karen; Tegnestam, Linda; Greenberg, June; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; Van Besien, Koen; Ely, Scott; Jayabalan, David; Sherbenou, Daniel; Coleman, Morton; Niesvizky, Ruben

2017-06-01

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

PubMed

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PubMed

Wang-Gillam, Andrea; Arnold, Susanne M; Bukowski, Ronald M; Rothenberg, Mace L; Cooper, Wendy; Wang, Kenneth K; Gauthier, Eric; Lockhart, A Craig

2012-02-01

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

The neotropical shrub Lupinus elegans, fromtemperate forests, may not adapt to climate change.

PubMed

Soto-Correa, J C; Sáenz-Romero, C; Lindig-Cisneros, R; de la Barrera, E

2013-05-01

Considering that their distribution is limited to altitudinal gradients along mountains that are likely to become warmer and drier, climate change poses an increased threat to temperate forest species from tropical regions. We studied whether the understorey shrub Lupinus elegans, endemic to temperate forests of west-central Mexico, will be able to withstand the projected temperature increase under seven climate change scenarios. Seeds were collected along an altitudinal gradient and grown in a shade-house over 7 months before determining their temperature tolerance as electrolyte leakage. The plants from colder sites tolerated lower temperatures, i.e. the temperature at which half of the maximum electrolyte leakage occurred (LT50), ranged from −6.4 ± 0.7 to −2.4 ± 0.3 °C. In contrast, no pattern was found for tolerance to high temperature (LT50 average 42.8 ± 0.3 °C). The climate change scenarios considered here consistently estimated an increase in air temperature during the present century that was higher for the maximum air temperature than for the mean or minimum. In particular, the anomaly from the normal maximum air temperature at the study region ranged from 2.8 °C by 2030 to 5.8 °C by 2090. In this respect, the inability of L. elegans to adapt to increasingly higher temperatures found here, in addition to a possible inhibition of reproduction caused by warmer winters, may limit its future distribution.

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

DiCostanzo, D; Ayan, A; Woollard, J

Purpose: To automate the daily verification of each patient’s treatment by utilizing the trajectory log files (TLs) written by the Varian TrueBeam linear accelerator while reducing the number of false positives including jaw and gantry positioning errors, that are displayed in the Treatment History tab of Varian’s Chart QA module. Methods: Small deviations in treatment parameters are difficult to detect in weekly chart checks, but may be significant in reducing delivery errors, and would be critical if detected daily. Software was developed in house to read TLs. Multiple functions were implemented within the software that allow it to operate viamore » a GUI to analyze TLs, or as a script to run on a regular basis. In order to determine tolerance levels for the scripted analysis, 15,241 TLs from seven TrueBeams were analyzed. The maximum error of each axis for each TL was written to a CSV file and statistically analyzed to determine the tolerance for each axis accessible in the TLs to flag for manual review. The software/scripts developed were tested by varying the tolerance values to ensure veracity. After tolerances were determined, multiple weeks of manual chart checks were performed simultaneously with the automated analysis to ensure validity. Results: The tolerance values for the major axis were determined to be, 0.025 degrees for the collimator, 1.0 degree for the gantry, 0.002cm for the y-jaws, 0.01cm for the x-jaws, and 0.5MU for the MU. The automated verification of treatment parameters has been in clinical use for 4 months. During that time, no errors in machine delivery of the patient treatments were found. Conclusion: The process detailed here is a viable and effective alternative to manually checking treatment parameters during weekly chart checks.« less

Effect of Surgical Curve Correction on Exercise Tolerance and Physical Capacities in Patients of Severe Spinal Deformity.

PubMed

Patil, Prateek C; Rathod, Ashok K; Borde, Mandar; Singh, Vishwajeet; Singh, Hemant U

2016-12-01

Traditionally, surgical intervention for patients with a spinal deformity has been considered for cosmetic benefits, but surgical intervention can alter the lung physiology or volumes and in turn leads to increase in physical capacity and exercise tolerance. Therefore, we conducted this to determine whether a surgical correction would restore the lung physiology, physical capacity and exercise tolerance in patients with kyphoscoliosis. To evaluate the usage of six-minute walk test scores and modified Borg scores as tools/measures for exercise tolerance in patients with spinal deformity and to study the effects of surgical correction of spinal deformity on exercise tolerance with above parameters as the measures. Thirty patients with spinal deformity, who had undergone surgery for deformity correction, were evaluated. All patients were investigated pre-operatively with x-rays of the spine (anteroposterior and lateral views). Clinical tests like breath holding time (after full inspiration) in number of seconds, modified Borg scores, six-minute walk test scores (heart rate, respiratory rate, maximum distance walked); were recorded as measures of exercise tolerance. The patients were followed up on the first, third, sixth and twelfth month post-operatively and tested clinically for breath holding time, modified Borg scores, six-minute walk test scores (heart rate, respiratory rate, maximum distance walked) and x-rays of the spine (anteroposterior and lateral views). In our study, breath holding time (p-value = 0.001) and modified Borg scores (p-value = 0.012) showed a significant improvement at 12 months post-operatively. We noted similar findings with heart rate, respiratory rate and maximum distance walked after a six-minute walk test. Improvements were noted in all the parameters, especially in the group of patients with greater than 60 degrees of cobb angle. However, the differences between the two groups (pre-operative cobb angle less than 60 degrees and pre-operative cobb angle more than 60 degrees) were not significant. The results were analysed and tested for significance using Student's t-test (paired and unpaired as appropriate) and Wilcoxon signed rank test. Surgical correction in cases of spinal deformity improves the cosmetic appearance and balance in the patients. Favourable results of surgical intervention were found in exercise tolerance with improvements in modified Borg scores, six-minute walk test results and breath holding time. The above parameters appear to be good tools for the assessment of physical capacity and exercise tolerance in patients with spinal deformity.

Some physiological aspects of artificial gravity. [gravitational effects on human orthostatic tolerance and physical fitness

NASA Technical Reports Server (NTRS)

Cramer, D. B.; Graybiel, A.

1973-01-01

The effects of increasing artificial gravity exposure on four aspects of physiological fitness are examined in four young men who, prior to exposure, were deconditioned with bed rest and water immersion. The four aspects of physiological fitness are orthostatic tolerance, exercise tolerance, forearm endurance, and maximum strength. Orthostatic tolerance was sharply reduced by deconditioning and was substantially improved by walking in simulated lunar gravity (1/6 g) for 2.5 hours daily for 7 days or by walking in 1/2 g and 1 g for 1 hour daily for 3 days. Exercise tolerance was also sharply reduced by deconditioning but did not significantly improve with increasing g-exposure. Walking in 1 g for 1 hour daily for 3 days raised exercise tolerance only a little above the low produced by deconditioning. Forearm endurance and maximum strength were relatively unaffected by deconditioning and subsequent g-exposure.

Association of hormonal responses and performance of student pilots during acceleration training on the human centrifuge

NASA Astrophysics Data System (ADS)

Wirth, D.; Rohleder, N.; Welsch, H.

2005-08-01

Prediction of student pilots' +Gz tolerance by stress hormone levels would be a useful tool in aviation medicine. The aim of the present study was to analyze the relationship between neuroendocrine parameters with performance during acceleration training on the human centrifuge (HC).We investigated 21 student pilots during self-controlled acceleration training on the HC. Adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine were measured after individual training sessions and at rest. Performance was defined by several characteristics including maximum tolerated acceleration. ACTH and cortisol, were significantly higher 20 minutes after acceleration training compared to the resting condition. Subjects tolerated a maximal acceleration of +6.69 Gz. HPA hormone levels and responses were associated with maximum tolerated acceleration +Gz. These findings support the expectation that acceleration- induced increases in stress hormones may enable the organism to tolerate a higher acceleration and could therefore be used as predictors for acceleration tolerance.

Plant Distribution Data Show Broader Climatic Limits than Expert-Based Climatic Tolerance Estimates

PubMed Central

Curtis, Caroline A.; Bradley, Bethany A.

2016-01-01

Background Although increasingly sophisticated environmental measures are being applied to species distributions models, the focus remains on using climatic data to provide estimates of habitat suitability. Climatic tolerance estimates based on expert knowledge are available for a wide range of plants via the USDA PLANTS database. We aim to test how climatic tolerance inferred from plant distribution records relates to tolerance estimated by experts. Further, we use this information to identify circumstances when species distributions are more likely to approximate climatic tolerance. Methods We compiled expert knowledge estimates of minimum and maximum precipitation and minimum temperature tolerance for over 1800 conservation plant species from the ‘plant characteristics’ information in the USDA PLANTS database. We derived climatic tolerance from distribution data downloaded from the Global Biodiversity and Information Facility (GBIF) and corresponding climate from WorldClim. We compared expert-derived climatic tolerance to empirical estimates to find the difference between their inferred climate niches (ΔCN), and tested whether ΔCN was influenced by growth form or range size. Results Climate niches calculated from distribution data were significantly broader than expert-based tolerance estimates (Mann-Whitney p values << 0.001). The average plant could tolerate 24 mm lower minimum precipitation, 14 mm higher maximum precipitation, and 7° C lower minimum temperatures based on distribution data relative to expert-based tolerance estimates. Species with larger ranges had greater ΔCN for minimum precipitation and minimum temperature. For maximum precipitation and minimum temperature, forbs and grasses tended to have larger ΔCN while grasses and trees had larger ΔCN for minimum precipitation. Conclusion Our results show that distribution data are consistently broader than USDA PLANTS experts’ knowledge and likely provide more robust estimates of climatic tolerance, especially for widespread forbs and grasses. These findings suggest that widely available expert-based climatic tolerance estimates underrepresent species’ fundamental niche and likely fail to capture the realized niche. PMID:27870859

Optimal design and use of retry in fault tolerant real-time computer systems

NASA Technical Reports Server (NTRS)

Lee, Y. H.; Shin, K. G.

1983-01-01

A new method to determin an optimal retry policy and for use in retry of fault characterization is presented. An optimal retry policy for a given fault characteristic, which determines the maximum allowable retry durations to minimize the total task completion time was derived. The combined fault characterization and retry decision, in which the characteristics of fault are estimated simultaneously with the determination of the optimal retry policy were carried out. Two solution approaches were developed, one based on the point estimation and the other on the Bayes sequential decision. The maximum likelihood estimators are used for the first approach, and the backward induction for testing hypotheses in the second approach. Numerical examples in which all the durations associated with faults have monotone hazard functions, e.g., exponential, Weibull and gamma distributions are presented. These are standard distributions commonly used for modeling analysis and faults.

40 CFR 180.505 - Emamectin; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Emamectin; tolerances for residues... § 180.505 Emamectin; tolerances for residues. (a) General. (1) Tolerances are established for combined residues of emamectin (a mixture of a minimum of 90% 4′-epi-methylamino-4′-deoxyavermectin B1a and maximum...

TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke.

PubMed

Nagpal, Anjali; Kremer, Karlea L; Hamilton-Bruce, Monica A; Kaidonis, Xenia; Milton, Austin G; Levi, Christopher; Shi, Songtao; Carey, Leeanne; Hillier, Susan; Rose, Miranda; Zacest, Andrew; Takhar, Parabjit; Koblar, Simon A

2016-07-01

Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation. Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell. The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial. © 2016 World Stroke Organization.

Guiding principle for crystalline Si photovoltaic modules with high tolerance to acetic acid

NASA Astrophysics Data System (ADS)

Masuda, Atsushi; Hara, Yukiko

2018-04-01

A guiding principle for highly reliable crystalline Si photovoltaic modules, especially those with high tolerance to acetic acid generated by hydrolysis reaction between water vapor and an ethylene-vinyl acetate (EVA) encapsulant, is proposed. Degradation behavior evaluated by the damp heat test strongly depends on Ag finger electrodes and also EVA encapsulants. The acetic acid concentration in EVA on the glass side directly determines the degradation behavior. The most important factor for high tolerance is the type of Ag finger electrode materials when using an EVA encapsulant. Photovoltaic modules using newly developed crystalline Si cells with improved Ag finger electrode materials keep their maximum power of 80% of the initial value even after the damp heat test at 85 °C and 85% relative humidity for 10000 h. The pattern of dark regions in electroluminescence images is also discussed on the basis of the dynamics of acetic acid in the modules.

Phase I/II clinical trial of 2-Difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma

PubMed Central

Skorupski, Katherine A.; O'Brien, Thomas G.; Guerrero, Teri; Rodriguez, Carlos O.; Burns, Mark R.

2011-01-01

Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumor regression in mouse models of SCC. The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase inhibitor, DFMO, and to determine whether this therapy results in reduction in tumor polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumor biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose of MQT 1426 when combined with DFMO was determined. Dose limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, 2 cats experienced objective tumor regression, and 6 cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted. PMID:22077408

40 CFR 180.422 - Tralomethrin; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

...-handling establishments, including food service, manufacturing, and processing establishments, such as... shall be limited to a maximum of 0.06 percent active ingredient. Contamination of food and food-contact...) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances...

Safety and efficacy of caffeine-augmented ECT in elderly depressives: a retrospective study.

PubMed

Kelsey, M C; Grossberg, G T

1995-07-01

Prior studies have shown that in younger depressives undergoing ECT whose seizure durations declined despite maximum settings on three different ECT devices, pretreatment with caffeine lengthened seizures and resulted in clinical improvement. Caffeine (half life, 140-270 minutes) was well tolerated even in patients with pre-existing cardiovascular disease. The purpose of this retrospective study was to determine the safety and efficacy of caffeine augmented ECT in elderly depressed patients. The charts of 14 elderly depressives (average age 75.6, range 59-83; 2 males, 12 females) who received caffeine-augmented ECT were reviewed. Patients pre- and post-ECT medications, blood pressure, pulse, and seizure times (cuff and EEG) for each ECT performed were noted. The following conclusions were drawn from our study: (1) Caffeine definitely increases the seizure length and was useful in our setting when the energy settings could not be increased anymore. (2) Caffeine augmentation inconsistently causes an increase in pulse rate, on average, in the elderly. (3) Caffeine inconsistently produces an increase in mean arterial pressure. (4) Caffeine did not consistently produce an increase in the maximum rate-pressure product. We conclude from this study that caffeine-augmented ECT is safe and effective in increasing seizure duration in the elderly. However, more research needs to be done to determine optimal dosing and tolerability.

Thermal adaptation in North American cicadas (Hemiptera: Cicadidae).

PubMed

Sanborn, Allen F; Heath, James E; Heath, Maxine S; Phillips, Polly K

2017-10-01

We determine and summarize the thermal responses for 118 species and subspecies of North American cicadas representing more than 50 years of fieldwork and experimentation. We investigate the role that habitat and behavior have on the thermal adaptation of the North American cicadas. There are general patterns of increasing thermal responses in warmer floristic provinces and increasing maximum potential temperature within a habitat. Altitude shows an inverse relationship with thermal responses. Comparison of thermal responses of species emerging early or late in the season within the same habitat show increases in the thermal responses along with the increasing environmental temperatures late in the summer. However, behavior, specifically the use of endothermy as a thermoregulatory strategy, can influence the values determined in a particular habitat. Subspecies generally do not differ in their thermal tolerances and thermal tolerances are consistent within a species over distances of more than 7600km. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxicity studies on agent GA (Phase 2): 90 day subchronic study of GA (Tabun) in cd rats. Appendices. Final report, July 1985-August 1991

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

Not Available

1992-03-01

The purpose of the report is to provide essential toxicologic information on Tabun administration over a 90 day period. This toxicologic information may be used to adjust the maximum-tolerated dose for subsequent dominant-lethal and two-generation reproduction studies. The objectives were to determine the toxic effects of nerve agent exposure (e.g., target organs); and to determine the effects of nerve agent GA on sperm morphology and motility and vaginal cytology.

High-temperature responses of North American cacti

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

Smith, S.D.; Didden-Zopfy, B.; Nobel, P.S.

1984-04-01

High-temperature tolerances of 14 species of North American cacti were investigated. A reduction in the proportion of chlorenchyma cells taking up a vital stain (neutral red) and reduced nocturnal acid accumulation were used as indicators of high-temperature damage. All species tolerated relatively high tissue temperatures, the mean maximum tolerance being 64/sup 0/C, with an absolute maximum of 69/sup 0/ for two species of ferocactus. Such tissue tolerances to high temperature may be unsurpassed in vascular plants. Morphological features can affect tissue temperatures. Specifically, thin-stemmed species such as the cylindropuntias attain lower maximum temperatures under identical microclimatic conditions than do moremore » massive species; they also tend to be less tolerant of high-temperature stress. Stem diameter changes of three species of columnar ceriod cacti along a Sonoran Desert latitudinal transect were previously attributed to adaptation to progressively colder temperatures northward. Such changes can also be interpreted as a morphological adaptation to high temperatures, particularly in the southern Sonoran Desert. Interspecific differences in high-temperature tolerance may account for distributional differences among other species. Acclimation of high-temperature tolerances in response to increasing day/night air temperatures was observed in all 14 species, especially at higher growh temperatures. From 40/sup 0/ day/30/sup 0/ night to 50/sup 0//40/sup 0/, the tolerable tissue temperatures increased an average of 6/sup 0/. Half-times for the acclimation shifts were 1-3d. Although cacti attain extremely high tissue temperatures in desert habitats, tolerance of high temperatures and pronounced acclimation potential allow them to occur in some of the hottest habitats in North America.« less

Cadmium, lead, tin, total mercury, and methylmercury in canned tuna commercialised in São Paulo, Brazil.

PubMed

de Paiva, Esther Lima; Morgano, Marcelo Antonio; Milani, Raquel Fernanda

2017-09-01

The objective of this work was to determine levels of inorganic contaminants in 30 samples of five commercial brands of canned tuna, acquired on the local market in Campinas, São Paulo, Brazil, in the year of 2015. Total mercury and methylmercury (MeHg+) were determined by atomic absorption with thermal decomposition and amalgamation; and cadmium, lead, and tin were determined by inductively coupled plasma optical emission spectrometry. Results indicated that 20% of the tuna samples surpassed limits determined by the Brazilian and European Commission legislation for cadmium; for lead, the maximum value found was 59 µg kg -1 and tin was not detected in any samples. The maximum values found for total Hg and MeHg+ were 261 and 258 µg kg -1 , respectively. As from the results obtained, it was estimated that the consumption of four cans per week (540 g) of tuna canned in water could surpass the provisional tolerable monthly intake for MeHg + by 100%.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

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

Pugh, Thomas J.; Chen Changhu; Rabinovitch, Rachel

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m{sup 2}, 1.3 mg/m{sup 2}, and 1.6 mg/m{sup 2}/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, definedmore » as any grade 4 hematologic toxicity, any grade {>=}3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for {>=}2 weeks. Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m{sup 2}. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m{sup 2} is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m{sup 2}.« less

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Phototrophic cultivation of NaCl-tolerant mutant of Spirulina platensis for enhanced C-phycocyanin production under optimized culture conditions and its dynamic modeling.

PubMed

Gupta, Apurva; Mohan, Devendra; Saxena, Rishi Kumar; Singh, Surendra

2018-02-01

Commercial cultivation of Spirulina sp. is highly popular due to the presence of high amount of C-phycocyanin (C-PC) and other valuable chemicals like carotenoids and γ-linolenic acid. In this study, the pH and the concentrations of nitrogen and carbon source were manipulated to achieve improved cell growth and C-PC production in NaCl-tolerant mutant of Spirulina platensis. In this study, highest C-PC (147 mg · L -1 ) and biomass (2.83 g · L -1 ) production was achieved when a NaCl-tolerant mutant of S. platensis was cultivated in a nitrate and bicarbonate sufficient medium (40 and 60 mM, respectively) at pH 9.0 under phototrophic conditions. Kinetic study of wildtype S. platensis and its NaCl-tolerant mutant was also done to determine optimum nitrate concentrations for maximum growth and C-PC production. Kinetic parameter of inhibition (Haldane model) was fitted to the relationship between specific growth rate and substrate concentration obtained from the growth curves. Results showed that the maximum specific growth rate (μ max ) for NaCl-tolerant mutant increased by 17.94% as compared to its wildtype counterpart, with a slight increase in half-saturation constant (K s ), indicating that this strain could grow well at high concentration of NaNO 3 . C-PC production rate (C max ) in mutant cells increased by 12.2% at almost half the value of K s as compared to its wildtype counterpart. Moreover, the inhibition constant (K i ) value was 207.85% higher in NaCl-tolerant mutant as compared to its wildtype strain, suggesting its ability to produce C-PC even at high concentrations of NaNO 3 . © 2017 Phycological Society of America.

Functional traits and plasticity in response to light in seedlings of four Iberian forest tree species.

PubMed

Sánchez-Gómez, David; Valladares, Fernando; Zavala, Miguel A

2006-11-01

We investigated the differential roles of physiological and morphological features on seedling survivorship along an experimental irradiance gradient in four dominant species of cool temperate-Mediterranean forests (Quercus robur L., Quercus pyrenaica Willd., Pinus sylvestris L. and Pinus pinaster Ait.). The lowest photochemical efficiency (F(v)/F(m) in dark-adapted leaves) was reached in deep shade (1% of full sunlight) in all species except Q. robur, which had the lowest photochemical efficiency in both deep shade and 100% of full sunlight. Species differed significantly in their survival in 1% of full sunlight but exhibited similar survivorship in 6, 20 and 100% of full sunlight. Shade-tolerant oaks had lower leaf area ratios, shoot to root ratios, foliage allocation ratios and higher rates of allocation to structural biomass (stem plus thick roots) than shade-intolerant pines. Overall phenotypic plasticity for each species, estimated as the difference between the minimum and the maximum mean values of the ecophysiological variables studied at the various irradiances divided by the maximum mean value of those variables, was inversely correlated with shade tolerance. Observed morphology, allocation and plasticity conformed to a conservative resource-use strategy, although observed differences in specific leaf area, which was higher in shade-tolerant species, supported a carbon gain maximization strategy. Lack of a congruent suite of traits underlying shade tolerance in the studied species provides evidence of adaptation to multiple selective forces. Although the study was based on only four species, the importance of ecophysiological variables as determinants of interspecific differences in survival in limiting light was demonstrated.

Axelrod Model of Social Influence with Cultural Hybridization

NASA Astrophysics Data System (ADS)

Radillo-Díaz, Alejandro; Pérez, Luis A.; Del Castillo-Mussot, Marcelo

2012-10-01

Since cultural interactions between a pair of social agents involve changes in both individuals, we present simulations of a new model based on Axelrod's homogenization mechanism that includes hybridization or mixture of the agents' features. In this new hybridization model, once a cultural feature of a pair of agents has been chosen for the interaction, the average of the values for this feature is reassigned as the new value for both agents after interaction. Moreover, a parameter representing social tolerance is implemented in order to quantify whether agents are similar enough to engage in interaction, as well as to determine whether they belong to the same cluster of similar agents after the system has reached the frozen state. The transitions from a homogeneous state to a fragmented one decrease in abruptness as tolerance is increased. Additionally, the entropy associated to the system presents a maximum within the transition, the width of which increases as tolerance does. Moreover, a plateau was found inside the transition for a low-tolerance system of agents with only two cultural features.

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

Evaluation of safety of lipomer doxycycline hydrochloride (lipomer DH).

PubMed

Dhumal, Rohit; Soni, Mahesh; Devarajan, Padma; Samad, Abdul; Gaikwad, Rajiv; Vanage, Geeta

2011-02-01

The nanoparticulate formulation of lipomer doxycycline hydrochloride (lipomer DH) has been synthesized for the treatment of Brucellosis to increase efficacy of the drug. The present study was undertaken to determine the intravenous safety of blank lipomer and Lipomer DH in terms of maximum tolerated dose in rats. It was observed that blank lipomer and lipomer DH were safe when administered intravenously at doses 2000 mg/kg Bw and 18 mg/kg bw respectively.

Elasticity in portion selection is predicted by severity of anorexia and food type in adolescents.

PubMed

Herzog, M; Douglas, C R; Kissileff, H R; Brunstrom, J M; Halmi, K A

2016-08-01

The size of portions that people select is an indicator of underlying mechanisms controlling food intake. Fears of eating excessive portions drive down the sizes of portions patients with anorexia nervosa (AN) can tolerate eating significantly below those of healthy controls (HC) (Kissileff et al., 2016). To determine whether patients with AN will also reduce the sizes of typical or ideal portions below those of controls, ANOVA was used to compare maximum tolerable, typical, and ideal portions of four foods (potatoes, rice, pizza, and M&M's) in the same group of 24 adolescent AN patients and 10 healthy adolescent controls (HC), on which only the maximal portion data were previously reported. Typical and ideal portion sizes did not differ on any food for AN, but for HC, typical portions sizes (kcals) became larger than ideal as the energy density of the food increased, and were significant for the most energy dense food. Ideal portions of low energy dense foods were the same for AN as for in HC. There was a significant 3-way (group × food × portion type) interaction, such that HC selected larger maximum than typical portions only for pizza. We therefore proposed that individuals of certain groups, depending on the food, can be flexible in the amounts of food chosen to be eaten. We call this difference between maximum-tolerable, and typical portion sizes selected "elasticity." Elasticity was significantly smaller for AN patients compared to HC for pizza and was significantly inversely correlated with severity of illness. This index could be useful for clinical assessment of AN patients, and those with eating problems such as in obesity and bulimia nervosa and tracking their response to treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phase I Study of Preoperative Chemoradiation With S-1 and Oxaliplatin in Patients With Locally Advanced Resectable Rectal Cancer

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

Hong, Yong Sang; Lee, Jae-Lyun; Park, Jin Hong

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m{sup 2}/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1-14 and 22-35. The initial dose of S-1 was 50 mg/m{supmore » 2}/day, gradually increasing to 60, 70, and 80 mg/m{sup 2}/day. Surgery was performed within 6 {+-} 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m{sup 2}/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m{sup 2}/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing.« less

Level of endogenous formaldehyde in maple syrup as determined by spectrofluorimetry.

PubMed

Lagacé, Luc; Guay, Stéphane; Martin, Nathalie

2003-01-01

The level of endogenous formaldehyde in maple syrup was established from a large number (n = 300) of authentic maple syrup samples collected during 2000 and 2001 in the province of Quebec, Canada. The average level of formaldehyde from these authentic samples was measured at 0.18 mg/kg in 2000 and 0.28 mg/kg in 2001, which is lower than previously published. These average values can be attributed to the improved spectrofluorimetric method used for the determination. However, the formaldehyde values obtained demonstrate a relatively large distribution with maximums observed at 1.04 and 1.54 mg/kg. These values are still under the maximum tolerance level of 2.0 mg/kg paraformaldehyde pesticide residue. Extensive heat treatment of maple syrup samples greatly enhanced the formaldehyde concentration of the samples, suggesting that extensive heat degradation of the sap constituents during evaporation could be responsible for the highest formaldehyde values in maple syrup.

New dynamic FET logic and serial memory circuits for VLSI GaAs technology

NASA Technical Reports Server (NTRS)

Eldin, A. G.

1991-01-01

The complexity of GaAs field effect transistor (FET) very large scale integration (VLSI) circuits is limited by the maximum power dissipation while the uniformity of the device parameters determines the functional yield. In this work, digital GaAs FET circuits are presented that eliminate the DC power dissipation and reduce the area to 50% of that of the conventional static circuits. Its larger tolerance to device parameter variations results in higher functional yield.

Suitable Environmental Ranges for Potential Coral Reef Habitats in the Tropical Ocean

PubMed Central

Guan, Yi; Hohn, Sönke; Merico, Agostino

2015-01-01

Coral reefs are found within a limited range of environmental conditions or tolerance limits. Estimating these limits is a critical prerequisite for understanding the impacts of climate change on the biogeography of coral reefs. Here we used the diagnostic model ReefHab to determine the current environmental tolerance limits for coral reefs and the global distribution of potential coral reef habitats as a function of six factors: temperature, salinity, nitrate, phosphate, aragonite saturation state, and light. To determine these tolerance limits, we extracted maximum and minimum values of all environmental variables in corresponding locations where coral reefs are present. We found that the global, annually averaged tolerance limits for coral reefs are 21.7—29.6 °C for temperature, 28.7—40.4 psu for salinity, 4.51 μmol L-1 for nitrate, 0.63 μmol L-1 for phosphate, and 2.82 for aragonite saturation state. The averaged minimum light intensity in coral reefs is 450 μmol photons m-2 s-1. The global area of potential reef habitats calculated by the model is 330.5 × 103 km2. Compared with previous studies, the tolerance limits for temperature, salinity, and nutrients have not changed much, whereas the minimum value of aragonite saturation in coral reef waters has decreased from 3.28 to 2.82. The potential reef habitat area calculated with ReefHab is about 121×103 km2 larger than the area estimated from the charted reefs, suggesting that the growth potential of coral reefs is higher than currently observed. PMID:26030287

Suitable environmental ranges for potential coral reef habitats in the tropical ocean.

PubMed

Guan, Yi; Hohn, Sönke; Merico, Agostino

2015-01-01

Coral reefs are found within a limited range of environmental conditions or tolerance limits. Estimating these limits is a critical prerequisite for understanding the impacts of climate change on the biogeography of coral reefs. Here we used the diagnostic model ReefHab to determine the current environmental tolerance limits for coral reefs and the global distribution of potential coral reef habitats as a function of six factors: temperature, salinity, nitrate, phosphate, aragonite saturation state, and light. To determine these tolerance limits, we extracted maximum and minimum values of all environmental variables in corresponding locations where coral reefs are present. We found that the global, annually averaged tolerance limits for coral reefs are 21.7-29.6 °C for temperature, 28.7-40.4 psu for salinity, 4.51 μmol L-1 for nitrate, 0.63 μmol L-1 for phosphate, and 2.82 for aragonite saturation state. The averaged minimum light intensity in coral reefs is 450 μmol photons m-2 s-1. The global area of potential reef habitats calculated by the model is 330.5 × 103 km2. Compared with previous studies, the tolerance limits for temperature, salinity, and nutrients have not changed much, whereas the minimum value of aragonite saturation in coral reef waters has decreased from 3.28 to 2.82. The potential reef habitat area calculated with ReefHab is about 121×103 km2 larger than the area estimated from the charted reefs, suggesting that the growth potential of coral reefs is higher than currently observed.

Impacts of Larval Connectivity on Coral Heat Tolerance

NASA Astrophysics Data System (ADS)

Pinsky, M. L.; Kleypas, J. A.; Thompson, D. M.; Castruccio, F. S.; Curchitser, E. N.; Watson, J. R.

2016-02-01

The sensitivity of corals to elevated temperature depends on their acclimation and adaptation to the local maximum temperature regime. Through larval dispersal, however, coral populations can receive larvae from regions that are significantly warmer or colder. If these exogenous larvae carry genetic-based tolerances to colder or warmer temperatures, then the thermal sensitivity of the receiving population may be lower or higher, respectively. Using a high-resolution Regional Ocean Modeling System (ROMS) configuration for the Coral Triangle region, we quantify the potential role of connectivity in determining the thermal stress threshold (TST) of a typical broadcast spawner. The model results suggest that even with a pelagic larval dispersal period of only 10 days, many reefs receive larvae from reefs that are warmer or cooler than the local temperature, and that accounting for this connectivity improves bleaching predictions. This has important implications for conservation planning, because connectivity may allow some reefs to have an inherited heat tolerance that is higher or lower than would be predicted based on local conditions alone.

Relaxed selection on the CBF/DREB1 regulatory genes and reduced freezing tolerance in the southern range of Arabidopsis thaliana.

PubMed

Zhen, Ying; Ungerer, Mark C

2008-12-01

Elucidating the molecular basis of adaptive phenotypic variation represents a central aim in evolutionary biology. Traits exhibiting patterns of clinal variation represent excellent models for studies of molecular adaptation, especially when variation in phenotype can be linked to organismal fitness in different environments. Natural accessions of the model plant species Arabidopsis thaliana exhibit clinal variation in freezing tolerance that follows a gradient of temperature variability across the species' native range (Zhen Y, Ungerer MC. 2008. Clinal variation in freezing tolerance among natural accessions of A. thaliana. New Phytol. 177:419-427). Here, we report that this pattern of variation is attributable, at least in part, to relaxed purifying selection on members of a small family of transcriptional activators (the CBF/DREB1s) in the species' southern range. These regulatory genes play a critical role in the ability of A. thaliana plants to undergo cold acclimation and thereby achieve maximum freezing tolerance. Relative to accessions from northern regions, accessions of A. thaliana from the southern part of their geographic range exhibit levels of nonsynonymous nucleotide polymorphism that are approximately 2.8-fold higher across this small gene subfamily. Relaxed selection on the CBF/DREB1s in southern accessions also has resulted in multiple mutations in regulatory regions resulting in abrogated expression of particular subfamily members in particular accessions. These coding-region and regulatory mutations compromise the ability of these genes to act as efficient transcriptional activators during the cold acclimation process, as determined by reductions in rates of induction and maximum levels of expression in the downstream genes they regulate. This study highlights the potential role of regulatory genes in underlying adaptive phenotypic variation in nature.

Thermal adaptation and phosphorus shape thermal performance in an assemblage of rainforest ants.

PubMed

Kaspari, Michael; Clay, Natalie A; Lucas, Jane; Revzen, Shai; Kay, Adam; Yanoviak, Stephen P

2016-04-01

We studied the Thermal Performance Curves (TPCs) of 87 species of rainforest ants and found support for both the Thermal Adaptation and Phosphorus-Tolerance hypotheses. TPCs relate a fitness proxy (here, worker speed) to environmental temperature. Thermal Adaptation posits that thermal generalists (ants with flatter, broader TPCs) are favored in the hotter, more variable tropical canopy compared to the cooler, less variable litter below. As predicted, species nesting in the forest canopy 1) had running speeds less sensitive to temperature; 2) ran over a greater range of temperatures; and 3) ran at lower maximum speeds. Tradeoffs between tolerance and maximum performance are often invoked for constraining the evolution of thermal generalists. There was no evidence that ant species traded off thermal tolerance for maximum speed, however. Phosphorus-Tolerance is a second mechanism for generating ectotherms able to tolerate thermal extremes. It posits that ants active at high temperatures invest in P-rich machinery to buffer their metabolism against thermal extremes. Phosphorus content in ant tissue varied three-fold, and as predicted, temperature sensitivity was lower and thermal range was higher in P-rich species. Combined, we show how the vertical distribution of hot and variable vs. cooler and stable microclimates in a single forest contribute to a diversity of TPCs and suggest that a widely varying P stoichiometry among these ants may drive some of these differences.

Determining the Optimal Spectral Sampling Frequency and Uncertainty Thresholds for Hyperspectral Remote Sensing of Ocean Color

NASA Technical Reports Server (NTRS)

Vandermeulen, Ryan A.; Mannino, Antonio; Neeley, Aimee; Werdell, Jeremy; Arnone, Robert

2017-01-01

Using a modified geostatistical technique, empirical variograms were constructed from the first derivative of several diverse remote sensing reflectance and phytoplankton absorbance spectra to describe how data points are correlated with distance across the spectra. The maximum rate of information gain is measured as a function of the kurtosis associated with the Gaussian structure of the output, and is determined for discrete segments of spectra obtained from a variety of water types (turbid river filaments, coastal waters, shelf waters, a dense Microcystis bloom, and oligotrophic waters), as well as individual and mixed phytoplankton functional types (PFTs; diatoms, chlorophytes, cyanobacteria, coccolithophores). Results show that a continuous spectrum of 5 to 7 nm spectral resolution is optimal to resolve the variability across mixed reflectance and absorbance spectra. In addition, the impact of uncertainty on subsequent derivative analysis is assessed, showing that a limit of 3 Gaussian noise (SNR 66) is tolerated without smoothing the spectrum, and 13 (SNR 15) noise is tolerated with smoothing.

Determining Metacarpophalangeal Flexion Angle Tolerance for Reliable Volumetric Joint Space Measurements by High-resolution Peripheral Quantitative Computed Tomography.

PubMed

Tom, Stephanie; Frayne, Mark; Manske, Sarah L; Burghardt, Andrew J; Stok, Kathryn S; Boyd, Steven K; Barnabe, Cheryl

2016-10-01

The position-dependence of a method to measure the joint space of metacarpophalangeal (MCP) joints using high-resolution peripheral quantitative computed tomography (HR-pQCT) was studied. Cadaveric MCP were imaged at 7 flexion angles between 0 and 30 degrees. The variability in reproducibility for mean, minimum, and maximum joint space widths and volume measurements was calculated for increasing degrees of flexion. Root mean square coefficient of variance values were < 5% under 20 degrees of flexion for mean, maximum, and volumetric joint spaces. Values for minimum joint space width were optimized under 10 degrees of flexion. MCP joint space measurements should be acquired at < 10 degrees of flexion in longitudinal studies.

A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

PubMed

Venugopal, B; Awada, A; Evans, T R J; Dueland, S; Hendlisz, A; Rasch, W; Hernes, K; Hagen, S; Aamdal, S

2015-10-01

CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.

PubMed

Hasanein, Parisa; Shakeri, Saeed

2014-11-05

Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Spring-Blade Impact Tester

NASA Technical Reports Server (NTRS)

Holmes, Alan M.; Champagne, James W.

1989-01-01

Record of energy relationships retrieved from compact, portable tester. Spring-blade impact tester developed to support evaluation of tolerance to damage of struts under consideration for use in Space Station. Approach offers potential for determining damage as function of change in relationship between applied and absorbed energies as applied energy successively increased with each impact. Impactor strikes specimen at moment of maximum kinetic energy after spring blades released from cocked position. Concept also provides potential for measuring behavior during impact, and energy relationships retrievable from oscilloscope traces of impact.

Pesticide Tolerances

EPA Pesticide Factsheets

EPA regulates pesticides used to protect crops and sets limits on the amount of pesticide remaining in or on foods in the U.S. The limits on pesticides on foods are called tolerances in the U.S. (maximum residue limits (MRLs) in many other countries).

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PubMed

Horton, Terzah M; Blaney, Susan M; Langevin, Anne-Marie; Kuhn, John; Kamen, Barton; Berg, Stacey L; Bernstein, Mark; Weitman, Steven

2005-03-01

To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02

PubMed Central

Lee, Eudocia Q.; Kuhn, John; Lamborn, Kathleen R.; Abrey, Lauren; DeAngelis, Lisa M.; Lieberman, Frank; Robins, H. Ian; Chang, Susan M.; Yung, W. K. Alfred; Drappatz, Jan; Mehta, Minesh P.; Levin, Victor A.; Aldape, Kenneth; Dancey, Janet E.; Wright, John J.; Prados, Michael D.; Cloughesy, Timothy F.; Gilbert, Mark R.; Wen, Patrick Y.

2012-01-01

The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID:23099651

Cold Tolerance of Mountain Pine Beetle (Coleoptera: Curculionidae) Eggs From the Historic and Expanded Ranges.

PubMed

Bleiker, K P; Smith, G D; Humble, L M

2017-10-01

Winter mortality is expected to be a key factor determining the ability of mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae), to expand its range in Canada. We determined the mortality rate and supercooling points of eggs from the beetle's historic range in southern British Columbia as well as the recently expanded range in north-central Alberta and tested if eggs require an extended period of chilling to reach their maximum cold tolerance. We found no effect of population source or acclimation time on egg cold tolerance. Although 50% of eggs can survive brief exposure to -20.5 °C (LT50), storage at 0.3 °C and -7.5 °C for 59 d resulted in 50% and 100% mortality, respectively. Our results indicate that eggs suffer significant prefreeze mortality and are not well-adapted to overwintering: eggs are unlikely to survive winter throughout much of the beetle's range. Our results provide information that can be used to help model the climatic suitability of mountain pine beetle, including how changes in seasonality associated with new or changing climates may affect winter survival. In addition to lower lethal temperatures, it is critical that the duration of exposure to sublethal cold temperatures are considered in a comprehensive index of cold tolerance and incorporated into survival and population models. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Assessment of potential probiotic properties of Lactobacillus spp., Lactococcus spp., and Pediococcus spp. strains isolated from kefir.

PubMed

Sabir, Firat; Beyatli, Yavuz; Cokmus, Cumhur; Onal-Darilmaz, Derya

2010-01-01

In this study, the metabolic activities (in terms of quantities of the produced lactic acid, hydrogen peroxide, and exopolysaccharides) of 8 strains of Lactobacillus spp., Lactococcus spp., and Pediococcus spp., were determined. Lactic acid levels produced by strains were 8.1 to 17.4 mg/L. The L. acidophilus Z1L strain produced the maximum amount (3.18 μg/mL) of hydrogen peroxide. The exopolysaccharides (EPS) production by the strains was ranged between 173 and 378 mg/L. The susceptibility of 7 different antibiotics against these strains was also tested. All strains were found to be sensitive to ampicillin. The tolerance of the strains to low pH, their resistance to bile salts of strains, and their abilities to autoaggregate and coaggregate with Escherichia coli ATCC 11229 were also evaluated. High EPS-producing strains showed significant autoaggregation and coaggregation ability with test bacteria (P < 0.01). A correlation also was determined between EPS production and acid-bile tolerance (P < 0.05). EPS production possibly affects or is involved in acid-bile tolerance and aggregation of Lactobacillus spp., Lactococcus spp., and Pediococcus spp. strains and supports the potential of L. acidophilus Z1L strain as new probiotic. © 2010 Institute of Food Technologists®

Defect Tolerant Semiconductors for Solar Energy Conversion.

PubMed

Zakutayev, Andriy; Caskey, Christopher M; Fioretti, Angela N; Ginley, David S; Vidal, Julien; Stevanovic, Vladan; Tea, Eric; Lany, Stephan

2014-04-03

Defect tolerance is the tendency of a semiconductor to keep its properties despite the presence of crystallographic defects. Scientific understanding of the origin of defect tolerance is currently missing. Here we show that semiconductors with antibonding states at the top of the valence band are likely to be tolerant to defects. Theoretical calculations demonstrate that Cu3N with antibonding valence band maximum has shallow intrinsic defects and no surface states, in contrast to GaN with bonding valence band maximum. Experimental measurements indicate shallow native donors and acceptors in Cu3N thin films, leading to 10(16)-10(17) cm(-3) doping with either electrons or holes depending on the growth conditions. The experimentally measured bipolar doping and the solar-matched optical absorption onset (1.4 eV) make Cu3N a promising candidate absorber for photovoltaic and photoelectrochemical solar cells, despite the calculated indirect fundamental band gap (1.0 eV). These conclusions can be extended to other materials with antibonding character of the valence band, defining a class of defect-tolerant semiconductors for solar energy conversion applications.

Temperature-stress resistance and tolerance along a latitudinal cline in North American Arabidopsis lyrata.

PubMed

Wos, Guillaume; Willi, Yvonne

2015-01-01

The study of latitudinal gradients can yield important insights into adaptation to temperature stress. Two strategies are available: resistance by limiting damage, or tolerance by reducing the fitness consequences of damage. Here we studied latitudinal variation in resistance and tolerance to frost and heat and tested the prediction of a trade-off between the two strategies and their costliness. We raised plants of replicate maternal seed families from eight populations of North American Arabidopsis lyrata collected along a latitudinal gradient in climate chambers and exposed them repeatedly to either frost or heat stress, while a set of control plants grew under standard conditions. When control plants reached maximum rosette size, leaf samples were exposed to frost and heat stress, and electrolyte leakage (PEL) was measured and treated as an estimate of resistance. Difference in maximum rosette size between stressed and control plants was used as an estimate of tolerance. Northern populations were more frost resistant, and less heat resistant and less heat tolerant, but-unexpectedly-they were also less frost tolerant. Negative genetic correlations between resistance and tolerance to the same and different thermal stress were generally not significant, indicating only weak trade-offs. However, tolerance to frost was consistently accompanied by small size under control conditions, which may explain the non-adaptive latitudinal pattern for frost tolerance. Our results suggest that adaptation to frost and heat is not constrained by trade-offs between them. But the cost of frost tolerance in terms of plant size reduction may be important for the limits of species distributions and climate niches.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Covariance Based Pre-Filters and Screening Criteria for Conjunction Analysis

NASA Astrophysics Data System (ADS)

George, E., Chan, K.

2012-09-01

Several relationships are developed relating object size, initial covariance and range at closest approach to probability of collision. These relationships address the following questions: - Given the objects' initial covariance and combined hard body size, what is the maximum possible value of the probability of collision (Pc)? - Given the objects' initial covariance, what is the maximum combined hard body radius for which the probability of collision does not exceed the tolerance limit? - Given the objects' initial covariance and the combined hard body radius, what is the minimum miss distance for which the probability of collision does not exceed the tolerance limit? - Given the objects' initial covariance and the miss distance, what is the maximum combined hard body radius for which the probability of collision does not exceed the tolerance limit? The first relationship above allows the elimination of object pairs from conjunction analysis (CA) on the basis of the initial covariance and hard-body sizes of the objects. The application of this pre-filter to present day catalogs with estimated covariance results in the elimination of approximately 35% of object pairs as unable to ever conjunct with a probability of collision exceeding 1x10-6. Because Pc is directly proportional to object size and inversely proportional to covariance size, this pre-filter will have a significantly larger impact on future catalogs, which are expected to contain a much larger fraction of small debris tracked only by a limited subset of available sensors. This relationship also provides a mathematically rigorous basis for eliminating objects from analysis entirely based on element set age or quality - a practice commonly done by rough rules of thumb today. Further, these relations can be used to determine the required geometric screening radius for all objects. This analysis reveals the screening volumes for small objects are much larger than needed, while the screening volumes for pairs of large objects may be inadequate. These relationships may also form the basis of an important metric for catalog maintenance by defining the maximum allowable covariance size for effective conjunction analysis. The application of these techniques promises to greatly improve the efficiency and completeness of conjunction analysis.

Intervarietal variations in various oxidative stress markers and antioxidant potential of finger millet (Eleusine coracana) subjected to drought stress.

PubMed

Bartwal, Arti; Pande, Anjali; Sharma, Priyadarshini; Arora, Sandeep

2016-07-01

Drought is a major form of abiotic stress leading to lower crop productivity. Experiment was carried out for selecting the most tolerant genotype among six different genotypes of finger millet under drought stress. Seeds of six finger millet genotypes were sown in pots and grown for 35 days. After this period, drought was induced by withholding watering for stressed plants while control plants were watered regularly for comparison. Among all six different varieties of finger millet screened (PR202, PES400, PRM6107, VL283, VL328 and VL149) under varying intensities of drought stress,PRM6107 and PR202 showed highest stress tolerance by limiting excessive accumulation of reactive oxygen species (ROS) through activation of ROS scavenging antioxidative enzymes. A 200% increase in ascorbate content was recorded in PRM6107 and PR202, while in other varieties limited increase in ascorbate content was observed. Maximum decrease in chlorophyll content was observed in VL328 (83%) while least drop was observed in VL149 (65%). Relative water content indicated that PR202 was able to retain maximum water content under stress, as it recorded least drop in relative water content (55%), contributing to its better survival under stress. In conclusion finger millet genotypes PRM6107 and PR202 possessed maximum drought tolerance potential and thus may be used for allele mining of drought tolerant genes, which can further be employed for the development of more drought stress tolerant staple crops using biotechnological approach.

Evaluating the efficacies of Maximum Tolerated Dose and metronomic chemotherapies: A mathematical approach

NASA Astrophysics Data System (ADS)

Guiraldello, Rafael T.; Martins, Marcelo L.; Mancera, Paulo F. A.

2016-08-01

We present a mathematical model based on partial differential equations that is applied to understand tumor development and its response to chemotherapy. Our primary aim is to evaluate comparatively the efficacies of two chemotherapeutic protocols, Maximum Tolerated Dose (MTD) and metronomic, as well as two methods of drug delivery. Concerning therapeutic outcomes, the metronomic protocol proves more effective in prolonging the patient's life than MTD. Moreover, a uniform drug delivery method combined with the metronomic protocol is the most efficient strategy to reduce tumor density.

Pilot Study on the Safety and Tolerability of Extended Release Niacin for HIV-infected Patients with Hypertriglyceridemia

PubMed Central

Souza, Scott A; Walsh, Erica J; Shippey, Ford; Shikuma, Cecilia

2010-01-01

Background To determine the safety and tolerability of extended release niacin (ERN) in HIV-infected patients. Methods This was a pilot, open-label, 36 week study evaluating the safety and tolerability of ERN in HIV-infected patients with hypertriglyceridemia. Subjects with cardiovascular disease, diabetes or liver disease were excluded. Subjects with persistent elevation of triglyceride (TG) >200 after 8 weeks on American Heart Association Step One and Two Diets were started on ERN 500mg once daily, with continuation of the diet and exercise recommendations until the end of the study. ERN was increased by 500mg every 4 weeks, to a maximum of 1500mg/day, depending on subject tolerability. Safety and tolerability of ERN were assessed. Results Ten subjects enrolled received ERN. Dose titration and maintenance to 1500mg/day were achieved in all 10 subjects. No subject required dose adjustment. Mild flushing was experienced in 8 subjects. Asymptomatic hypophosphotemia was noted in 4 subjects; all resolved with oral phosphate supplementation. Median TG was reduced by 254 mg/dL (p<0.05). Non-significant changes were noted in liver enzymes, HDL, LDL, and total cholesterol. Fasting insulin and glucose levels did not change with treatment. Conclusion In this pilot study, ERN was well-tolerated and resulted in reduction of TG. Although the results of this study are promising, the study is limited in the small number of subjects. Further investigation is warranted. PMID:20533755

Phenological cues drive an apparent trade-off between freezing tolerance and growth in the family Salicaceae.

PubMed

Savage, Jessica A; Cavender-Bares, Jeannine

2013-08-01

With increasing concern about the ecological consequences of global climate change, there has been renewed interest in understanding the processes that determine species range limits. We tested a long-hypothesized trade-off between freezing tolerance and growth rate that is often used to explain species range limits. We grew 24 willow and poplar species (family Salicaceae) collected from across North America in a greenhouse common garden under two climate treatments. Maximum entropy models were used to describe species distributions and to estimate species-specific climate parameters. A range of traits related to freezing tolerance, including senescence, budburst, and susceptibility to different temperature minima during and after acclimation were measured. As predicted, species from colder climates exhibited higher freezing tolerance and slower growth rates than species from warmer climates under certain environmental conditions. However, the average relative growth rate (millimeters per meter per day) of northern species markedly increased when a subset of species was grown under a long summer day length (20.5 h), indicating that genetically based day-length cues are required for growth regulation in these species. We conclude that the observed relationship between freezing tolerance and growth rate is not driven by differences in species' intrinsic growth capacity but by differences in the environmental cues that trigger growth. We propose that the coordinated evolution of freezing tolerance and growth phenology could be important in circumscribing willow and poplar range limits and may have important implications for species' current and future distributions.

More grain per drop of water: Screening rice genotype for physiological parameters of drought tolerance

NASA Astrophysics Data System (ADS)

Massanelli, J.; Meadows-McDonnell, M.; Konzelman, C.; Moon, J. B.; Kumar, A.; Thomas, J.; Pereira, A.; Naithani, K. J.

2016-12-01

Meeting agricultural water demands is becoming progressively difficult due to population growth and changes in climate. Breeding stress-resilient crops is a viable solution, as information about genetic variation and their role in stress tolerance is becoming available due to advancement in technology. In this study we screened eight diverse rice genotypes for photosynthetic capacity under greenhouse conditions. These include the Asian rice (Oryza sativa) genotypes, drought sensitive Nipponbare, and a transgenic line overexpressing the HYR gene in Nipponbare; six genotypes (Vandana, Bengal, Nagina-22, Glaberrima, Kaybonnet, Ai Chueh Ta Pai Ku) and an African rice O. glaberrima, all selected for varying levels of drought tolerance. We collected CO2 and light response curve data under well-watered and simulated drought conditions in greenhouse. From these curves we estimated photosynthesis model parameters, such as the maximum carboxylation rate (Vcmax), the maximum electron transport rate (Jmax), the maximum gross photosynthesis rate, daytime respiration (Rd), and quantum yield (f). Our results suggest that O. glaberrima and Nipponbare were the most sensitive to drought because Vcmax and Pgmax declined under drought conditions; other drought tolerant genotypes did not show significant changes in these model parameters. Our integrated approach, combining genetic information and photosynthesis modeling, shows promise to quantify drought response parameters and improve crop yield under drought stress conditions.

Seasonal and geographical variation in heat tolerance and evaporative cooling capacity in a passerine bird.

PubMed

Noakes, Matthew J; Wolf, Blair O; McKechnie, Andrew E

2016-03-01

Intraspecific variation in avian thermoregulatory responses to heat stress has received little attention, despite increasing evidence that endothermic animals show considerable physiological variation among populations. We investigated seasonal (summer versus winter) variation in heat tolerance and evaporative cooling in an Afrotropical ploceid passerine, the white-browed sparrow-weaver (Plocepasser mahali; ∼ 47 g) at three sites along a climatic gradient with more than 10 °C variation in mid-summer maximum air temperature (Ta). We measured resting metabolic rate (RMR) and total evaporative water loss (TEWL) using open flow-through respirometry, and core body temperature (Tb) using passive integrated transponder tags. Sparrow-weavers were exposed to a ramped profile of progressively higher Ta between 30 and 52 °C to elicit maximum evaporative cooling capacity (N=10 per site per season); the maximum Ta birds tolerated before the onset of severe hyperthermia (Tb ≈ 44 °C) was considered to be their hyperthermia threshold Ta (Ta,HT). Our data reveal significant seasonal acclimatisation of heat tolerance, with a desert population of sparrow-weavers reaching significantly higher Ta in summer (49.5 ± 1.4 °C, i.e. higher Ta,HT) than in winter (46.8 ± 0.9 °C), reflecting enhanced evaporative cooling during summer. Moreover, desert sparrow-weavers had significantly higher heat tolerance and evaporative cooling capacity during summer compared with populations from more mesic sites (Ta,HT=47.3 ± 1.5 and 47.6 ± 1.3 °C). A better understanding of the contributions of local adaptation versus phenotypic plasticity to intraspecific variation in avian heat tolerance and evaporative cooling capacity is needed for modelling species' responses to changing climates. © 2016. Published by The Company of Biologists Ltd.

Selected important fragrance sensitizers in perfumes--current exposures.

PubMed

Rastogi, Suresh Chandra; Johansen, Jeanne Duus; Bossi, Rossana

2007-04-01

Contact allergy to fragrance ingredients is frequent. Recommendations and regulations of some of the most frequent and potent fragrance allergens have recently been introduced. To investigate current exposures to 4 important fragrance allergens in hydroalcoholic cosmetic products. 25 popular perfume products of Danish as well as international brands were purchased from the Danish retail market. Contents of 4 important fragrance allergens, isoeugenol, hydroxy-iso-hexyl 3-cyclohexene carboxaldehyde (HICC, Lyral), were determined by gas chromatography-mass spectrometry, and atranol and chloro-atranol were determined by liquid chromatography-tandem mass spectrometry. Isoeugenol was found in 56%, HICC in 72%, atranol in 59%, and chloro-atranol in 36% of the 22 eau de toilette/eau de parfum products. The concentrations of isoeugenol were, in all products, below the recommended maximum concentration of 0.02%. HICC reached a maximum of 0.2%, which is 10-fold higher than maximum tolerable concentration considered safe by the EU Scientific Committee. The median concentrations of atranol and chloro-atranol in the investigated products were similar to those found in similar products in 2003. A significant decrease in the frequency of presence of chloro-atranol in the products was observed. There is still a wide-spread exposure to potent fragrance allergens in perfumes.

Accumulation of 19-kDa plasma membrane polypeptide during induction of freezing tolerance in wheat suspension-cultured cells by abscisic acid.

PubMed

Koike, M; Takezawa, D; Arakawa, K; Yoshida, S

1997-06-01

Suspension-cultured cells derived from immature embryos of winter wheat (Triticum aestivum L. cv. Chihoku) were used in experiments designed to obtain clues to the mechanism of the ABA-induced development of freezing tolerance. Cultured cells treated with 50 microM ABA for 5 d at 23 degrees C acquired the maximum level of freezing tolerance (LT50; -21.6 degrees C). The increased freezing tolerance of ABA-treated cells was closely associated with the remarkable accumulation of 19-kDa polypeptides in the plasma membrane. The 19-kDa polypeptide components were isolated by preparative gel electrophoresis and were further separated into one major (AWPM-19) and other minor polypeptide components by Tricine-SDS-PAGE. N-terminal amino acid sequence of AWPM-19 was determined, and a cDNA clone encoding AWPM-19 was isolated by PCR from the library prepared from the ABA-treated cultured cells. The cDNA clone (WPM-1) encoded a 18.9 kDa hydrophobic polypeptide with four putative membrane spanning domains and with a high pI value (10.2). Expression of WPM-1 mRNA was dramatically induced by 50 microM ABA within a few hours. These results suggest that the AWPM-19 might be closely associated with the ABA-induced increase in freezing tolerance in wheat cultured cells.

Oxidation at through-hole defects in fused slurry silicide coated columbium alloys FS-85 and Cb-752

NASA Technical Reports Server (NTRS)

Levine, S. R.

1973-01-01

Metal recession and interstitial contamination at 0.08-centimeter-diameter through-hole intentional defects in fused slurry silicide coated FS-85 and Cb-752 columbium alloys were studied to determine the tolerance of these materials to coating defects. Five external pressure reentry simulation exposures to 1320 C and 4.7 x 1,000 N/sq m (maximum pressure) resulted in a consumed metal zone having about twice the initial defect diameter for both alloys with an interstitial contamination zone extending about three to four initial defect diameters. Self-healing occurred in the 1.33 x 10 N/sq m, 1320 C exposures and to a lesser extent in internal pressure reentry cycles to 1320 C and 1.33 x 100 N/sq m (maximum pressure).

Rapid change in the thermal tolerance of a tropical lizard.

PubMed

Leal, Manuel; Gunderson, Alex R

2012-12-01

The predominant view is that the thermal physiology of tropical ectotherms, including lizards, is not labile over ecological timescales. We used the recent introduction (∼35 years ago) of the Puerto Rican lizard Anolis cristatellus to Miami, Florida, to test this thermal rigidity hypothesis. We measured lower (critical thermal minimum [CT(min)]) and upper (critical thermal maximum [CT(max)]) thermal tolerances and found that the introduced population tolerates significantly colder temperatures (by ∼3°C) than does the Puerto Rican source population; however, CT(max) did not differ. These results mirror the thermal regimes experienced by each population: Miami reaches colder ambient temperatures than Puerto Rico, but maximum ambient temperatures are similar. The differences in CT(min) were observed even though lizards from both sites experienced nearly identical conditions for 49 days before CT(min) measurement. Our results demonstrate that changes in thermal tolerance occurred relatively rapidly (∼35 generations), which strongly suggests that the thermal physiology of tropical lizards is more labile than previously proposed.

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

An increased rectal maximum tolerable volume and long anal canal are associated with poor short-term response to biofeedback therapy for patients with anismus with decreased bowel frequency and normal colonic transit time.

PubMed

Rhee, P L; Choi, M S; Kim, Y H; Son, H J; Kim, J J; Koh, K C; Paik, S W; Rhee, J C; Choi, K W

2000-10-01

Biofeedback is an effective therapy for a majority of patients with anismus. However, a significant proportion of patients still failed to respond to biofeedback, and little has been known about the factors that predict response to biofeedback. We evaluated the factors associated with poor response to biofeedback. Biofeedback therapy was offered to 45 patients with anismus with decreased bowel frequency (less than three times per week) and normal colonic transit time. Any differences in demographics, symptoms, and parameters of anorectal physiologic tests were sought between responders (in whom bowel frequency increased up to three times or more per week after biofeedback) and nonresponders (in whom bowel frequency remained less than three times per week). Thirty-one patients (68.9 percent) responded to biofeedback and 14 patients (31.1 percent) did not. Anal canal length was longer in nonresponders than in responders (4.53 +/- 0.5 vs. 4.08 +/- 0.56 cm; P = 0.02), and rectal maximum tolerable volume was larger in nonresponders than in responders. (361 +/- 87 vs. 302 +/- 69 ml; P = 0.02). Anal canal length and rectal maximum tolerable volume showed significant differences between responders and nonresponders on multivariate analysis (P = 0.027 and P = 0.034, respectively). This study showed that a long anal canal and increased rectal maximum tolerable volume are associated with poor short-term response to biofeedback for patients with anismus with decreased bowel frequency and normal colonic transit time.

Nitric oxide evokes pain in humans on intracutaneous injection.

PubMed

Holthusen, H; Arndt, J O

1994-01-03

To test the hypothesis that nitric oxide (NO) acts algetically in humans, we determined pain intensity/dose relations for intracutaneously applied NO solutions. NO, dissolved in isoosmolar phosphate buffer, was injected in the forearm of six volunteers and the subjects rated NO-evoked pain continuously with the help of an electronically controlled visual analogue scale. Pain always occurred at a NO dose of 12 nmol, increased with dose and reached the tolerance maximum at 50 nmol. This shows for the first time the genuine pain evoking properties of NO.

Limited tolerance by insects to high temperatures across tropical elevational gradients and the implications of global warming for extinction.

PubMed

García-Robledo, Carlos; Kuprewicz, Erin K; Staines, Charles L; Erwin, Terry L; Kress, W John

2016-01-19

The critical thermal maximum (CTmax), the temperature at which motor control is lost in animals, has the potential to determine if species will tolerate global warming. For insects, tolerance to high temperatures decreases with latitude, suggesting that similar patterns may exist along elevational gradients as well. This study explored how CTmax varies among species and populations of a group of diverse tropical insect herbivores, the rolled-leaf beetles, across both broad and narrow elevational gradients. Data from 6,948 field observations and 8,700 museum specimens were used to map the elevational distributions of rolled-leaf beetles on two mountains in Costa Rica. CTmax was determined for 1,252 individual beetles representing all populations across the gradients. Initial morphological identifications suggested a total of 26 species with populations at different elevations displaying contrasting upper thermal limits. However, compared with morphological identifications, DNA barcodes (cytochrome oxidase I) revealed significant cryptic species diversity. DNA barcodes identified 42 species and haplotypes across 11 species complexes. These 42 species displayed much narrower elevational distributions and values of CTmax than the 26 morphologically defined species. In general, species found at middle elevations and on mountaintops are less tolerant to high temperatures than species restricted to lowland habitats. Species with broad elevational distributions display high CTmax throughout their ranges. We found no significant phylogenetic signal in CTmax, geography, or elevational range. The narrow variance in CTmax values for most rolled-leaf beetles, especially high-elevation species, suggests that the risk of extinction of insects may be substantial under some projected rates of global warming.

Limited tolerance by insects to high temperatures across tropical elevational gradients and the implications of global warming for extinction

PubMed Central

García-Robledo, Carlos; Kuprewicz, Erin K.; Staines, Charles L.; Erwin, Terry L.; Kress, W. John

2016-01-01

The critical thermal maximum (CTmax), the temperature at which motor control is lost in animals, has the potential to determine if species will tolerate global warming. For insects, tolerance to high temperatures decreases with latitude, suggesting that similar patterns may exist along elevational gradients as well. This study explored how CTmax varies among species and populations of a group of diverse tropical insect herbivores, the rolled-leaf beetles, across both broad and narrow elevational gradients. Data from 6,948 field observations and 8,700 museum specimens were used to map the elevational distributions of rolled-leaf beetles on two mountains in Costa Rica. CTmax was determined for 1,252 individual beetles representing all populations across the gradients. Initial morphological identifications suggested a total of 26 species with populations at different elevations displaying contrasting upper thermal limits. However, compared with morphological identifications, DNA barcodes (cytochrome oxidase I) revealed significant cryptic species diversity. DNA barcodes identified 42 species and haplotypes across 11 species complexes. These 42 species displayed much narrower elevational distributions and values of CTmax than the 26 morphologically defined species. In general, species found at middle elevations and on mountaintops are less tolerant to high temperatures than species restricted to lowland habitats. Species with broad elevational distributions display high CTmax throughout their ranges. We found no significant phylogenetic signal in CTmax, geography, or elevational range. The narrow variance in CTmax values for most rolled-leaf beetles, especially high-elevation species, suggests that the risk of extinction of insects may be substantial under some projected rates of global warming. PMID:26729867

Thermal Tolerance in Anuran Embryos with Different Reproductive Modes: Relationship to Altitude

PubMed Central

Lynch, John D.

2013-01-01

Anurans are ectothermic animals very sensitive to temperature, mainly during the embryonic stage. In addition, environmental temperature decreases with altitude, and the amphibian fauna changes. Therefore, we studied the relationship between the embryonic thermal tolerances of twelve species of anurans and the temperatures of their microhabitat along an altitudinal gradient from 430 m to 2600 m. We hypothesized that there is a strong thermal adjustment of embryos to their microhabitat and, consequently, that temperature could be a limiting factor of altitudinal distribution of the anurans. We also compared the embryonic thermal tolerances according to six postulated reproductive modes of the study species. We found a significant relationship between the maximum and minimum thermal tolerances of the anuran embryos and the maximum and minimum temperatures of their microhabitat and altitudinal distribution. We also found a wide range of embryonic thermal tolerances for aquatic breeding species and a narrower range for terrestrial breeding species. Particularly, embryos of direct development species were the most sensitive to temperature. These results show the strong thermal adjustment of anuran embryos to their microhabitat and elevation and do not reject the hypothesis that temperature can be a limiting factor of their altitudinal distribution. PMID:23766678

Lambda network having 2.sup.m-1 nodes in each of m stages with each node coupled to four other nodes for bidirectional routing of data packets between nodes

DOEpatents

Napolitano, Jr., Leonard M.

1995-01-01

The Lambda network is a single stage, packet-switched interprocessor communication network for a distributed memory, parallel processor computer. Its design arises from the desired network characteristics of minimizing mean and maximum packet transfer time, local routing, expandability, deadlock avoidance, and fault tolerance. The network is based on fixed degree nodes and has mean and maximum packet transfer distances where n is the number of processors. The routing method is detailed, as are methods for expandability, deadlock avoidance, and fault tolerance.

Gyro-based Maximum-Likelihood Thruster Fault Detection and Identification

NASA Technical Reports Server (NTRS)

Wilson, Edward; Lages, Chris; Mah, Robert; Clancy, Daniel (Technical Monitor)

2002-01-01

When building smaller, less expensive spacecraft, there is a need for intelligent fault tolerance vs. increased hardware redundancy. If fault tolerance can be achieved using existing navigation sensors, cost and vehicle complexity can be reduced. A maximum likelihood-based approach to thruster fault detection and identification (FDI) for spacecraft is developed here and applied in simulation to the X-38 space vehicle. The system uses only gyro signals to detect and identify hard, abrupt, single and multiple jet on- and off-failures. Faults are detected within one second and identified within one to five accords,

[Insulin, glucagon and growth hormone responses during glucose, arginine and insulin tolerance tests in children with hyperthyroidism].

PubMed

Kato, T; Matsuura, N; Fujita, H; Fujieda, K; Nohara, Y; Mikami, Y; Abe, K; Fukushima, N

1985-06-20

There are many reports of glucose intolerance in adult patients with hyperthyroidism but few reports of glucose intolerance in hyperthyroid children. In this study, we measured plasma levels of glucose, insulin, glucagon and growth hormone in hyperthyroid children and control subjects by the use of three kinds of tolerance tests: an oral glucose tolerance test, an arginine tolerance test and an insulin tolerance test. In the oral glucose tolerance test, mean fasting glucose levels (79.6 +/- 1.4 mg/dl) rose to maximum levels (157.3 +/- 4.3 mg/dl) at 30 min in hyperthyroid children which were significantly higher than the levels in control subjects (p less than 0.01). The maximum levels of glucose fell slowly and returned to fasting levels at 180 min. In this test, plasma insulin levels increased from basal levels (12.7 +/- 1.9 microU/ml) to maximum levels (120.8 +/- 22.1 microU/ml) at 30 min in the prepubertal age group of hyperthyroidism. On the other hand, in the pubertal age group of hyperthyroidism, maximum levels of insulin were observed at 60 min, but not at 30 min. These maximum levels of insulin of both hyperthyroid age groups were significantly higher than those in the control subjects (p less than 0.05, p less than 0.01 respectively). There was no difference in insulin-glucose ratio at 30 min (delta IRI/delta BG) and insulinogenic index (I.I.) at 0 to 60 min between these two groups of hyperthyroid children and control subjects. However, I.I. at 0 to 120 min and 0 to 180 min decreased significantly in the pubertal age group of hyperthyroidism as compared with those in the control group (p less than 0.05, p less than 0.02 respectively). In the oral glucose tolerance test, plasma glucagon levels decreased from basal levels (74.1 +/- 4.3 pg/ml) to minimum levels (36.4 +/- 4.7 pg/ml) at 90 min in hyperthyroidism, which were significantly lower than those in the controls (p less than 0.05). However, there was no difference in -epsilon delta IRG/epsilon delta BG (cumulative glucagon response/cumulative glucose response) between the subjects with hyperthyroidism and the controls. On the other hand, lower responses of blood glucose, insulin, glucagon and growth hormone to arginine were observed in subjects with hyperthyroidism than in the controls. Moreover in the insulin tolerance test, there was no difference in glucagon and growth hormone response between the subjects with hyperthyroidism and the controls. Thus our conclusions are as follows: A marked increase in blood glucose after oral glucose load was observed in spite of normal insulin-glucose ratio in hyperthyroid children, suggesting the existence of peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

14 CFR 27.571 - Fatigue evaluation of flight structure.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 27.309, except that maneuvering load factors need not exceed the maximum values expected in operation... paragraph (a)(3) of this section. (b) Fatigue tolerance evaluation. It must be shown that the fatigue tolerance of the structure ensures that the probability of catastrophic fatigue failure is extremely remote...

NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities in the United States and Canada

EPA Pesticide Factsheets

The purpose of this document is to provide detailed guidance on data requirements that meet the North American Free Trade Agreement standards for the establishment of pesticide import tolerances or maximum residue levels in Canada and the United States.

Effects of long-term self-massage at the musculotendinous junction on hamstring extensibility, stiffness, stretch tolerance, and structural indices: A randomized controlled trial.

PubMed

Akazawa, Naoki; Okawa, Naomi; Kishi, Masaki; Nakatani, Kiyoshi; Nishikawa, Katsuya; Tokumura, Daichi; Matsui, Yuji; Moriyama, Hideki

2016-09-01

The purpose of this study was to examine the effect of long-term self-massage at the musculotendinous junction on hamstring extensibility, stiffness, stretch tolerance, and structural indices. Single-blind, randomized, controlled trial. Laboratory. Thirty-seven healthy men. The right or left leg of each participant was randomly assigned to the massage group, and the other leg was assigned to the control group. The participants conducted self-massage at the musculotendinous junction for 3 min daily, five times per week, for 12 weeks. Hamstring extensibility, stiffness, stretch tolerance, and structural indices were measured by a blinded examiner prior to the massage intervention and after 6 and 12 weeks of intervention. The maximum hip flexion angle (HFA) and the maximum passive pressure after 6 and 12 weeks of intervention in the massage group were significantly higher than prior to intervention. The visual analog scale (for pain perception) at maximum HFA, the stiffness of the hamstring, and the structural indices did not differ in either group over the 12 week period. Our results suggest that long-term self-massage at the musculotendinous junction increases hamstring extensibility by improving stretch tolerance. However, this intervention does not change hamstring stiffness. University Hospital Medical Information Network registration number UMIN000011233. Copyright © 2016 Elsevier Ltd. All rights reserved.

System of matrix metalloproteinases and cytokine secretion in type 2 diabetes mellitus and impaired carbohydrate tolerance associated with arterial hypertension.

PubMed

Kologrivova, I V; Suslova, T E; Koshel'skaya, O A; Vinnitskaya, I V; Trubacheva, O A

2014-03-01

The study included patients with type 2 diabetes mellitus and impaired carbohydrate tolerance associated with arterial hypertension, patients with arterial hypertension, and healthy volunteers. We evaluated the levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinase type 1 (TIMP-1), glucose, insulin, C-peptide, glycated hemoglobin, and spontaneous and mitogen-activated cytokine secretion (IL-2, IL4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ). Patients with type 2 diabetes mellitus in combination with arterial hypertension exhibited maximum TIMP-1 levels and TIMP-1/MMP-2, TIMP-1/ MMP-9 ratios as well as enhanced secretion of TNF-α, IL-6, IL-17 and reduced secretion of IL-10 in comparison with healthy individuals. The observed shifts are probably determined the development of systemic hyperinsulinemia in patients suffering from type 2 diabetes mellitus coupled with arterial hypertension.

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

NONE

As part of the R and D program towards a fourth generation light source, a Self-Amplified Spontaneous Emission (SASE) demonstration is being prepared. The Visible-Infrared SASE Amplifier (VISA) undulator will be installed at Brookhaven National Laboratory by the end of the year. The VISA undulator is an in-vacuum, 4-meter long, 1.8 cm period, pure-permanent magnet device, with a novel, strong focusing, permanent magnet FODO array included within the fixed, 6 mm undulator gap. The undulator is constructed of 99 cm long segments. To attain maximum SASE gain requires establishing overlap of electron and photon beams to within 50 {micro}m rms.more » This imposes challenging tolerances on mechanical fabrication and magnetic field quality, and necessitates use of laser straightness interferometry for calibration and alignment of the magnetic axes of the undulator segments. This paper describes the magnetic centerline determination, and the fiducialization and alignment processes which were performed to meet the tolerance goal.« less

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

Ruland, Robert E.

As part of the R and D program towards a fourth generation light source, a Self-Amplified Spontaneous Emission (SASE) demonstration is being prepared. The Visible-Infrared SASE Amplifier (VISA) undulator is being installed at Brookhaven National Laboratory. The VISA undulator is an in-vacuum, 4-meter long, 1.8 cm period, pure-permanent magnet device, with a novel, strong focusing, permanent magnet FODO array included within the fixed, 6 mm undulator gap. The undulator is constructed of 99 cm long segments. To attain maximum SASE gain requires establishing overlap of electron and photon beams to within 50 pm rms. This imposes challenging tolerances on mechanicalmore » fabrication and magnetic field quality, and necessitates use of laser straightness interferometry for calibration and alignment of the magnetic axes of the undulator segments. This paper describes the magnetic centerline determination, and the fiducialization and alignment processes, which were performed to meet the tolerance goal.« less

Effects of exercise-based cardiac rehabilitation in patients after percutaneous coronary intervention: A meta-analysis of randomized controlled trials

PubMed Central

Yang, Xinyu; Li, Yanda; Ren, Xiaomeng; Xiong, Xingjiang; Wu, Lijun; Li, Jie; Wang, Jie; Gao, Yonghong; Shang, Hongcai; Xing, Yanwei

2017-01-01

In this study, we assessed the effect of rehabilitation exercise after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). We performed a meta-analysis to determine the effects of exercise in patients after PCI. The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, the Embase database, China National Knowledge Internet (CNKI), China Biology Medicine (CBM), and the Wanfang Database were searched for randomized controlled trials (RCTs). The key words used for the searches were PCI, exercise, walking, jogging, Tai Chi, and yoga. Six studies with 682 patients met our inclusion criteria; we chose the primary endpoint events of cardiac death, recurrence of myocardial infarction (MI), repeated PCI, coronary artery bypass grafting (CABG), and restenosis, and the secondary endpoint measures included recurrent angina, treadmill exercise (total exercise time, ST-segment decline, angina, and maximum exercise tolerance). The results showed that exercise was not clearly associated with reductions in cardiac death, recurrence of MI, repeated PCI, CABG, or restenosis. However, the exercise group exhibited greater improvements in recurrent angina, total exercise time, ST-segment decline, angina, and maximum exercise tolerance than did the control group. Future studies need to expand the sample size and improve the quality of reporting of RCTs. PMID:28303967

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours.

PubMed

Bahleda, Rastislav; Hollebecque, Antoine; Varga, Andrea; Gazzah, Anas; Massard, Christophe; Deutsch, Eric; Amellal, Nadia; Farace, Françoise; Ould-Kaci, Mahmoud; Roux, Flavien; Marzin, Kristell; Soria, Jean-Charles

2015-11-17

This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

PubMed

Wensing, Georg; Haase, Claus; Brendel, Erich; Böttcher, Michael Friedrich

2007-12-01

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects.

PubMed

Park, Sang-In; Lee, Howard; Oh, Jaeseong; Lim, Kyoung Soo; Jang, In-Jin; Kim, Jeong-Ae; Jung, Jong Hyuk; Yu, Kyung-Sang

2015-01-01

In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets. A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study. The plasma DPP-4 activity-time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97-1.04) and 0.92 (0.82-1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration-time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80-1.25. Both the FDC and separate tablets were well tolerated. The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin sustained release can be a convenient therapeutic option in patients with type 2 diabetes mellitus requiring a combination approach.

Gross mismatch between thermal tolerances and environmental temperatures in a tropical freshwater snail: climate warming and evolutionary implications.

PubMed

Polgar, Gianluca; Khang, Tsung Fei; Chua, Teddy; Marshall, David J

2015-01-01

The relationship between acute thermal tolerance and habitat temperature in ectotherm animals informs about their thermal adaptation and is used to assess thermal safety margins and sensitivity to climate warming. We studied this relationship in an equatorial freshwater snail (Clea nigricans), belonging to a predominantly marine gastropod lineage (Neogastropoda, Buccinidae). We found that tolerance of heating and cooling exceeded average daily maximum and minimum temperatures, by roughly 20°C in each case. Because habitat temperature is generally assumed to be the main selective factor acting on the fundamental thermal niche, the discordance between thermal tolerance and environmental temperature implies trait conservation following 'in situ' environmental change, or following novel colonisation of a thermally less-variable habitat. Whereas heat tolerance could relate to an historical association with the thermally variable and extreme marine intertidal fringe zone, cold tolerance could associate with either an ancestral life at higher latitudes, or represent adaptation to cooler, higher-altitudinal, tropical lotic systems. The broad upper thermal safety margin (difference between heat tolerance and maximum environmental temperature) observed in this snail is grossly incompatible with the very narrow safety margins typically found in most terrestrial tropical ectotherms (insects and lizards), and hence with the emerging prediction that tropical ectotherms, are especially vulnerable to environmental warming. A more comprehensive understanding of climatic vulnerability of animal ectotherms thus requires greater consideration of taxonomic diversity, ecological transition and evolutionary history. Copyright © 2014 Elsevier Ltd. All rights reserved.

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

PubMed Central

Iyengar, Tara; Ramanathan, Ramesh K.; Lewandowski, Karen; Anthony, Stephen P.; Donehower, Ross C.; Westin, Eric; Hurt, Karla; Hynes, Scott M.; McKane, Scott

2013-01-01

Summary Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40–195 mg/m2) were combined with 500 mg/m2 of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Anti-tumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m2 over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m2, 70 mg/m2, and 195 mg/m2; 13 at 105 mg/m2; six at 150 mg/m2). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m2); reversible infusion-related reaction (150 mg/m2); thrombocytopenia (195 mg/m2); and fatigue (195 mg/m2). The maximum tolerated dose was defined as 150 mg/m2. The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m2. Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles. PMID:22492020

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

PubMed

Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

2013-02-01

This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

[Effects of different rootstocks on the weak light tolerance ability of summer black grape based on 4 photo-response models].

PubMed

Han, Xiao; Wang, Hai Bo; Wang, Xiao di; Shi, Xiang Bin; Wang, Bao Liang; Zheng, Xiao Cui; Wang, Zhi Qiang; Liu, Feng Zhi

2017-10-01

The photo response curves of 11 rootstock-scion combinations including summer black/Beta, summer black/1103P, summer black/101-14, summer black/3309C, summer black/140Ru, summer black/5C, summer black/5BB, summer black/420A, summer black/SO4, summer black/Kangzhen No.1, summer black/Huapu No.1 were fitted by rectangular hyperbola mo-del, non-rectangular hyperbola model, modified rectangular hyperbola model and exponential model respectively, and the differences of imitative effects were analyzed by determination coefficiency, light compensation point, light saturation point, initial quantum efficiency, maximum photosynthetic rate and dark respiration rate. The result showed that the fit coefficients of all four models were above 0.98, and there was no obvious difference on the fitted values of light compensation point among the four models. The modified rectangular hyperbola model fitted best on light saturation point, apparent quantum yield, maximum photosynthetic rate and dark respiration rate, and had the minimum AIC value based on the akaike information criterion, therefore, the modified rectangular hyperbola model was the best one. The clustering analysis indicated that summer black/SO4 and summer black/420A combinations had low light compensation point, high apparent quantum yield and low dark respiration rate among 11 rootstock-scion combinations, suggesting that these two combinations could use weak light more efficiently due to their less respiratory consumption and higher weak light tolerance. The Topsis comparison method ranked summer black/SO4 and summer black/420A combinations as No. 1 and No. 2 respectively in weak light tolerance ability, which was consistent with cluster analysis. Consequently, summer black has the highest weak light tolerance in case grafted on 420A or SO4, which could be the most suitable rootstock-scion combinations for protected cultivation.

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-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

46 CFR 162.018-5 - Blow-down adjustment and popping tolerance.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., CONSTRUCTION, AND MATERIALS: SPECIFICATIONS AND APPROVAL ENGINEERING EQUIPMENT Safety Relief Valves, Liquefied Compressed Gas § 162.018-5 Blow-down adjustment and popping tolerance. (a) Safety relief valves shall be so.... Safety relief valves shall be designed to open sharply and reach full lift and capacity at the maximum...

77 FR 66721 - Metconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-07

... information in support of this action. EPA has sufficient data to assess the hazards of and to make a... tolerance shows that there will be no increase in the maximum reasonably balanced dietary burden for beef cattle, swine, or poultry but a small increase for diary cattle. There is no increase for beef cattle...

76 FR 82152 - Cyhalofop-butyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-30

... original long-term studies were approaching a maximum tolerated dose. In addition, there were no positive....regulations.gov , or, if only available in hard copy, at the OPP Regulatory Public Docket in Rm. S-4400, One..., identified by docket ID number EPA-HQ-OPP-2011-0283, by one of the following methods: Federal eRulemaking...

Lambda network having 2{sup m{minus}1} nodes in each of m stages with each node coupled to four other nodes for bidirectional routing of data packets between nodes

DOEpatents

Napolitano, L.M. Jr.

1995-11-28

The Lambda network is a single stage, packet-switched interprocessor communication network for a distributed memory, parallel processor computer. Its design arises from the desired network characteristics of minimizing mean and maximum packet transfer time, local routing, expandability, deadlock avoidance, and fault tolerance. The network is based on fixed degree nodes and has mean and maximum packet transfer distances where n is the number of processors. The routing method is detailed, as are methods for expandability, deadlock avoidance, and fault tolerance. 14 figs.

The provision of clearances accuracy in piston - cylinder mating

NASA Astrophysics Data System (ADS)

Glukhov, V. I.; Shalay, V. V.

2017-08-01

The paper is aimed at increasing the quality of the pumping equipment in oil and gas industry. The main purpose of the study is to stabilize maximum values of productivity and durability of the pumping equipment based on the selective assembly of the cylinder-piston kinematic mating by optimization criterion. It is shown that the minimum clearance in the piston-cylinder mating is formed by maximum material dimensions. It is proved that maximum material dimensions are characterized by their own laws of distribution within the tolerance limits for the diameters of the cylinder internal mirror and the outer cylindrical surface of the piston. At that, their dispersion zones should be divided into size groups with a group tolerance equal to half the tolerance for the minimum clearance. The techniques for measuring the material dimensions - the smallest cylinder diameter and the largest piston diameter according to the envelope condition - are developed for sorting them into size groups. Reliable control of the dimensions precision ensures optimal minimum clearances of the piston-cylinder mating in all the size groups of the pumping equipment, necessary for increasing the equipment productivity and durability during the production, operation and repair processes.

Avian thermoregulation in the heat: evaporative cooling in five Australian passerines reveals within-order biogeographic variation in heat tolerance.

PubMed

McKechnie, Andrew E; Gerson, Alexander R; McWhorter, Todd J; Smith, Eric Krabbe; Talbot, William A; Wolf, Blair O

2017-07-01

Evaporative heat loss pathways vary among avian orders, but the extent to which evaporative cooling capacity and heat tolerance vary within orders remains unclear. We quantified the upper limits to thermoregulation under extremely hot conditions in five Australian passerines: yellow-plumed honeyeater ( Lichenostomus ornatus ; ∼17 g), spiny-cheeked honeyeater ( Acanthagenys rufogularis ; ∼42 g), chestnut-crowned babbler ( Pomatostomus ruficeps ; ∼52 g), grey butcherbird ( Cracticus torquatus ; ∼86 g) and apostlebird ( Struthidea cinerea ; ∼118 g). At air temperatures ( T a ) exceeding body temperature ( T b ), all five species showed increases in T b to maximum values around 44-45°C, accompanied by rapid increases in resting metabolic rate above clearly defined upper critical limits of thermoneutrality and increases in evaporative water loss (EWL) to levels equivalent to 670-860% of baseline rates at thermoneutral T a Maximum cooling capacity, quantified as the fraction of metabolic heat production dissipated evaporatively, ranged from 1.20 to 2.17, consistent with the known range for passerines, and well below the corresponding ranges for columbids and caprimulgids. Heat tolerance limit (HTL, the maximum T a tolerated) scaled positively with body mass, varying from 46°C in yellow-plumed honeyeaters to 52°C in a single apostlebird, but was lower than that of three southern African ploceid passerines investigated previously. We argue this difference is functionally linked to a smaller scope for increases in EWL above baseline levels. Our data reiterate the reliance of passerines in general on respiratory evaporative heat loss via panting, but also reveal substantial within-order variation in heat tolerance and evaporative cooling capacity. © 2017. Published by The Company of Biologists Ltd.

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

PubMed Central

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

2016-01-01

Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. Conclusion. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. PMID:27789778

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

2016-11-01

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Pesticide tolerant and phosphorus solubilizing Pseudomonas sp. strain SGRAJ09 isolated from pesticides treated Achillea clavennae rhizosphere soil.

PubMed

Rajasankar, R; Manju Gayathry, G; Sathiavelu, A; Ramalingam, C; Saravanan, V S

2013-05-01

In this study, an attempt was made to identify an effective phosphate solubilizing bacteria from pesticide polluted field soil. Based on the formation of solubilization halo on Pikovskaya's agar, six isolates were selected and screened for pesticide tolerance and phosphate (P) solubilization ability through liquid assay. The results showed that only one strain (SGRAJ09) obtained from Achillea clavennae was found to tolerate maximum level of the pesticides tested and it was phylogenetically identified as Pseudomonas sp. It possessed a wide range of pesticide tolerance, ranging from 117 μg mL(-1) for alphamethrin to 2,600 μg mL(-1) for endosulfan. The available P concentrations increased with the maximum and double the maximum dose of monocrotophos and imidacloprid, respectively. On subjected to FT-IR and HPLC analysis, the presence of organic acids functional group in the culture broth and the production of gluconic acid as dominant acid aiding the P solubilization were identified. On comparison with control broth, monocrotophos and imidacloprid added culture broth showed quantitatively high organic acids production. In addition to gluconic acid production, citric and acetic acids were also observed in the pesticide amended broth. Furthermore, the Pseudomonas sp. strain SGRAJ09 possessed all the plant growth promoting traits tested. In presence of monocrotophos and imidacloprid, its plant growth promoting activities were lower than that of the pesticides unamended treatment.

High-potential accumulation and tolerance in the submerged hydrophyte Hydrilla verticillata (L.f.) Royle for nickel-contaminated water.

PubMed

Song, Yang; Zhang, Ling-Lei; Li, Jia; He, Xiao-Jia; Chen, Min; Deng, Yun

2018-06-18

Water contamination by nickel (Ni) has become an increasing concern in recent decades. Hydrilla verticillata (L.f.) Royle has been recognized as a promising accumulator of several potentially toxic elements (PTEs) in phytoremediation, but its Ni-accumulation characteristics and its mechanisms of tolerance to Ni remain largely unknown. This research investigated the biochemical responses of leaves and stems of H. verticillata to various concentrations of Ni (5, 10, 15, 20, and 40 μM) over periods of 7, 14, or 21 days. Plants accumulated considerable Ni to a maximum amount of 1080 mg kg -1 dry weight (DW) with a maximum bioconcentration factor of 1100; thus, high Ni accumulation was detected in H. verticillata. Low concentrations (5-15 μM) or short durations (less than 14 days) of Ni exposure might promote plant growth without adversely affecting normal metabolism. After peaking at day 14, a decline in bioaccumulation was unexpectedly observed as a long-term effect of Ni toxicity. Malondialdehyde content and the activities of defense-related enzymes changed in a similar pattern after treatment with Ni, increasing with both Ni concentration and exposure time to a peak (often at 5-15 μM on day 14), followed by a decline. Through a comprehensive analysis of all the test parameters, the tolerance thresholds were determined to be > 40.0 μM, 24.0 μM, and 15.8 μM at days 7, 14, and 21, respectively. Hydrilla verticillata could be a "high-potential accumulator" capable of decontaminating aquatic bodies polluted by Ni within the threshold range. Copyright © 2018 Elsevier Inc. All rights reserved.

Ethanol Production and Maximum Cell Growth Are Highly Correlated with Membrane Lipid Composition during Fermentation as Determined by Lipidomic Analysis of 22 Saccharomyces cerevisiae Strains

PubMed Central

Henderson, Clark M.; Lozada-Contreras, Michelle; Jiranek, Vladimir; Longo, Marjorie L.

2013-01-01

Optimizing ethanol yield during fermentation is important for efficient production of fuel alcohol, as well as wine and other alcoholic beverages. However, increasing ethanol concentrations during fermentation can create problems that result in arrested or sluggish sugar-to-ethanol conversion. The fundamental cellular basis for these problem fermentations, however, is not well understood. Small-scale fermentations were performed in a synthetic grape must using 22 industrial Saccharomyces cerevisiae strains (primarily wine strains) with various degrees of ethanol tolerance to assess the correlation between lipid composition and fermentation kinetic parameters. Lipids were extracted at several fermentation time points representing different growth phases of the yeast to quantitatively analyze phospholipids and ergosterol utilizing atmospheric pressure ionization-mass spectrometry methods. Lipid profiling of individual fermentations indicated that yeast lipid class profiles do not shift dramatically in composition over the course of fermentation. Multivariate statistical analysis of the data was performed using partial least-squares linear regression modeling to correlate lipid composition data with fermentation kinetic data. The results indicate a strong correlation (R2 = 0.91) between the overall lipid composition and the final ethanol concentration (wt/wt), an indicator of strain ethanol tolerance. One potential component of ethanol tolerance, the maximum yeast cell concentration, was also found to be a strong function of lipid composition (R2 = 0.97). Specifically, strains unable to complete fermentation were associated with high phosphatidylinositol levels early in fermentation. Yeast strains that achieved the highest cell densities and ethanol concentrations were positively correlated with phosphatidylcholine species similar to those known to decrease the perturbing effects of ethanol in model membrane systems. PMID:23064336

Ethanol production and maximum cell growth are highly correlated with membrane lipid composition during fermentation as determined by lipidomic analysis of 22 Saccharomyces cerevisiae strains.

PubMed

Henderson, Clark M; Lozada-Contreras, Michelle; Jiranek, Vladimir; Longo, Marjorie L; Block, David E

2013-01-01

Optimizing ethanol yield during fermentation is important for efficient production of fuel alcohol, as well as wine and other alcoholic beverages. However, increasing ethanol concentrations during fermentation can create problems that result in arrested or sluggish sugar-to-ethanol conversion. The fundamental cellular basis for these problem fermentations, however, is not well understood. Small-scale fermentations were performed in a synthetic grape must using 22 industrial Saccharomyces cerevisiae strains (primarily wine strains) with various degrees of ethanol tolerance to assess the correlation between lipid composition and fermentation kinetic parameters. Lipids were extracted at several fermentation time points representing different growth phases of the yeast to quantitatively analyze phospholipids and ergosterol utilizing atmospheric pressure ionization-mass spectrometry methods. Lipid profiling of individual fermentations indicated that yeast lipid class profiles do not shift dramatically in composition over the course of fermentation. Multivariate statistical analysis of the data was performed using partial least-squares linear regression modeling to correlate lipid composition data with fermentation kinetic data. The results indicate a strong correlation (R(2) = 0.91) between the overall lipid composition and the final ethanol concentration (wt/wt), an indicator of strain ethanol tolerance. One potential component of ethanol tolerance, the maximum yeast cell concentration, was also found to be a strong function of lipid composition (R(2) = 0.97). Specifically, strains unable to complete fermentation were associated with high phosphatidylinositol levels early in fermentation. Yeast strains that achieved the highest cell densities and ethanol concentrations were positively correlated with phosphatidylcholine species similar to those known to decrease the perturbing effects of ethanol in model membrane systems.

Postoperative Intensity-Modulated Radiotherapy in Low-Risk Endometrial Cancers: Final Results of a Phase I Study

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

Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.i; Cilla, Savino M.P.; Ferrandina, Gabriella

2010-04-15

Purpose: To determine the maximum tolerated dose of short-course radiotherapy (intensity-modulated radiotherapy technique) to the upper two thirds of the vagina in endometrial cancers with low risk of local recurrence. Patients and Methods: A Phase I clinical trial was performed. Eligible patients had low-risk resected primary endometrial adenocarcinomas. Radiotherapy was delivered in 5 fractions over 1 week. The planning target volume was the clinical target volume plus 5 mm. The clinical target volume was defined as the upper two thirds of the vagina as evidenced at CT simulation by a vaginal radio-opaque device. The planning target volume was irradiated bymore » a seven-field intensity-modulated radiotherapy technique, planned by the Plato Sunrise inverse planning system. A first cohort of 6 patients received 25 Gy (5-Gy fractions), and a subsequent cohort received 30 Gy (6-Gy fractions). The Common Toxicity Criteria scale, version 3.0, was used to score toxicity. Results: Twelve patients with endometrial cancer were enrolled. Median age was 58 years (range, 49-74 years). Pathologic stage was IB (83.3%) and IC (16.7%). Median tumor size was 30 mm (range, 15-50 mm). All patients completed the prescribed radiotherapy. No patient experienced a dose-limiting toxicity at the first level, and the radiotherapy dose was escalated from 25 to 30 Gy. No patients at the second dose level experienced dose-limiting toxicity. The most common Grade 2 toxicity was gastrointestinal, which was tolerable and manageable. Conclusions: The maximum tolerated dose of short-course radiotherapy was 30 Gy at 6 Gy per fraction. On the basis of this result, we are conducting a Phase II study with radiotherapy delivered at 30 Gy.« less

A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma.

PubMed

Markowitz, Joseph; Luedke, Eric A; Grignol, Valerie P; Hade, Erinn M; Paul, Bonnie K; Mundy-Bosse, Bethany L; Brooks, Taylor R; Dao, Thao-Vi; Kondalasula, Sri V; Lesinski, Gregory B; Olencki, Thomas; Kendra, Kari L; Carson, William E

2014-01-01

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

Tocotrienols and Whey Protein Isolates Substantially Increase Exercise Endurance Capacity in Diet -Induced Obese Male Sprague-Dawley Rats

PubMed Central

Aguila, Jay; McConell, Glenn K.; McAinch, Andrew J.; Mathai, Michael L.

2016-01-01

Background and Aims Obesity and impairments in metabolic health are associated with reductions in exercise capacity. Both whey protein isolates (WPIs) and vitamin E tocotrienols (TCTs) exert favorable effects on obesity-related metabolic parameters. This research sought to determine whether these supplements improved exercise capacity and increased glucose tolerance in diet-induced obese rats. Methods Six week old male rats (n = 35) weighing 187 ± 32g were allocated to either: Control (n = 9), TCT (n = 9), WPI (n = 8) or TCT + WPI (n = 9) and placed on a high-fat diet (40% of energy from fat) for 10 weeks. Animals received 50mg/kg body weight and 8% of total energy intake per day of TCTs and/or WPIs respectively. Food intake, body composition, glucose tolerance, insulin sensitivity, exercise capacity, skeletal muscle glycogen content and oxidative enzyme activity were determined. Results Both TCT and WPI groups ran >50% longer (2271 ± 185m and 2195 ± 265m respectively) than the Control group (1428 ± 139m) during the run to exhaustion test (P<0.05), TCT + WPI did not further improve exercise endurance (2068 ± 104m). WPIs increased the maximum in vitro activity of beta-hydroxyacyl-CoA in the soleus muscle (P<0.05 vs. Control) but not in the plantaris. Citrate synthase activity was not different between groups. Neither supplement had any effect on weight gain, adiposity, glucose tolerance or insulin sensitivity. Conclusion Ten weeks of both TCTs and WPIs increased exercise endurance by 50% in sedentary, diet-induced obese rats. These positive effects of TCTs and WPIs were independent of body weight, adiposity or glucose tolerance. PMID:27058737

Lack of Physiological Depth Patterns in Conspecifics of Endemic Antarctic Brown Algae: A Trade-Off between UV Stress Tolerance and Shade Adaptation?

PubMed Central

Gómez, Iván; Huovinen, Pirjo

2015-01-01

A striking characteristic of endemic Antarctic brown algae is their broad vertical distribution. This feature is largely determined by the shade adaptation in order to cope with the seasonal variation in light availability. However, during spring-summer months, when light penetrates deep in the water column these organisms have to withstand high levels of solar radiation, including UV. In the present study we examine the light use characteristics in parallel to a potential for UV tolerance (measured as content of phenolic compounds, antioxidant activity and maximum quantum yield of fluorescence) in conspecific populations of four Antarctic brown algae (Ascoseira mirabilis, Desmarestia menziesii, D. anceps and Himantothallus grandifolius) distributed over a depth gradient between 5 and 30 m. The main results indicated that a) photosynthetic efficiency was uniform along the depth gradient in all the studied species, and b) short-term (6 h) exposure to UV radiation revealed a high tolerance measured as chlorophyll fluorescence, phlorotannin content and antioxidant capacity. Multivariate analysis of similarity indicated that light requirements for photosynthesis, soluble phlorotannins and antioxidant capacity are the variables determining the responses along the depth gradient in all the studied species. The suite of physiological responses of algae with a shallower distribution (A. mirabilis and D. menziesii) differed from those with deeper vertical range (D. anceps and H. grandifolius). These patterns are consistent with the underwater light penetration that defines two zones: 0–15 m, with influence of UV radiation (1% of UV-B and UV-A at 9 m and 15 m respectively) and a zone below 15 m marked by PAR incidence (1% up to 30 m). These results support the prediction that algae show a UV stress tolerance capacity along a broad depth range according to their marked shade adaptation. The high contents of phlorotannins and antioxidant potential appear to be strongly responsible for the lack of clear depth patterns in light demand characteristics and UV tolerance. PMID:26252953

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects

PubMed Central

Kim, Yu Kyong; Choi, Mun Ju; Oh, Tae Young; Yu, Kyung-Sang; Lee, SeungHwan

2017-01-01

A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread®) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration–time curve to the last quantifiable concentration (AUC0–t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration–time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815–0.990) for Cmax and 0.904 (0.836–0.978) for AUC0–t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF. PMID:29158663

Pharmacokinetics and Safety of MP-376 (Levofloxacin Inhalation Solution) in Cystic Fibrosis Subjects▿

PubMed Central

Geller, David E.; Flume, Patrick A.; Griffith, David C.; Morgan, Elizabeth; White, Dan; Loutit, Jeffery S.; Dudley, Michael N.

2011-01-01

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (Cmax) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean Cmax for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin Cmax ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development. PMID:21444699

How Will Copper Contamination Constrain Future Global Steel Recycling?

PubMed

Daehn, Katrin E; Cabrera Serrenho, André; Allwood, Julian M

2017-06-06

Copper in steel causes metallurgical problems, but is pervasive in end-of-life scrap and cannot currently be removed commercially once in the melt. Contamination can be managed to an extent by globally trading scrap for use in tolerant applications and dilution with primary iron sources. However, the viability of long-term strategies can only be evaluated with a complete characterization of copper in the global steel system and this is presented in this paper. The copper concentration of flows along the 2008 steel supply chain is estimated from a survey of literature data and compared with estimates of the maximum concentration that can be tolerated in steel products. Estimates of final steel demand and scrap supply by sector are taken from a global stock-saturation model to determine when the amount of copper in the steel cycle will exceed that which can be tolerated. Best estimates show that quantities of copper arising from conventional scrap preparation can be managed in the global steel system until 2050 assuming perfectly coordinated trade and extensive dilution, but this strategy will become increasingly impractical. Technical and policy interventions along the supply chain are presented to close product loops before this global constraint.

Can chilling tolerance of C4 photosynthesis in Miscanthus be transferred to sugarcane?

USDA-ARS?s Scientific Manuscript database

The goal of this study was to investigate if chilling tolerance of C4 photosynthesis in Miscanthus can be transferred to sugarcane. Net leaf CO2 uptake (Asat) and the maximum operating efficiency of photosystem II ('PSII) were measured in warm conditions (25 °C/20 °C), and then during and following ...

77 FR 8741 - Spirotetramat; Pesticide Tolerances for Emergency Exemptions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-15

... on onion, dry bulb under section 408(l)(6) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U... pesticide on dry bulb onions. This regulation establishes a maximum permissible level for residues of... degradates, in or on onion, dry bulb at 0.3 parts per million (ppm). This time-limited tolerance expires on...

Rotor with Flattened Exit Pressure Profile

NASA Technical Reports Server (NTRS)

Baltas, Constantine (Inventor); Prasad, Dilip (Inventor); Gallagher, Edward J. (Inventor)

2015-01-01

A rotor blade comprises an airfoil extending radially from a root section to a tip section and axially from a leading edge to a trailing edge, the leading and trailing edges defining a curvature therebetween. The curvature determines a relative exit angle at a relative span height between the root section and the tip section, based on an incident flow velocity at the leading edge of the airfoil and a rotational velocity at the relative span height. In operation of the rotor blade, the relative exit angle determines a substantially flat exit pressure ratio profile for relative span heights from 75% to 95%, wherein the exit pressure ratio profile is constant within a tolerance of 10% of a maximum value of the exit pressure ratio profile.

Gas exchange and the coagulation system of the blood during the effect on the body of high concentrations of oxygen and carbon dioxide

NASA Technical Reports Server (NTRS)

Palosh, L.; Agadzhanyan, N. A.; Davydov, G. A.; Rybakov, B. K.; Sergiyenko, A. S.

1974-01-01

Maximum permissible concentrations of oxygen and carbon dioxide in a controlled atmosphere were determined by evaluating their effects on human gas exchange, blood coagulation, and tolerances to acute hypoxia, acceleration, and physical loads. It was found that functional disturbances depend on the concentration of respiratory gases and the length of stay in an altered atmosphere. By changing the atmospheric composition and by bringing the gaseous environment into accordance with the work and rest regimen and energy expenditures, the general reactivity of the body changes favorably.

Assessment of anoxia tolerance and photoperiod dependence of GABAergic polarity in the pond snail Lymnaea stagnalis.

PubMed

Buck, Leslie T; Bond, Hilary C; Malik, Aqsa

2017-01-01

The pond snail Lymnaea stagnalis is reported to be anoxia-tolerant and if the tolerance mechanism is similar to that of the anoxia-tolerant painted turtle, GABA should play an important role. A potentially confounding factor investigating the role of GABA in anoxia tolerance are reports that GABA has both inhibitory and excitatory effects within L. stagnalis central ganglion. We therefore set out to determine if seasonality or photoperiod has an impact on: 1) the anoxia-tolerance of the intact pond snail, and 2) the response of isolated neuroganglia cluster F neurons to exogenous GABA application. L. stagnalis maintained on a natural summer light cycle were unable to survive any period of anoxic exposure, while those maintained on a natural winter light cycle survived a maximum of 4h. Using intracellular sharp electrode recordings from pedal ganglia cluster F neurons we show that there is a photoperiod dependent shift in the response to GABA. Snails exposed to a 16h:8h light:dark cycle in an environmental chamber (induced summer phenotype) exhibited hyperpolarizing inhibitory responses and those exposed to a 8h:16h light:dark cycle (induced winter phenotype) exhibited depolarizing excitatory responses to GABA application. Using gramicidin-perforated patch recordings we also found a photoperiod dependent shift in the reversal potential for GABA. We conclude that the opposing responses of L. stagnalis central neurons to GABA results from a shift in intracellular chloride concentration that is photoperiod dependent and is likely mediated through the relative efficacy of cation chloride co-transporters. Although the physiological ramifications of the photoperiod dependent shift are unknown this work potentially has important implications for the impact of artificial light pollution on animal health. Copyright © 2016 Elsevier Inc. All rights reserved.

Screening of Trichoderma isolates for their potential of biosorption of nickel and cadmium.

PubMed

Nongmaithem, Nabakishor; Roy, Ayon; Bhattacharya, Prateek Madhab

2016-01-01

Fourteen Trichoderma isolates were evaluated for their tolerance to two heavy metals, nickel and cadmium. Three isolates, MT-4, UBT-18, and IBT-I, showed high levels of nickel tolerance, whereas MT-4, UBT-18, and IBT-II showed better tolerance of cadmium than the other isolates. Under nickel stress, biomass production increased up to a Ni concentration of 60ppm in all strains but then decreased as the concentrations of nickel were further increased. Among the nickel-tolerant isolates, UBT-18 produced significantly higher biomass upon exposure to nickel (up to 150ppm); however, the minimum concentration of nickel required to inhibit 50% of growth (MIC50) was highest in IBT-I. Among the cadmium-tolerant isolates, IBT-II showed both maximum biomass production and a maximum MIC50 value in cadmium stress. As the biomass of the Trichoderma isolates increased, a higher percentage of nickel removal was observed up to a concentration of 40ppm, followed by an increase in residual nickel and a decrease in biomass production at higher nickel concentrations in the medium. The increase in cadmium concentrations resulted in a decrease in biomass production and positively correlated with an increase in residual cadmium in the culture broth. Nickel and cadmium stress also influenced the sensitivity of the Trichoderma isolates to soil fungistasis. Isolates IBT-I and UBT-18 were most tolerant to fungistasis under nickel and cadmium stress, respectively. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Non-destructive Determination of Shikimic Acid Concentration in Transgenic Maize Exhibiting Glyphosate Tolerance Using Chlorophyll Fluorescence and Hyperspectral Imaging

PubMed Central

Feng, Xuping; Yu, Chenliang; Chen, Yue; Peng, Jiyun; Ye, Lanhan; Shen, Tingting; Wen, Haiyong; He, Yong

2018-01-01

The development of transgenic glyphosate-tolerant crops has revolutionized weed control in crops in many regions of the world. The early, non-destructive identification of superior plant phenotypes is an important stage in plant breeding programs. Here, glyphosate-tolerant transgenic maize and its parental wild-type control were studied at 2, 4, 6, and 8 days after glyphosate treatment. Visible and near-infrared hyperspectral imaging and chlorophyll fluorescence imaging techniques were applied to monitor the performance of plants. In our research, transgenic maize, which was highly tolerant to glyphosate, was phenotyped using these high-throughput non-destructive methods to validate low levels of shikimic acid accumulation and high photochemical efficiency of photosystem II as reflected by maximum quantum yield and non-photochemical quenching in response to glyphosate. For hyperspectral imaging analysis, the combination of spectroscopy and chemometric methods was used to predict shikimic acid concentration. Our results indicated that a partial least-squares regression model, built on optimal wavelengths, effectively predicted shikimic acid concentrations, with a coefficient of determination value of 0.79 for the calibration set, and 0.82 for the prediction set. Moreover, shikimic acid concentration estimates from hyperspectral images were visualized on the prediction maps by spectral features, which could help in developing a simple multispectral imaging instrument for non-destructive phenotyping. Specific physiological effects of glyphosate affected the photochemical processes of maize, which induced substantial changes in chlorophyll fluorescence characteristics. A new data-driven method, combining mean fluorescence parameters and featuring a screening approach, provided a satisfactory relationship between fluorescence parameters and shikimic acid content. The glyphosate-tolerant transgenic plants can be identified with the developed discrimination model established on important wavelengths or sensitive fluorescence parameters 6 days after glyphosate treatment. The overall results indicated that both hyperspectral imaging and chlorophyll fluorescence imaging techniques could provide useful tools for stress phenotyping in maize breeding programs and could enable the detection and evaluation of superior genotypes, such as glyphosate tolerance, with a non-destructive high-throughput technique. PMID:29686693

Non-destructive Determination of Shikimic Acid Concentration in Transgenic Maize Exhibiting Glyphosate Tolerance Using Chlorophyll Fluorescence and Hyperspectral Imaging.

PubMed

Feng, Xuping; Yu, Chenliang; Chen, Yue; Peng, Jiyun; Ye, Lanhan; Shen, Tingting; Wen, Haiyong; He, Yong

2018-01-01

The development of transgenic glyphosate-tolerant crops has revolutionized weed control in crops in many regions of the world. The early, non-destructive identification of superior plant phenotypes is an important stage in plant breeding programs. Here, glyphosate-tolerant transgenic maize and its parental wild-type control were studied at 2, 4, 6, and 8 days after glyphosate treatment. Visible and near-infrared hyperspectral imaging and chlorophyll fluorescence imaging techniques were applied to monitor the performance of plants. In our research, transgenic maize, which was highly tolerant to glyphosate, was phenotyped using these high-throughput non-destructive methods to validate low levels of shikimic acid accumulation and high photochemical efficiency of photosystem II as reflected by maximum quantum yield and non-photochemical quenching in response to glyphosate. For hyperspectral imaging analysis, the combination of spectroscopy and chemometric methods was used to predict shikimic acid concentration. Our results indicated that a partial least-squares regression model, built on optimal wavelengths, effectively predicted shikimic acid concentrations, with a coefficient of determination value of 0.79 for the calibration set, and 0.82 for the prediction set. Moreover, shikimic acid concentration estimates from hyperspectral images were visualized on the prediction maps by spectral features, which could help in developing a simple multispectral imaging instrument for non-destructive phenotyping. Specific physiological effects of glyphosate affected the photochemical processes of maize, which induced substantial changes in chlorophyll fluorescence characteristics. A new data-driven method, combining mean fluorescence parameters and featuring a screening approach, provided a satisfactory relationship between fluorescence parameters and shikimic acid content. The glyphosate-tolerant transgenic plants can be identified with the developed discrimination model established on important wavelengths or sensitive fluorescence parameters 6 days after glyphosate treatment. The overall results indicated that both hyperspectral imaging and chlorophyll fluorescence imaging techniques could provide useful tools for stress phenotyping in maize breeding programs and could enable the detection and evaluation of superior genotypes, such as glyphosate tolerance, with a non-destructive high-throughput technique.

Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers.

PubMed

dos Santos, Fábio Monteiro; Gonçalves, José Carlos Saraiva; Caminha, Ricardo; da Silveira, Gabriel Estolano; Neves, Claúdia Silvana de Miranda; Gram, Karla Regina da Silva; Ferreira, Carla Teixeira; Jacqmin, Philippe; Noël, François

2009-10-01

This study was undertaken to model the relationship between clonazepam plasma concentrations and a central nervous system adverse effect (impairment of the psychomotor performance) following the oral administration of immediate-release tablets of clonazepam in healthy volunteers. Such a (P)pharmacokinetic/(P)pharmacodynamic (PK/PD) study is important to interpret properly the consequences of determined levels of plasma concentrations of psychoactive therapeutic drugs reported to be involved in road-traffic accidents. Twenty-three male subjects received a single oral dose of 4 mg clonazepam. Plasma concentration, determined by on-line solid phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry, and psychomotor performance, quantified through the Digit Symbol Substitution Test, were monitored for 72 hours. A 2-compartment open model with first order absorption and lag-time better fitted the plasma clonazepam concentrations. Clonazepam decreased the psychomotor performance by 72 +/- 3.7% (observed maximum effect), 1.5 to 4 hours (25th-75th percentile) after drug administration. A simultaneous population PK/PD model based on a sigmoid Emax model with time-dependent tolerance described well the time course of effect. Such acute tolerance could minimize the risk of accident as a result of impairment of motor skill after a single dose of clonazepam. However, an individual analysis of the data revealed a great interindividual variation in the relationship between clonazepam effect and plasma concentration, indicating that the phenomenon of acute tolerance can be predicted at a population, but not individual, level.

Temperature tolerance of young-of-the-year cisco, Coregonus artedii

USGS Publications Warehouse

Edsall, Thomas A.; Colby, Peter J.

1970-01-01

Young-of-the-year ciscoes (Coregonus artedii) acclimated to 2, 5, 10, 20 and 25 C and tested for tolerance to high and low temperatures provide the first detailed description of the thermal tolerance of coregonids in North America. The upper ultimate lethal temperature of the young ciscoes was 26 C (6 C higher than the maximum sustained temperature tolerated by adult ciscoes in nature) and the ultimate lower lethal temperature approached 0 C (near that commonly tolerated in nature by adult ciscoes). The temperature of 26 C is slightly higher than the lowest ultimate upper lethal temperature recorded for North American freshwater fishes; however, published information on the depth distributions of fishes in the Great Lakes suggests that some of the other coregonids may be less tolerant of high temperatures than the cisco.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

PubMed

Nabors, Louis B; Fiveash, John B; Markert, James M; Kekan, Manasi S; Gillespie, George Y; Huang, Zhi; Johnson, Martin J; Meleth, Sreelatha; Kuo, Huichien; Gladson, Candece L; Fathallah-Shaykh, Hassan M

2010-03-01

To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Phase 1 dose-escalation clinical trial. Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

Interspecific variation in thermoregulation among three sympatric bats inhabiting a hot, semi-arid environment.

PubMed

Cory Toussaint, Dawn; McKechnie, Andrew E

2012-12-01

Bats in hot roosts experience some of the most thermally challenging environments of any endotherms, but little is known about how heat tolerance and evaporative cooling capacity vary among species. We investigated thermoregulation in three sympatric species (Nycteris thebaica, Taphozous mauritianus and Sauromys petrophilus) in a hot, semi-arid environment by measuring body temperature (T(b)), metabolic rate and evaporative water loss (EWL) at air temperatures (T(a)) of 10-42 °C. S. petrophilus was highly heterothermic with no clear thermoneutral zone, and exhibited rapid increases in EWL at high T(a) to a maximum of 23.7 ± 7.4 mg g⁻¹ h⁻¹ at T(a) ≈ 42 °C, with a concomitant maximum T(b) of 43.7 ± 1.0 °C. T. mauritianus remained largely normothermic at T(a)s below thermoneutrality and increased EWL to 14.7 ± 1.3 mg g⁻¹ h⁻¹ at T(a) ≈ 42 °C, with a maximum T(b) of 42.9 ± 1.6 °C. In N. thebaica, EWL began increasing at lower T (a) than in either of the other species and reached a maximum of 18.6 ± 2.1 mg g⁻¹ h⁻¹ at T(a) = 39.4 °C, with comparatively high maximum T(b) values of 45.0 ± 0.9 °C. Under the conditions of our study, N. thebaica was considerably less heat tolerant than the other two species. Among seven species of bats for which data on T(b) as well as roost temperatures in comparison to outside T(a) are available, we found limited evidence for a correlation between overall heat tolerance and the extent to which roosts are buffered from high T(a).

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours

PubMed Central

Bahleda, Rastislav; Hollebecque, Antoine; Varga, Andrea; Gazzah, Anas; Massard, Christophe; Deutsch, Eric; Amellal, Nadia; Farace, Françoise; Ould-Kaci, Mahmoud; Roux, Flavien; Marzin, Kristell; Soria, Jean-Charles

2015-01-01

Background: This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. Methods: In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). Results: The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade ⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. Conclusions: MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours. PMID:26512876

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

23 CFR 658.17 - Weight.

Code of Federal Regulations, 2012 CFR

2012-04-01

... the bridge formula. (c) The maximum gross weight upon any one axle, including any one axle of a group... following formula, referred to as the Bridge Gross Weight Formula: EC14OC91.012 except that two consecutive... derived from the Bridge Formula, up to a maximum of 80,000 pounds, including all enforcement tolerances...

23 CFR 658.17 - Weight.

Code of Federal Regulations, 2011 CFR

2011-04-01

... the bridge formula. (c) The maximum gross weight upon any one axle, including any one axle of a group... following formula, referred to as the Bridge Gross Weight Formula: EC14OC91.012 except that two consecutive... derived from the Bridge Formula, up to a maximum of 80,000 pounds, including all enforcement tolerances...

Characterization of boron tolerant bacteria isolated from a fly ash dumping site for bacterial boron remediation.

PubMed

Edward Raja, Chellaiah; Omine, Kiyoshi

2013-08-01

Boron is an essential micronutrient for plants, but can above certain concentrations be toxic to living organisms. A major environmental concern is the removal of boron from contaminated water and fly ash. For this purpose, the samples were collected from a fly ash dumping site, Nagasaki prefecture, Japan. The chemical characteristics and heavy metal concentration of the samples were performed by X-ray fluorescent analysis and leaching test. For bacterial analysis, samples were collected in sterile plastic sheets and isolation was carried out by serial dilution method. The boron tolerant isolates that showed values of maximum inhibitory concentration toward boron ranging from 100 to 260 mM level were screened. Based on 16S rRNA sequencing and phylogenetic analysis, the isolates were most closely related to the genera Bacillus, Lysinibacillus, Microbacterium and Ralstonia. The boron tolerance of these strains was also associated with resistant to several heavy metals, such as As (III), Cr (VI), Cd, Cu, Pb, Ni, Se (III) and Zn. Indeed, these strains were arsenic oxidizing bacteria confirmed by silver nitrate test. These strains exhibited their salt resistances ranging from 4 to 15 % were determined in Trypticase soy agar medium. The boron tolerant strains were capable of removing 0.1-2.0 and 2.7-3.7 mg l(-1) boron from the medium and fly ash at 168 h. Thus, we have successfully identified the boron tolerant and removal bacteria from a fly ash dumping site for boron remediation.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interference Fit Life Factors for Roller Bearings

NASA Technical Reports Server (NTRS)

Oswald, Fred B.; Zaretsky, Erwin V.; Poplawski, Joseph V.

2008-01-01

The effect of hoop stresses in reducing cylindrical roller bearing fatigue life was determined for various classes of inner ring interference fit. Calculations were performed for up to seven interference fit classes for each of ten bearing sizes. Each fit was taken at tightest, average and loosest values within the fit class for RBEC-5 tolerance, thus requiring 486 separate analyses. The hoop stresses were superimposed on the Hertzian principal stresses created by the applied radial load to calculate roller bearing fatigue life. The method was developed through a series of equations to calculate the life reduction for cylindrical roller bearings based on interference fit. All calculated lives are for zero initial bearing internal clearance. Any reduction in bearing clearance due to interference fit was compensated by increasing the initial (unmounted) clearance. Results are presented as tables and charts of life factors for bearings with light, moderate and heavy loads and interference fits ranging from extremely light to extremely heavy and for bearing accuracy class RBEC 5 (ISO class 5). Interference fits on the inner bearing ring of a cylindrical roller bearing can significantly reduce bearing fatigue life. In general, life factors are smaller (lower life) for bearings running under light load where the unfactored life is highest. The various bearing series within a particular bore size had almost identical interference fit life factors for a particular fit. The tightest fit at the high end of the RBEC-5 tolerance band defined in ANSI/ABMA shaft fit tables produces a life factor of approximately 0.40 for an inner-race maximum Hertz stress of 1200 MPa (175 ksi) and a life factor of 0.60 for an inner-race maximum Hertz stress of 2200 MPa (320 ksi). Interference fits also impact the maximum Hertz stress-life relation.

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

PubMed Central

Vlainić, Josipa; Jembrek, Maja Jazvinšćak; Vlainić, Toni; Štrac, Dubravka Švob; Peričić, Danka

2012-01-01

Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABAA receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABAA receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABAA receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of [3H]flunitrazepam binding sites. Results: A single (2 h) or repeated (2 h daily for 2 or 3 d) short-term exposure to zolpidem affected neither the maximum number of [3H]flunitrazepam binding sites nor the affinity. In both control and short-term zolpidem treated groups, addition of GABA (1 nmol/L–1 mmol/L) enhanced [3H]flunitrazepam binding in a concentration-dependent manner. The maximum enhancement of [3H]flunitrazepam binding in short-term zolpidem treated group was not significantly different from that in the control group. In contrast, long-term exposure to zolpidem resulted in significantly increase in the maximum number of [3H]flunitrazepam binding sites without changing the affinity. Furthermore, long-term exposure to zolpidem significantly decreased the ability of GABA to stimulate [3H]flunitrazepam binding. Conclusion: The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABAA receptors that could be related to the development of tolerance and dependence. PMID:22922343

Dynamics of leaf hydraulic conductance with water status: quantification and analysis of species differences under steady state

PubMed Central

Scoffoni, Christine; McKown, Athena D.; Rawls, Michael; Sack, Lawren

2012-01-01

Leaf hydraulic conductance (Kleaf) is a major determinant of photosynthetic rate in well-watered and drought-stressed plants. Previous work assessed the decline of Kleaf with decreasing leaf water potential (Ψleaf), most typically using rehydration kinetics methods, and found that species varied in the shape of their vulnerability curve, and that hydraulic vulnerability correlated with other leaf functional traits and with drought sensitivity. These findings were tested and extended, using a new steady-state evaporative flux method under high irradiance, and the function for the vulnerability curve of each species was determined individually using maximum likelihood for 10 species varying strongly in drought tolerance. Additionally, the ability of excised leaves to recover in Kleaf with rehydration was assessed, and a new theoretical framework was developed to estimate how rehydration of measured leaves may affect estimation of hydraulic parameters. As hypothesized, species differed in their vulnerability function. Drought-tolerant species showed shallow linear declines and more negative Ψleaf at 80% loss of Kleaf (P80), whereas drought-sensitive species showed steeper, non-linear declines, and less negative P80. Across species, the maximum Kleaf was independent of hydraulic vulnerability. Recovery of Kleaf after 1 h rehydration of leaves dehydrated below their turgor loss point occurred only for four of 10 species. Across species without recovery, a more negative P80 correlated with the ability to maintain Kleaf through both dehydration and rehydration. These findings indicate that resistance to Kleaf decline is important not only in maintaining open stomata during the onset of drought, but also in enabling sustained function during drought recovery. PMID:22016424

Growth characterization of individual rye sourdough bacteria by isothermal microcalorimetry.

PubMed

Mihhalevski, A; Sarand, I; Viiard, E; Salumets, A; Paalme, T

2011-02-01

The present work tests the feasibility of the isothermal microcalorimetry method to study the performance of individual lactic acid bacteria during solid-state fermentation in rye sourdough. Another aim was to elucidate the key factors leading to the formation of different microbial consortia in laboratory and industrial sourdough during continuous backslopping propagation. Strains of the individual LAB isolated from industrial and laboratory sourdough cycle were grown in 10 kGy irradiated rye dough in vials of an isothermal calorimeter and the power-time curves were obtained. Sugars, organic acids and free amino acids in the sourdough were measured. The OD-time curves of the LAB strains during growth in flour extract or MRS (De Man, Rogosa and Sharpe) broth were also determined. The maximum specific growth rates of Lactobacillus sakei, Lactobacillus brevis, Lactobacillus curvatus and Leuconostoc citreum strains that dominated in backslopped laboratory sourdough were higher than those of Lactobacillus helveticus, Lactobacillus panis, Lactobacillus vaginalis, Lactobacillus casei and Lactobacillus pontis strains originating from industrial sourdough. Industrial strains had higher specific growth rates below pH 4·8. It was supposed that during long-run industrial backslopping processes, the oxygen sensitive species start to dominate because of the O(2) protective effect of rye sourdough. Measurements of the power-time curves revealed that the LAB strains dominating in the industrial sourdough cycle had better acid tolerance but lower maximum growth rate and oxygen tolerance than species isolated from a laboratory sourdough cycle. Isothermal microcalorimetry combined with chemical analysis is a powerful method for characterization of sourdough fermentation process and determination of growth characteristics of individual bacteria in sourdough. © 2010 The Authors. Journal of Applied Microbiology © 2010 The Society for Applied Microbiology.

A verified design of a fault-tolerant clock synchronization circuit: Preliminary investigations

NASA Technical Reports Server (NTRS)

Miner, Paul S.

1992-01-01

Schneider demonstrates that many fault tolerant clock synchronization algorithms can be represented as refinements of a single proven correct paradigm. Shankar provides mechanical proof that Schneider's schema achieves Byzantine fault tolerant clock synchronization provided that 11 constraints are satisfied. Some of the constraints are assumptions about physical properties of the system and cannot be established formally. Proofs are given that the fault tolerant midpoint convergence function satisfies three of the constraints. A hardware design is presented, implementing the fault tolerant midpoint function, which is shown to satisfy the remaining constraints. The synchronization circuit will recover completely from transient faults provided the maximum fault assumption is not violated. The initialization protocol for the circuit also provides a recovery mechanism from total system failure caused by correlated transient faults.

Flaw tolerance promoted by dissipative deformation mechanisms between material building blocks

NASA Astrophysics Data System (ADS)

Verho, Tuukka; Buehler, Markus J.

2014-09-01

Novel high-performance composite materials often draw inspiration from natural materials such as bone or mollusc shells. A prime feature of such composites is that they are, like their natural counterparts, quasibrittle. They are tolerant to material flaws up to a certain characteristic flaw-tolerant size scale, exhibiting high strength and toughness, but start to behave in a brittle manner when sufficiently large flaws are present. Here, we establish that better flaw tolerance can be achieved by maximizing fracture toughness relative to the maximum elastic energy available in the material, and we demonstrate this concept with simple two-dimensional coarse-grained simulations where the transition from brittle to quasibrittle behaviour is examined.

Tolerance analyses of a quadrupole magnet for advanced photon source upgrade

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

Liu, J., E-mail: Jieliu@aps.anl.gov; Jaski, M., E-mail: jaski@aps.anl.gov; Borland, M., E-mail: borland@aps.anl.gov

2016-07-27

Given physics requirements, the mechanical fabrication and assembly tolerances for storage ring magnets can be calculated using analytical methods [1, 2]. However, this method is not easy for complicated magnet designs [1]. In this paper, a novel method is proposed to determine fabrication and assembly tolerances consistent with physics requirements, through a combination of magnetic and mechanical tolerance analyses. In this study, finite element analysis using OPERA is conducted to estimate the effect of fabrication and assembly errors on the magnetic field of a quadrupole magnet and to determine the allowable tolerances to achieve the specified magnetic performances. Based onmore » the study, allowable fabrication and assembly tolerances for the quadrupole assembly are specified for the mechanical design of the quadrupole magnet. Next, to achieve the required assembly level tolerances, mechanical tolerance stackup analyses using a 3D tolerance analysis package are carried out to determine the part and subassembly level fabrication tolerances. This method can be used to determine the tolerances for design of other individual magnets and of magnet strings.« less

40 CFR 180.1052 - 2,2,5-trimethyl-3-dichloro-acetyl-1,3-oxazolidine; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false 2,2,5-trimethyl-3-dichloro-acetyl-1,3... Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR... diisobutylthiocarbamate applied to corn fields before the corn plants emerge from the soil with a maximum of 0.5 pound of...

Isolation of a lead tolerant novel bacterial species, Achromobacter sp. TL-3: assessment of bioflocculant activity.

PubMed

Batta, Neha; Subudhi, Sanjukta; Lal, Banwari; Devi, Arundhuti

2013-11-01

Lead is one of the four heavy metals that has a profound damaging effects on human health. In the recent past there has been an increasing global concern for development of sustainable bioremediation technologies for detoxification of lead contaminant. Present investigation highlights for lead biosorption by a newly isolated novel bacterial species; Achromobacter sp. TL-3 strain, isolated from activated sludge samples contaminated with heavy metals (collected from oil refinery, Assam, North-East India). For isolation of lead tolerant bacteria, sludge samples were enriched into Luria Broth medium supplemented separately with a range of lead nitrate; 250, 500, 750, 1000, 1250 and 1500 ppm respectively. The bacterial consortium that could tolerate 1500 ppm of lead nitrate was selected further for purification of lead tolerant bacterial isolates. Purified lead tolerant bacterial isolates were then eventually inoculated into production medium supplemented with ethanol and glycerol as carbon and energy source to investigate for bioflocculant production. Bioflocculant production was estimated by monitoring the potential of lead tolerant bacterial isolate to flocculate Kaolin clay in presence of 1% CaCl2. Compared to other isolates, TL-3 isolate demonstrated for maximum bioflocculant activity of 95% and thus was identified based on 16S rRNA gene sequence analysis. TL3 isolate revealed maximum homology (98%) with Achromobacter sp. and thus designated as Achromobacter sp. TL-3. Bioflocculant activity of TL-3 isolate was correlated with the change in pH and growth. Achromobacter sp. TL-3 has significant potential for lead biosorption and can be effectively employed for detoxification of lead contaminated waste effluents/waste waters.

Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects.

PubMed

Kim, Bo-Hyung; Kim, Jung-Ryul; Lim, Kyoung Soo; Shin, Hyun-Suk; Yoon, Seo Hyun; Cho, Joo-Youn; Jang, In-Jin; Shin, Sang-Goo; Yu, Kyung-Sang

2012-12-01

Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix(®)) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX(®)), has recently been developed. This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects. This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study. The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (I(max)) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

Resilience of rice (Oryza spp.) pollen germination and tube growth to temperature stress.

PubMed

Coast, Onoriode; Murdoch, Alistair J; Ellis, Richard H; Hay, Fiona R; Jagadish, Krishna S V

2016-01-01

Resilience of rice cropping systems to potential global climate change will partly depend on the temperature tolerance of pollen germination (PG) and tube growth (PTG). Pollen germination of high temperature-susceptible Oryza glaberrima Steud. (cv. CG14) and Oryza sativa L. ssp. indica (cv. IR64) and high temperature-tolerant O. sativa ssp. aus (cv. N22), was assessed on a 5.6-45.4 °C temperature gradient system. Mean maximum PG was 85% at 27 °C with 1488 μm PTG at 25 °C. The hypothesis that in each pollen grain, the minimum temperature requirements (Tn ) and maximum temperature limits (Tx ) for germination operate independently was accepted by comparing multiplicative and subtractive probability models. The maximum temperature limit for PG in 50% of grains (Tx(50) ) was the lowest (29.8 °C) in IR64 compared with CG14 (34.3 °C) and N22 (35.6 °C). Standard deviation (sx ) of Tx was also low in IR64 (2.3 °C) suggesting that the mechanism of IR64's susceptibility to high temperatures may relate to PG. Optimum germination temperatures and thermal times for 1 mm PTG were not linked to tolerating high temperatures at anthesis. However, the parameters Tx(50) and sx in the germination model define new pragmatic criteria for successful and resilient PG, preferable to the more traditional cardinal (maximum and minimum) temperatures. © 2014 John Wiley & Sons Ltd.

Systematic review: effective management strategies for lactose intolerance.

PubMed

Shaukat, Aasma; Levitt, Michael D; Taylor, Brent C; MacDonald, Roderick; Shamliyan, Tatyana A; Kane, Robert L; Wilt, Timothy J

2010-06-15

Lactose intolerance resulting in gastrointestinal symptoms is a common health concern. Diagnosis and management of this condition remain unclear. To assess the maximum tolerable dose of lactose and interventions for reducing symptoms of lactose intolerance among persons with lactose intolerance and malabsorption. Multiple electronic databases, including MEDLINE and the Cochrane Library, for trials published in English from 1967 through November 2009. Randomized, controlled trials of individuals with lactose intolerance or malabsorption. Three investigators independently reviewed articles, extracted data, and assessed study quality. 36 unique randomized studies (26 on lactase- or lactose-hydrolyzed milk supplements, lactose-reduced milk, or tolerable doses of lactose; 7 on probiotics; 2 on incremental lactose administration for colonic adaptation; and 1 on another agent) met inclusion criteria. Moderate-quality evidence indicated that 12 to 15 g of lactose (approximately 1 cup of milk) is well tolerated by most adults. Evidence was insufficient that lactose-reduced solution or milk with a lactose content of 0 to 2 g, compared with greater than 12 g, is effective in reducing symptoms of lactose intolerance. Evidence for probiotics, colonic adaptation, and other agents was also insufficient. Most studies evaluated persons with lactose malabsorption rather than lactose intolerance. Variation in enrollment criteria, outcome reporting, and the composition and dosing of studied agents precluded pooling of results and limited interpretation. Most individuals with presumed lactose intolerance or malabsorption can tolerate 12 to 15 g of lactose. Additional studies are needed to determine the effectiveness of lactose intolerance treatment.

Evaluation of Pyrolysis Oil as Carbon Source for Fungal Fermentation

PubMed Central

Dörsam, Stefan; Kirchhoff, Jennifer; Bigalke, Michael; Dahmen, Nicolaus; Syldatk, Christoph; Ochsenreither, Katrin

2016-01-01

Pyrolysis oil, a complex mixture of several organic compounds, produced during flash pyrolysis of organic lignocellulosic material was evaluated for its suitability as alternative carbon source for fungal growth and fermentation processes. Therefore several fungi from all phyla were screened for their tolerance toward pyrolysis oil. Additionally Aspergillus oryzae and Rhizopus delemar, both established organic acid producers, were chosen as model organisms to investigate the suitability of pyrolysis oil as carbon source in fungal production processes. It was observed that A. oryzae tolerates pyrolysis oil concentrations between 1 and 2% depending on growth phase or stationary production phase, respectively. To investigate possible reasons for the low tolerance level, eleven substances from pyrolysis oil including aldehydes, organic acids, small organic compounds and phenolic substances were selected and maximum concentrations still allowing growth and organic acid production were determined. Furthermore, effects of substances to malic acid production were analyzed and compounds were categorized regarding their properties in three groups of toxicity. To validate the results, further tests were also performed with R. delemar. For the first time it could be shown that small amounts of phenolic substances are beneficial for organic acid production and A. oryzae might be able to degrade isoeugenol. Regarding pyrolysis oil toxicity, 2-cyclopenten-1-on was identified as the most toxic compound for filamentous fungi; a substance never described for anti-fungal or any other toxic properties before and possibly responsible for the low fungal tolerance levels toward pyrolysis oil. PMID:28066378

Evaluation of Pyrolysis Oil as Carbon Source for Fungal Fermentation.

PubMed

Dörsam, Stefan; Kirchhoff, Jennifer; Bigalke, Michael; Dahmen, Nicolaus; Syldatk, Christoph; Ochsenreither, Katrin

2016-01-01

Pyrolysis oil, a complex mixture of several organic compounds, produced during flash pyrolysis of organic lignocellulosic material was evaluated for its suitability as alternative carbon source for fungal growth and fermentation processes. Therefore several fungi from all phyla were screened for their tolerance toward pyrolysis oil. Additionally Aspergillus oryzae and Rhizopus delemar , both established organic acid producers, were chosen as model organisms to investigate the suitability of pyrolysis oil as carbon source in fungal production processes. It was observed that A. oryzae tolerates pyrolysis oil concentrations between 1 and 2% depending on growth phase or stationary production phase, respectively. To investigate possible reasons for the low tolerance level, eleven substances from pyrolysis oil including aldehydes, organic acids, small organic compounds and phenolic substances were selected and maximum concentrations still allowing growth and organic acid production were determined. Furthermore, effects of substances to malic acid production were analyzed and compounds were categorized regarding their properties in three groups of toxicity. To validate the results, further tests were also performed with R. delemar . For the first time it could be shown that small amounts of phenolic substances are beneficial for organic acid production and A. oryzae might be able to degrade isoeugenol. Regarding pyrolysis oil toxicity, 2-cyclopenten-1-on was identified as the most toxic compound for filamentous fungi; a substance never described for anti-fungal or any other toxic properties before and possibly responsible for the low fungal tolerance levels toward pyrolysis oil.

Thermal tolerance affects mutualist attendance in an ant-plant protection mutualism

PubMed Central

Fitzpatrick, Ginny; Lanan, Michele C.; Bronstein, Judith L.

2014-01-01

Mutualism is an often-complex interaction among multiple species, each of which may respond differently to abiotic conditions. The effects of temperature on the formation, dissolution, and success of these and other species interactions remain poorly understood. We studied the thermal ecology of the mutualism between the cactus Ferocactus wislizeni and its ant defenders (Forelius pruinosus, Crematogaster opuntiae, Solenopsis aurea, and Solenopsis xyloni) in the Sonoran Desert, USA. The ants are attracted to extrafloral nectar produced by the plants and in exchange protect the plants from herbivores; there is a hierarchy of mutualist effectiveness based on aggression toward herbivores. We determined the relationship between temperature and ant activity on plants, the thermal tolerance of each ant species, and ant activity in relation to the thermal environment of plants. Temperature played a role in determining which species interact as mutualists. Three of the four ant species abandoned the plants during the hottest part of the day (up to 40°C), returning when surface temperature began to decrease in the afternoon. The least effective ant mutualist, F. pruinosus, had a significantly higher critical thermal maximum than the other three species, was active across the entire range of plant surface temperatures observed (13.8-57.0°C), and visited plants that reached the highest temperatures. F. pruinosus occupied some plants full-time and invaded plants occupied by more dominant species when those species were thermally excluded. Combining data on thermal tolerance and mutualist effectiveness provides a potentially powerful tool for predicting the effects of temperature on mutualisms and mutualistic species. PMID:25012597

The Effects of Metabolic Work Rate and Ambient Environment on Physiological Tolerance Times While Wearing Explosive and Chemical Personal Protective Equipment

PubMed Central

Costello, Joseph T.; Stewart, Kelly L.; Stewart, Ian B.

2015-01-01

This study evaluated the physiological tolerance times when wearing explosive and chemical (>35 kg) personal protective equipment (PPE) in simulated environmental extremes across a range of differing work intensities. Twelve healthy males undertook nine trials which involved walking on a treadmill at 2.5, 4, and 5.5 km·h−1 in the following environmental conditions, 21, 30, and 37°C wet bulb globe temperature (WBGT). Participants exercised for 60 min or until volitional fatigue, core temperature reached 39°C, or heart rate exceeded 90% of maximum. Tolerance time, core temperature, skin temperature, mean body temperature, heart rate, and body mass loss were measured. Exercise time was reduced in the higher WBGT environments (WBGT37 < WBGT30 < WBGT21; P < 0.05) and work intensities (5.5 < 4 < 2.5 km·h−1; P < 0.001). The majority of trials (85/108; 78.7%) were terminated due to participant's heart rate exceeding 90% of their maximum. A total of eight trials (7.4%) lasted the full duration. Only nine (8.3%) trials were terminated due to volitional fatigue and six (5.6%) due to core temperatures in excess of 39°C. These results demonstrate that physiological tolerance times are influenced by the external environment and workload and that cardiovascular strain is the limiting factor to work tolerance when wearing this heavy multilayered PPE. PMID:25866818

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.

Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose.

PubMed

Doyle, G; Furey, S; Berlin, R; Cooper, S; Jayawardena, S; Ashraf, E; Baird, L

1999-07-01

Delineation of non-steroidal anti-inflammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies which demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a propionic acid NSAID, has, in most such studies, exhibited a favourable profile in terms of gastrointestinal bleeding. Since 1984, ibuprofen has been available as a non-prescription analgesic/antipyretic with a limit of 1200 mg/day for 10 days of continuous use. Trials and spontaneously reported adverse experiences suggest that gastrointestinal symptoms and bleeding are rare. This study prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum non-prescription dose and duration of ibuprofen use in healthy subjects representative of a non-prescription analgesic user population. Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413, 16% with placebo vs. 161 out of 833, 19% with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by >/= 1% of subjects were: dyspepsia, abdominal pain, nausea, diarrhoea, flatulence, and constipation. Seventeen (1.4%) subjects had positive occult blood tests: their frequency was comparable between treatments. When used as directed to treat episodic pain, non-prescription ibuprofen at the maximum dose of 1200 mg/day for 10 days, is well-tolerated.

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

36 CFR 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

Reaction time in pilots during intervals of high sustained g.

PubMed

Truszczynski, Olaf; Lewkowicz, Rafal; Wojtkowiak, Mieczyslaw; Biernacki, Marcin P

2014-11-01

An important problem for pilots is visual disturbances occurring under +Gz acceleration. Assessment of the degree of intensification of these disturbances is generally accepted as the acceleration tolerance level (ATL) criterion determined in human centrifuges. The aim of this research was to evaluate the visual-motor responses of pilots during rapidly increasing acceleration contained in cyclic intervals of +6 Gz to the maximum ATL. The study involved 40 male pilots ages 32-41 yr. The task was a quick and faultless response to the light stimuli presented on a light bar during exposure to acceleration until reaching the ATL. Simple response time (SRT) measurements were performed using a visual-motor analysis system throughout the exposures which allowed assessment of a pilot's ATL. There were 29 pilots who tolerated the initial phase of interval acceleration and achieved +6 Gz, completing the test at ATL. Relative to the control measurements, the obtained results indicate a significant effect of the applied acceleration on response time. SRT during +6 Gz exposure was not significantly longer compared with the reaction time between each of the intervals. SRT and erroneous reactions indicated no statistically significant differences between the "lower" and "higher" ATL groups. SRT measurements over the +6-Gz exposure intervals did not vary between "lower" and "higher" ATL groups and, therefore, are not useful in predicting pilot performance. The gradual exposure to the maximum value of +6 Gz with exposure to the first three intervals on the +6-Gz plateau effectively differentiated pilots.

Impact of left ventricular assist device speed adjustment on exercise tolerance and markers of wall stress.

PubMed

Hayward, Christopher S; Salamonsen, Robert; Keogh, Anne M; Woodard, John; Ayre, Peter; Prichard, Roslyn; Kotlyar, Eugene; Macdonald, Peter S; Jansz, Paul; Spratt, Phillip

2015-09-01

Left ventricular assist devices are crucial in rehabilitation of patients with end-stage heart failure. Whether cardiopulmonary function is enhanced with higher pump output is unknown. 10 patients (aged 39±16 years, mean±SD) underwent monitored adjustment of pump speed to determine minimum safe low speed and maximum safe high speed at rest. Patients were then randomized to these speed settings and underwent three 6-minute walk tests (6MWT) and symptom-limited cardiopulmonary stress tests (CPX) on separate days. Pump speed settings (low, normal and high) resulted in significantly different resting pump flows of 4.43±0.6, 5.03±0.94, and 5.72±1.2 l/min (P<.001). There was a significant enhancement of pump flows (greater at higher speed settings) with exercise (P<0.05). Increased pump speed was associated with a trend to increased 6MWT distance (P=.10); and CPX exercise time (p=.27). Maximum workload achieved and peak oxygen consumption were significantly different comparing low to high pump speed settings only (P<.05). N-terminal-pro-B-type natriuretic peptide release was significantly reduced at higher pump speed with exercise (P<.01). We have found that alteration of pump speed setting resulted in significant variation in estimated pump flow. The high-speed setting was associated with lower natriuretic hormone release consistent with lower myocardial wall stress. This did not, however, improve exercise tolerance.

Optimal therapies of a virus replication model with pharmacological delays based on reverse transcriptase inhibitors and protease inhibitors

NASA Astrophysics Data System (ADS)

Pei, Yongzhen; Li, Changguo; Liang, Xiyin

2017-11-01

A short delay in the pharmacological effect on account of the time required for drug absorption, distribution, and penetration into target cells after application of any anti-viral drug, is defined by the pharmacological delay (Herz et al 1996 Proc. Natl Acad. Sci. USA 93 7247-51). In this paper, a virus replication model with Beddington-DeAngelis incidence rate and the pharmacological and intracellular delays is presented to describe the treatment to cure the virus infection. The optimal controls represent the efficiency of reverse transcriptase inhibitors and protease inhibitors in suppressing viral production and prohibiting new infections. Due to the fact that both the control and state variables contain delays, we derive a necessary conditions for our optimal problem. Based on these results, numerical simulations are implemented not only to show the optimal therapeutic schedules for different infection and release rates, but also to compare the effective of three treatment programs. Furthermore, comparison of therapeutic effects under different maximum tolerable dosages is shown. Our research indicates that (1) the proper and specific treatment program should be determined according to the infection rates of different virus particles; (2) the optimal combined drug treatment is the most efficient; (3) the appropriate proportion of medicament must be formulated during the therapy due to the non-monotonic relationship between maximum tolerable dosages and therapeutic effects; (4) the therapeutic effect is advantageous when the pharmacological delay is considered.

A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Siegel, Abby B.; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S.; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Flaig, Thomas W.; Tsai, Wei Yann; Wu, David P. H.; Lee, Valerie; Greenlee, Heather

2013-01-01

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests. PMID:23757319

Brushed permanent magnet DC MLC motor operation in an external magnetic field.

PubMed

Yun, J; St Aubin, J; Rathee, S; Fallone, B G

2010-05-01

Linac-MR systems for real-time image-guided radiotherapy will utilize the multileaf collimators (MLCs) to perform conformal radiotherapy and tumor tracking. The MLCs would be exposed to the external fringe magnetic fields of the linac-MR hybrid systems. Therefore, an experimental investigation of the effect of an external magnetic field on the brushed permanent magnet DC motors used in some MLC systems was performed. The changes in motor speed and current were measured for varying external magnetic field strengths up to 2000 G generated by an EEV electromagnet. These changes in motor characteristics were measured for three orientations of the motor in the external magnetic field, mimicking changes in motor orientations due to installation and/or collimator rotations. In addition, the functionality of the associated magnetic motor encoder was tested. The tested motors are used with the Varian 120 leaf Millennium MLC (Maxon Motor half leaf and full leaf motors) and the Varian 52 leaf MKII MLC (MicroMo Electronics leaf motor) including a carriage motor (MicroMo Electronics). In most cases, the magnetic encoder of the motors failed prior to any damage to the gearbox or the permanent magnet motor itself. This sets an upper limit of the external magnetic field strength on the motor function. The measured limits of the external magnetic fields were found to vary by the motor type. The leaf motor used with a Varian 52 leaf MKII MLC system tolerated up to 450 +/- 10 G. The carriage motor tolerated up to 2000 +/- 10 G field. The motors used with the Varian 120 leaf Millennium MLC system were found to tolerate a maximum of 600 +/- 10 G. The current Varian MLC system motors can be used for real-time image-guided radiotherapy coupled to a linac-MR system, provided the fringe magnetic fields at their locations are below the determined tolerance levels. With the fringe magnetic fields of linac-MR systems expected to be larger than the tolerance levels determined, some form of magnetic shielding would be required.

Thermal tolerances of fishes occupying groundwater and surface-water dominated streams

USGS Publications Warehouse

Farless, Nicole; Brewer, Shannon K.

2017-01-01

A thermal tolerance study mimicking different stream environments could improve our ecological understanding of how increasing water temperatures affect stream ectotherms and improve our ability to predict organism responses based on river classification schemes. Our objective was to compare the thermal tolerances of stream fishes of different habitat guilds among 3 exposure periods: critical thermal maximum (CTmax, increase of 2°C/h until loss of equilibrium [LOE] and death [D]), and 2 longer-term treatments (net daily increase of 1°C) that mimicked spring-fed (SF; 4°C daily increase) and non-spring-fed (NSF; 8°C daily increase) conditions. Fishes in the pelagic habitat guild had a 1°C higher average CTmax than benthic fishes. Thermal responses of species depended on exposure period with higher and increased variation in tolerances associated with the SF and NSF exposure periods. Logperch, Orangebelly Darter, Orangethroat Darter, and Southern Redbelly Dace were more sensitive to thermal increases regardless of SF or NSF treatment than were the 3 remaining species (Brook Silverside, Central Stoneroller, and Redspot Chub), which represented average thermal responses among the species tested. The 3 species that had a higher thermal response to CTmax-D (lethal endpoint of death) also were able to increase their tolerances more than other species in both SF and NSF treatments. Our data indicate finer guild designations may be useful for predicting thermal-response patterns. A diel thermal refuge increases the thermal responses of ectotherms to daily maxima, but the patterns across our SF and NSF treatments were similar suggesting minimum refuge temperatures may be more important than maximums. Nonetheless, stream temperature cooling over a 24-h period is important to ectotherm thermal tolerances, a result suggesting that sources of cooler water to streams might benefit from protection.

Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.

PubMed

Gidal, Barry E; 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

2016-10-25

To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. 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. 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. 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. NCT00518713 and NCT01160770. This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment. © 2016 American Academy of Neurology.

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

Identifying a maximum tolerated contour in two-dimensional dose-finding

PubMed Central

Wages, Nolan A.

2016-01-01

The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided. PMID:26910586

Evaluation of 14 Organic Solvents and Carriers for Screening Applications in Zebrafish Embryos and Larvae

PubMed Central

Maes, Jan; Verlooy, Lien; Buenafe, Olivia E.; de Witte, Peter A. M.; Esguerra, Camila V.; Crawford, Alexander D.

2012-01-01

Zebrafish are rapidly growing in popularity as an in vivo model system for chemical genetics, drug discovery, and toxicology, and more recently also for natural product discovery. Experiments involving the pharmacological evaluation of small molecules or natural product extracts in zebrafish bioassays require the effective delivery of these compounds to embryos and larvae. While most samples to be screened are first solubilized in dimethyl sulfoxide (DMSO), which is then diluted in the embryo medium, often this method is not sufficient to prevent the immediate or eventual precipitation of the sample. Certain compounds and extracts are also not highly soluble in DMSO. In such instances the use of carriers and/or other solvents might offer an alternative means to achieve the required sample concentration. Towards this end, we determined the maximum tolerated concentration (MTC) of several commonly used solvents and carriers in zebrafish embryos and larvae at various developmental stages. Solvents evaluated for this study included acetone, acetonitrile, butanone, dimethyl formamide, DMSO, ethanol, glycerol, isopropanol, methanol, polyethylene glycol (PEG-400), propylene glycol, and solketal, and carriers included albumin (BSA) and cyclodextrin (2-hydroxypropyl-beta-cyclodextrin, or HPBCD). This study resulted in the identification of polyethylene glycol (PEG400), propylene glycol, and methanol as solvents that were relatively well-tolerated over a range of developmental stages. In addition, our results showed that acetone was well-tolerated by embryos but not by larvae, and 1% cyclodextrin (HPBCD) was well-tolerated by both embryos and larvae, indicating the utility of this carrier for compound screening in zebrafish. However, given the relatively small differences (2–3 fold) between concentrations that are apparently safe and those that are clearly toxic, further studies – e.g. omics analyses –should be carried out to determine which cellular processes and signalling pathways are affected by any solvents and carriers that are used for small-molecule screens in zebrafish. PMID:23082109

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

PubMed Central

Adjei, Alex A.; Cohen, Roger B.; Franklin, Wilbur; Morris, Clive; Wilson, David; Molina, Julian R.; Hanson, Lorelei J.; Gore, Lia; Chow, Laura; Leong, Stephen; Maloney, Lara; Gordon, Gilad; Simmons, Heidi; Marlow, Allison; Litwiler, Kevin; Brown, Suzy; Poch, Gregory; Kane, Katie; Haney, Jerry; Eckhardt, S. Gail

2009-01-01

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. PMID:18390968

Overcoming the Practical Barriers to Spinal Cord Cell Transplantation for ALS

DTIC Science & Technology

2012-10-01

ABSTRACT: This grant will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Rigorous...Surgical Technique) will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Aim 2 (Graft...connected to a rigid needle of the same gauge as the floating cannula one – Figure 7) using the maximum volume/number of injections could result in

Integrated Data and Control Level Fault Tolerance Techniques for Signal Processing Computer Design

DTIC Science & Technology

1990-09-01

TOLERANCE TECHNIQUES FOR SIGNAL PROCESSING COMPUTER DESIGN G. Robert Redinbo I. INTRODUCTION High-speed signal processing is an important application of...techniques and mathematical approaches will be expanded later to the situation where hardware errors and roundoff and quantization noise affect all...detect errors equal in number to the degree of g(X), the maximum permitted by the Singleton bound [13]. Real cyclic codes, primarily applicable to

36 CFR § 1192.4 - Miscellaneous instructions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... General § 1192.4 Miscellaneous instructions. (a) Dimensional conventions. Dimensions that are not noted as minimum or maximum are absolute. (b) Dimensional tolerances. All dimensions are subject to conventional...

Avian thermoregulation in the heat: resting metabolism, evaporative cooling and heat tolerance in Sonoran Desert songbirds.

PubMed

Smith, Eric Krabbe; O'Neill, Jacqueline J; Gerson, Alexander R; McKechnie, Andrew E; Wolf, Blair O

2017-09-15

We examined thermoregulatory performance in seven Sonoran Desert passerine bird species varying in body mass from 10 to 70 g - lesser goldfinch, house finch, pyrrhuloxia, cactus wren, northern cardinal, Abert's towhee and curve-billed thrasher. Using flow-through respirometry, we measured daytime resting metabolism, evaporative water loss and body temperature at air temperatures ( T air ) between 30 and 52°C. We found marked increases in resting metabolism above the upper critical temperature ( T uc ), which for six of the seven species fell within a relatively narrow range (36.2-39.7°C), but which was considerably higher in the largest species, the curve-billed thrasher (42.6°C). Resting metabolism and evaporative water loss were minimal below the T uc and increased with T air and body mass to maximum values among species of 0.38-1.62 W and 0.87-4.02 g H 2 O h -1 , respectively. Body temperature reached maximum values ranging from 43.5 to 45.3°C. Evaporative cooling capacity, the ratio of evaporative heat loss to metabolic heat production, reached maximum values ranging from 1.39 to 2.06, consistent with known values for passeriforms and much lower than values in taxa such as columbiforms and caprimulgiforms. These maximum values occurred at heat tolerance limits that did not scale with body mass among species, but were ∼50°C for all species except the pyrrhuloxia and Abert's towhee (48°C). High metabolic costs associated with respiratory evaporation appeared to drive the limited heat tolerance in these desert passeriforms, compared with larger desert columbiforms and galliforms that use metabolically more efficient mechanisms of evaporative heat loss. © 2017. Published by The Company of Biologists Ltd.

76 FR 5780 - Determination of Regulated Status of Alfalfa Genetically Engineered for Tolerance to the...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-02

...] Determination of Regulated Status of Alfalfa Genetically Engineered for Tolerance to the Herbicide Glyphosate... for tolerance to the herbicide glyphosate based on APHIS' final environmental impact statement. FOR... regulated status of alfalfa genetically engineered for tolerance to the herbicide glyphosate based on an...

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

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

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

Relationship between fish size and upper thermal tolerance

USGS Publications Warehouse

Recsetar, Matthew S.; Zeigler, Matthew P.; Ward, David L.; Bonar, Scott A.; Caldwell, Colleen A.

2012-01-01

Using critical thermal maximum (CTMax) tests, we examined the relationship between upper temperature tolerances and fish size (fry-adult or subadult lengths) of rainbow trout Oncorhynchus mykiss (41-200-mm TL), Apache trout O. gilae apache (40-220-mm TL), largemouth bass Micropterus salmoides (72-266-mm TL), Nile tilapia Oreochromis niloticus (35-206-mm TL), channel catfish Ictalurus punctatus (62-264 mm-TL), and Rio Grande cutthroat trout O. clarkii virginalis (36-181-mm TL). Rainbow trout and Apache trout were acclimated at 18°C, Rio Grande cutthroat trout were acclimated at 14°C, and Nile tilapia, largemouth bass, and channel catfish were acclimated at 25°C, all for 14 d. Critical thermal maximum temperatures were estimated and data were analyzed using simple linear regression. There was no significant relationship (P > 0.05) between thermal tolerance and length for Nile tilapia (P = 0.33), channel catfish (P = 0.55), rainbow trout (P = 0.76), or largemouth bass (P = 0.93) for the length ranges we tested. There was a significant negative relationship between thermal tolerance and length for Rio Grande cutthroat trout (R2 = 0.412, P 2 = 0.1374, P = 0.028); however, the difference was less than 1°C across all lengths of Apache trout tested and about 1.3°C across all lengths of Rio Grande cutthroat trout tested. Because there was either no or at most a slight relationship between upper thermal tolerance and size, management and research decisions based on upper thermal tolerance should be similar for the range of sizes within each species we tested. However, the different sizes we tested only encompassed life stages ranging from fry to adult/subadult, so thermal tolerance of eggs, alevins, and larger adults should also be considered before making management decisions affecting an entire species.

40 CFR 180.2020 - Non-food determinations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Non-food determinations. 180.2020... TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From a Tolerance § 180.2020 Non-food determinations. The following pesticide...

40 CFR 180.2020 - Non-food determinations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Non-food determinations. 180.2020... TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From a Tolerance § 180.2020 Non-food determinations. The following pesticide...

40 CFR 180.2020 - Non-food determinations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Non-food determinations. 180.2020... TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From a Tolerance § 180.2020 Non-food determinations. The following pesticide...

40 CFR 180.2020 - Non-food determinations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Non-food determinations. 180.2020... TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From a Tolerance § 180.2020 Non-food determinations. The following pesticide...

40 CFR 180.2020 - Non-food determinations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Non-food determinations. 180.2020... TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From a Tolerance § 180.2020 Non-food determinations. The following pesticide...

Seasonal variation in thermal tolerance, oxygen consumption, antioxidative enzymes and non-specific immune indices of Indian hill trout, Barilius bendelisis (Hamilton, 1807) from central Himalaya, India.

PubMed

Sharma, Neeraj Kumar; Akhtar, M S; Pandey, Nityanand; Singh, Ravindra; Singh, Atul Kumar

2015-08-01

We studied the season dependent thermal tolerance, oxygen consumption, respiratory burst response and antioxidative enzyme activities in juveniles of Barilius bendelisis. The critical thermal maximum (CTmax), lethal thermal maximum (LTmax), critical thermal minimum (CTmin) and lethal thermal minimum (LTmin) were significantly different at five different seasons viz. winter (10.64°C), spring (16.25°C), summer (22.11°C), rainy (20.87°C) and autumn (17.77°C). The highest CTmax was registered in summer (36.02°C), and lowest CTmin was recorded during winter (2.77°C). Water temperature, dissolved oxygen and pH were strongly related to CTmax, LTmax, CTmin and LTmin suggesting seasonal acclimatization of B. bendelisis. The thermal tolerance polygon area of the B. bendelisis juveniles within the range of seasonal temperature (10.64-22.11°C) was calculated as 470.92°C(2). Oxygen consumption rate was significantly different (p<0.05) between seasons with maximum value during summer (57.66mgO2/kg/h) and lowest in winter (32.60mgO2/kg/h). Total white blood cell count including neutrophil and monocytes also showed significant difference (p<0.05) between seasons with maximum value during summer and minimum number in winter and were found correlated to temperature, dissolved oxygen, pH and respiratory burst activity. Respiratory burst activity of blood phagocytes significantly differed (p<0.05) among seasons with higher value during summer (0.163 OD540nm) and minimum in winter season (0.054 OD540nm). The activity of superoxide dismutase, catalase and glutathione-s-transferase both in liver and gill, also varied significantly (p<0.05) during different seasons. Overall results of this study suggest that multiple environmental factors play a role in seasonal acclimation in B. bendelisis, which modulate the thermal tolerance, oxygen consumption, respiratory burst activity and status of anti-oxidative potential in wild environment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cardiovascular responses to a high-volume continuous circuit resistance training protocol.

PubMed

Gotshalk, Lincoln A; Berger, Richard A; Kraemer, William J

2004-11-01

The purpose of this investigation was to determine the level of cardiovascular stress elicited by continuous and prolonged circuit resistance training (CRT). Each of the 11 men who volunteered as a subject were tested to determine oxygen consumption and heart rate responses to a submaximal and maximal treadmill protocol and a CRT session consisting of 10 exercises and 10 repetitions at 40% of 1 repetition maximum (1RM) for each station with 4.6 circuits performed. The physiological stress of the CRT in this study was evident by the sustained heart rate of more than 70% of maximum for 16.6 minutes, with the last 12 minutes at more than 80%. Despite the large anaerobic component in CRT, Vo(2) was sustained at 50% or more of maximum for the final 12 minutes. Treadmill running, involving large muscle groups, increased Vo(2) more rapidly than CRT, where alternating larger and smaller muscle groups were used. In addition, at the same Vo(2) heart rate differed significantly between the 2 modes of activity. Heart rate in CRT was higher (at 165) than the heart rate of 150 found during treadmill running at the same 50% Vo(2). Such workouts may be used in a training cycle in classical linear periodization or in a nonlinear program day targeting local muscular endurance under intense cardiorespiratory conditions, which may help individuals develop enhanced toleration of physiological environments where high cardiovascular demands and higher lactate concentrations are present.

Predicting one repetition maximum equations accuracy in paralympic rowers with motor disabilities.

PubMed

Schwingel, Paulo A; Porto, Yuri C; Dias, Marcelo C M; Moreira, Mônica M; Zoppi, Cláudio C

2009-05-01

Predicting one repetition maximum equations accuracy in paralympic rowers Resistance training intensity is prescribed using percentiles of the maximum strength, defined as the maximum tension generated for a muscle or muscular group. This value is found through the application of the one maximal repetition (1RM) test. One maximal repetition test demands time and still is not appropriate for some populations because of the risk it offers. In recent years, the prediction of maximal strength, through predicting equations, has been used to prevent the inconveniences of the 1RM test. The purpose of this study was to verify the accuracy of 12 1RM predicting equations for disabled rowers. Nine male paralympic rowers (7 one-leg amputated rowers and 2 cerebral paralyzed rowers; age, 30 +/- 7.9 years; height, 175.1 +/- 5.9 cm; weight, 69 +/- 13.6 kg) performed 1RM test for lying T-bar row and flat barbell bench press exercises to determine upper-body strength and leg press exercise to determine lower-body strength. One maximal repetition test was performed, and based on submaximal repetitions loads, several linear and exponential equations models were tested with regard of their accuracy. We did not find statistical differences for lying T-bar row and bench press exercises between measured and predicted 1RM values (p = 0.84 and 0.23 for lying T-bar row and flat barbell bench press, respectively); however, leg press exercise reached a high significant difference between measured and predicted values (p < 0.01). In conclusion, rowers with motor disabilities tolerate 1RM testing procedures, and predicting 1RM equations are accurate for bench press and lying T-bar row, but not for leg press, in this kind of athlete.

Phase I Study of Concomitant Pemetrexed and Cisplatin Plus External Beam Radiation Therapy in Patients with Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Carcinomas.

PubMed

Elquza, Emad; Babiker, Hani M; Howell, Krisha J; Kovoor, Andrew I; Brown, Thomas David; Patel, Hitendra; Malangone, Steven A; Borad, Mitesh J; Dragovich, Tomislav

2016-01-01

To establish the maximum tolerated dose (MTD) and safety profile of bi-weekly Pemetrexed (PEM) when combined with weekly cisplatin (CDDP) and standard dose external beam radiation (EBRT) in patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) carcinomas. We conducted an open label, single institution, phase I dose escalation study designed to evaluate up to 15-35 patients with advanced or metastatic esophageal and GEJ carcinomas. 10 patients were treated with bi-weekly PEM, weekly CDDP, and EBRT. The MTD of bi-weekly PEM was determined to be 500 mg/m(2).

Potato Annexin STANN1 Promotes Drought Tolerance and Mitigates Light Stress in Transgenic Solanum tuberosum L. Plants.

PubMed

Szalonek, Michal; Sierpien, Barbara; Rymaszewski, Wojciech; Gieczewska, Katarzyna; Garstka, Maciej; Lichocka, Malgorzata; Sass, Laszlo; Paul, Kenny; Vass, Imre; Vankova, Radomira; Dobrev, Peter; Szczesny, Pawel; Marczewski, Waldemar; Krusiewicz, Dominika; Strzelczyk-Zyta, Danuta; Hennig, Jacek; Konopka-Postupolska, Dorota

2015-01-01

Annexins are a family of calcium- and membrane-binding proteins that are important for plant tolerance to adverse environmental conditions. Annexins function to counteract oxidative stress, maintain cell redox homeostasis, and enhance drought tolerance. In the present study, an endogenous annexin, STANN1, was overexpressed to determine whether crop yields could be improved in potato (Solanum tuberosum L.) during drought. Nine potential potato annexins were identified and their expression characterized in response to drought treatment. STANN1 mRNA was constitutively expressed at a high level and drought treatment strongly increased transcription levels. Therefore, STANN1 was selected for overexpression analysis. Under drought conditions, transgenic potato plants ectopically expressing STANN1 were more tolerant to water deficit in the root zone, preserved more water in green tissues, maintained chloroplast functions, and had higher accumulation of chlorophyll b and xanthophylls (especially zeaxanthin) than wild type (WT). Drought-induced reductions in the maximum efficiency and the electron transport rate of photosystem II (PSII), as well as the quantum yield of photosynthesis, were less pronounced in transgenic plants overexpressing STANN1 than in the WT. This conferred more efficient non-photochemical energy dissipation in the outer antennae of PSII and probably more efficient protection of reaction centers against photooxidative damage in transgenic plants under drought conditions. Consequently, these plants were able to maintain effective photosynthesis during drought, which resulted in greater productivity than WT plants despite water scarcity. Although the mechanisms underlying this stress protection are not yet clear, annexin-mediated photoprotection is probably linked to protection against light-induced oxidative stress.

Potato Annexin STANN1 Promotes Drought Tolerance and Mitigates Light Stress in Transgenic Solanum tuberosum L. Plants

PubMed Central

Szalonek, Michal; Sierpien, Barbara; Rymaszewski, Wojciech; Gieczewska, Katarzyna; Garstka, Maciej; Lichocka, Malgorzata; Sass, Laszlo; Paul, Kenny; Vass, Imre; Vankova, Radomira; Dobrev, Peter; Szczesny, Pawel; Marczewski, Waldemar; Krusiewicz, Dominika; Strzelczyk-Zyta, Danuta; Hennig, Jacek; Konopka-Postupolska, Dorota

2015-01-01

Annexins are a family of calcium- and membrane-binding proteins that are important for plant tolerance to adverse environmental conditions. Annexins function to counteract oxidative stress, maintain cell redox homeostasis, and enhance drought tolerance. In the present study, an endogenous annexin, STANN1, was overexpressed to determine whether crop yields could be improved in potato (Solanum tuberosum L.) during drought. Nine potential potato annexins were identified and their expression characterized in response to drought treatment. STANN1 mRNA was constitutively expressed at a high level and drought treatment strongly increased transcription levels. Therefore, STANN1 was selected for overexpression analysis. Under drought conditions, transgenic potato plants ectopically expressing STANN1 were more tolerant to water deficit in the root zone, preserved more water in green tissues, maintained chloroplast functions, and had higher accumulation of chlorophyll b and xanthophylls (especially zeaxanthin) than wild type (WT). Drought-induced reductions in the maximum efficiency and the electron transport rate of photosystem II (PSII), as well as the quantum yield of photosynthesis, were less pronounced in transgenic plants overexpressing STANN1 than in the WT. This conferred more efficient non-photochemical energy dissipation in the outer antennae of PSII and probably more efficient protection of reaction centers against photooxidative damage in transgenic plants under drought conditions. Consequently, these plants were able to maintain effective photosynthesis during drought, which resulted in greater productivity than WT plants despite water scarcity. Although the mechanisms underlying this stress protection are not yet clear, annexin-mediated photoprotection is probably linked to protection against light-induced oxidative stress. PMID:26172952

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

PubMed

Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

2011-02-01

The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

Isothermal pumping analysis for high-altitude tethered balloons

PubMed Central

Kuo, Kirsty A.; Hunt, Hugh E. M.

2015-01-01

High-altitude tethered balloons have potential applications in communications, surveillance, meteorological observations and climate engineering. To maintain balloon buoyancy, power fuel cells and perturb atmospheric conditions, fluids could be pumped from ground level to altitude using the tether as a hose. This paper examines the pumping requirements of such a delivery system. Cases considered include delivery of hydrogen, sulfur dioxide (SO2) and powders as fluid-based slurries. Isothermal analysis is used to determine the variation of pressures and velocities along the pipe length. Results show that transport of small quantities of hydrogen to power fuel cells and maintain balloon buoyancy can be achieved at pressures and temperatures that are tolerable in terms of both the pipe strength and the current state of pumping technologies. To avoid solidification, transport of SO2 would require elevated temperatures that cannot be tolerated by the strength fibres in the pipe. While the use of particle-based slurries rather than SO2 for climate engineering can reduce the pipe size significantly, the pumping pressures are close to the maximum bursting pressure of the pipe. PMID:26543573

Isothermal pumping analysis for high-altitude tethered balloons.

PubMed

Kuo, Kirsty A; Hunt, Hugh E M

2015-06-01

High-altitude tethered balloons have potential applications in communications, surveillance, meteorological observations and climate engineering. To maintain balloon buoyancy, power fuel cells and perturb atmospheric conditions, fluids could be pumped from ground level to altitude using the tether as a hose. This paper examines the pumping requirements of such a delivery system. Cases considered include delivery of hydrogen, sulfur dioxide (SO2) and powders as fluid-based slurries. Isothermal analysis is used to determine the variation of pressures and velocities along the pipe length. Results show that transport of small quantities of hydrogen to power fuel cells and maintain balloon buoyancy can be achieved at pressures and temperatures that are tolerable in terms of both the pipe strength and the current state of pumping technologies. To avoid solidification, transport of SO2 would require elevated temperatures that cannot be tolerated by the strength fibres in the pipe. While the use of particle-based slurries rather than SO2 for climate engineering can reduce the pipe size significantly, the pumping pressures are close to the maximum bursting pressure of the pipe.

Can chilling tolerance of C 4 photosynthesis in Miscanthus be transferred to sugarcane?

DOE PAGES

Glowacka, Katarzyna; Ahmed, Aasifuddin; Sharma, Shailendra; ...

2015-07-29

Our goal is to investigate whether chilling tolerance of C 4 photosynthesis in Miscanthus can be transferred to sugarcane by hybridization. Net leaf CO 2 uptake (A sat) and we measured the maximum operating efficiency of photosystem II (Ф PSII) in warm conditions (25 °C/20 °C), and then during and following a chilling treatment of 10 °C/5 °C for 11 day in controlled environment chambers.

High Efficiency, Low EMI and Positioning Tolerant Wireless Charging of EVs

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

Chabaan, Rakan

The objective of this project is to develop, implement, and demonstrate a wireless power transfer (WPT) system that is capable of the following metrics: Total system efficiencies of more than 85 percent with minimum 20 cm coil-to-coil gap; System output power at least 6.6 kW; but design system up to 19.2 kW for future higher power study; Maximum lateral positioning tolerance achievable while meeting regulatory emission guidelines.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

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...

A two-dimensional biased coin design for dual-agent dose-finding trials.

PubMed

Sun, Zhichao; Braun, Thomas M

2015-12-01

Given the limited efficacy observed with single agents, there is growing interest in Phase I clinical trial designs that allow for identification of the maximum tolerated combination of two agents. Existing parametric designs may suffer from over- or under-parameterization. Thus, we have designed a nonparametric approach that can be easily understood and implemented for combination trials. We propose a two-stage adaptive biased coin design that extends existing methods for single-agent trials to dual-agent dose-finding trials. The basic idea of our design is to divide the entire trial into two stages and apply the biased coin design, with modification, in each stage. We compare the operating characteristics of our design to four competing parametric approaches via simulation in several numerical examples. Under all simulation scenarios we have examined, our method performs well in terms of identification of the maximum tolerated combination and allocation of patients relative to the performance of its competitors. In our design, stopping rule criteria and the distribution of the total sample size among the two stages are context-dependent, and both need careful consideration before adopting our design in practice. Efficacy is not a part of the dose-assignment algorithm, nor used to define the maximum tolerated combination. Our design inherits the favorable statistical properties of the biased coin design, is competitive with existing designs, and promotes patient safety by limiting patient exposure to toxic combinations whenever possible. © The Author(s) 2015.

Further evidence that a terminal drought tolerance QTL of pearl millet is associated with reduced salt uptake

PubMed Central

Sharma, Parbodh C.; Singh, Dhananjay; Sehgal, Deepmala; Singh, Gurbachan; Hash, C.T.; Yadav, Rattan S.

2014-01-01

Earlier, we established that a major drought tolerance QTL on linkage group 2 of pearl millet is also associated with reduced salt uptake and enhanced growth under salt stress. Present study was undertaken to re-assess the performance of drought tolerant (PRLT 2/89-33) and drought sensitive (H 77/833-2) parents along with two QTL-NILs (ICMR 01029 and ICMR 01040), under salinity stress specifically imposed during post-flowering growth stages when plants had developed their ion sinks in full. Time course changes in ionic accumulation and their compartmentalization in different plant parts was studied, specifically to monitor and capture changes conferred by the two alleles at this QTL, at small intervals. Amongst different plant parts, higher accumulation of toxic ion Na+ was recorded in roots. Further, the Na+ concentration in roots of the testcross hybrid of the drought-sensitive parent (H 77/833-2) reached its maximum at ECiw 15 dS m−1 within 24 h after salinity imposition, whereas it continued to increase with time in the testcross hybrids of the drought tolerant parent PRLT 2/89-33 as well as those of its QTL-NILs (ICMR 01029 and ICMR 01004) and reached at its maximum at 120 h stage. Comparison of differential distribution of toxic ions in individual leaves revealed that Na+ ions were not uniformly distributed in the leaves of the drought-tolerant parent and drought-tolerant QTL-NILs; but accumulated preferentially in the older leaves, whereas the hybrid of the drought-sensitive parent showed significantly higher Na+ concentration in all main stem leaves irrespective of their age. Dynamics of chlorophyll and proline concentration variation studied under salt stress at late flowering stages revealed a greater reduction, almost twice, in both leaf chlorophyll and proline concentrations in younger leaves in the hybrids of the sensitive parent as compared to the tolerant parent and QTL NILs. Imposition of salinity stress even at flowering stage affected the yield performance in pearl millet, wherein higher yield was recorded in drought tolerant parent and the two QTL-NILs compared to drought sensitive parent. PMID:24895469

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer

PubMed Central

Torkelson, Carolyn J.; Sweet, Erin; Martzen, Mark R.; Sasagawa, Masa; Wenner, Cynthia A.; Gay, Juliette; Putiri, Amy; Standish, Leanna J.

2012-01-01

Introduction. Orally administered preparations from the Trametes versicolor (Tv) mushroom have been hypothesized to improve immune response in women with breast cancer after standard chemotherapy and radiotherapy. Methods. A phase I, two-center, dose escalation study was done to determine the maximum tolerated dose of a Tv preparation when taken daily in divided doses for 6 weeks after recent completion of radiotherapy. Eleven participants were recruited and nine women completed the study. Each cohort was comprised of three participants given one of three doses of Tv (3, 6, or 9 grams). Immune data was collected pre- and postradiation, at 3 on-treatment time points and after a 3-week washout. Results. Nine adverse events were reported (7 mild, 1 moderate, and 1 severe), suggesting that Tv was well tolerated. Immunological results indicated trends in (1) increased lymphocyte counts at 6 and 9 grams/day; (2) increased natural killer cell functional activity at 6 grams/day; (3) dose-related increases in CD8+ T cells and CD19+ B cells , but not CD4+ T cells or CD16+56+ NK cells. Conclusion. These findings show that up to 9 grams/day of a Tv preparation is safe and tolerable in women with breast cancer in the postprimary treatment setting. This Tv preparation may improve immune status in immunocompromised breast cancer patients following standard primary oncologic treatment. PMID:22701186

Alternatives to Weight Tolerance Permits

DOT National Transportation Integrated Search

2000-10-01

A complex web of government regulations in the United States establishes maximum weights for vehicles on public roads. The primary purpose is to ensure compatibility of roadway design and operations with vehicle weight and dimensions. Of particular c...

Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer

PubMed Central

Conlon, Kevin C.; Lugli, Enrico; Welles, Hugh C.; Rosenberg, Steven A.; Fojo, Antonio Tito; Morris, John C.; Fleisher, Thomas A.; Dubois, Sigrid P.; Perera, Liyanage P.; Stewart, Donn M.; Goldman, Carolyn K.; Bryant, Bonita R.; Decker, Jean M.; Chen, Jing; Worthy, Tat'Yana A.; Figg, William D.; Peer, Cody J.; Sneller, Michael C.; Lane, H. Clifford; Yovandich, Jason L.; Creekmore, Stephen P.; Roederer, Mario; Waldmann, Thomas A.

2015-01-01

Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. PMID:25403209

Concentrations of gatifloxacin in plasma and urine and penetration into prostatic and seminal fluid, ejaculate, and sperm cells after single oral administrations of 400 milligrams to volunteers.

PubMed

Naber, C K; Steghafner, M; Kinzig-Schippers, M; Sauber, C; Sörgel, F; Stahlberg, H J; Naber, K G

2001-01-01

Gatifloxacin (GTX), a new fluoroquinolone with extended antibacterial activity, is an interesting candidate for the treatment of chronic bacterial prostatitis (CBP). Besides the antibacterial spectrum, the concentrations in the target tissues and fluids are crucial for the treatment of CBP. Thus, it was of interest to investigate its penetration into prostatic and seminal fluid. GTX concentrations in plasma, urine, ejaculate, prostatic and seminal fluid, and sperm cells were determined by a high-performance liquid chromatography method after oral intake of a single 400-mg dose in 10 male Caucasian volunteers in the fasting state. Simultaneous application of the renal contrast agent iohexol was used to estimate the maximal possible contamination of ejaculate and prostatic and seminal fluid by urine. GTX was well tolerated. The means (standard deviations) for the following parameters were as indicated: time to maximum concentration of drug in serum, 1.66 (0. 91) h; maximum concentration of drug in serum, 2.90 (0.39) microg/ml; area under the concentration-time curve from 0 to 24 h, 25.65 microg. h/ml; and half life, 7.2 (0.90) h. Within 12 h about 50% of the drug was excreted unchanged into the urine. The mean renal clearance was 169 ml/min. The gatifloxacin concentrations in ejaculate, seminal fluid, and prostatic fluid were in the range of the corresponding plasma concentrations which were 1.92 (0.27) microg/ml at approximately the same time point (4 h after drug intake). The concentrations in sperm cells (0.195, 0.076, and 0.011 microg/ml) could be determined in three subjects. The good penetration into prostatic and seminal fluid, the good tolerance, and the previously reported broad antibacterial spectrum suggest that GTX may be a good alternative for the treatment of chronic bacterial prostatitis. Clinical studies should be performed to confirm this assumption.

Concentrations of Gatifloxacin in Plasma and Urine and Penetration into Prostatic and Seminal Fluid, Ejaculate, and Sperm Cells after Single Oral Administrations of 400 Milligrams to Volunteers

PubMed Central

Naber, Christoph K.; Steghafner, Michaela; Kinzig-Schippers, Martina; Sauber, Christian; Sörgel, Fritz; Stahlberg, Hans-Jürgen; Naber, Kurt G.

2001-01-01

Gatifloxacin (GTX), a new fluoroquinolone with extended antibacterial activity, is an interesting candidate for the treatment of chronic bacterial prostatitis (CBP). Besides the antibacterial spectrum, the concentrations in the target tissues and fluids are crucial for the treatment of CBP. Thus, it was of interest to investigate its penetration into prostatic and seminal fluid. GTX concentrations in plasma, urine, ejaculate, prostatic and seminal fluid, and sperm cells were determined by a high-performance liquid chromatography method after oral intake of a single 400-mg dose in 10 male Caucasian volunteers in the fasting state. Simultaneous application of the renal contrast agent iohexol was used to estimate the maximal possible contamination of ejaculate and prostatic and seminal fluid by urine. GTX was well tolerated. The means (standard deviations) for the following parameters were as indicated: time to maximum concentration of drug in serum, 1.66 (0.91) h; maximum concentration of drug in serum, 2.90 (0.39) μg/ml; area under the concentration-time curve from 0 to 24 h, 25.65 μg · h/ml; and half life, 7.2 (0.90) h. Within 12 h about 50% of the drug was excreted unchanged into the urine. The mean renal clearance was 169 ml/min. The gatifloxacin concentrations in ejaculate, seminal fluid, and prostatic fluid were in the range of the corresponding plasma concentrations which were 1.92 (0.27) μg/ml at approximately the same time point (4 h after drug intake). The concentrations in sperm cells (0.195, 0.076, and 0.011 μg/ml) could be determined in three subjects. The good penetration into prostatic and seminal fluid, the good tolerance, and the previously reported broad antibacterial spectrum suggest that GTX may be a good alternative for the treatment of chronic bacterial prostatitis. Clinical studies should be performed to confirm this assumption. PMID:11120980

A simple spectrophotometric determination of meptyldinocap by its hydrolysis.

PubMed

Kurup, Sunita; Pillai, Ajai Kumar

2013-01-01

A simple spectrophotometric method is proposed for the determination of meptyldinocap (2,4-dinitro-6-octylphenyl crotonate). The method is based on the hydrolysis of meptyldinocap by hydroxylamine solution in alkaline medium to give 2,4-dinitro-6-octylphenol (2,4-DNOP), having maximum absorption at 380 nm. The reaction is found to be instantaneous in presence of ethanol. Beer's law is valid over the concentration range of 1.2-13 microg mL(-1) with molar absorptivity and Sandell's sensitivity of 3.22 x 10(6) L mol(-1) cm(-1) and 0.0001 microg cm(-2) respectively. The limit of detection and quantification were 0.0892 and 0.2703 microg mL(-1), respectively. The tolerance limits of interfering ions are discussed. All variables were studied in order to optimize the reaction conditions. The validity of the method was checked by its simultaneous determination in fruits and water samples and the results were statistically compared with those of a reference method by applying the Student's t-test and F-test.

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer.

PubMed

Marshall, John; Shapiro, Geoffrey I; Uttenreuther-Fischer, Martina; Ould-Kaci, Mahmoud; Stopfer, Peter; Gordon, Michael S

2013-02-01

To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. The MTD was determined from dose-limiting toxicities in the first cycle. Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

78 FR 32146 - Triforine; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-29

... America Holding Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act... triforine residues to be imported into the United States. III. Aggregate Risk Assessment and Determination... determination on aggregate exposure for triforine including exposure resulting from the tolerances established...

Aerothermal performance and damage tolerance of a Rene 41 metallic standoff thermal protection system at Mach 6.7

NASA Technical Reports Server (NTRS)

Avery, D. E.

1984-01-01

A flight-weight, metallic thermal protection system (TPS) model applicable to Earth-entry and hypersonic-cruise vehicles was subjected to multiple cycles of both radiant and aerothermal heating in order to evaluate its aerothermal performance, structural integrity, and damage tolerance. The TPS was designed for a maximum operating temperature of 2060 R and featured a shingled, corrugation-stiffened corrugated-skin heat shield of Rene 41, a nickel-base alloy. The model was subjected to 10 radiant heating tests and to 3 radiant preheat/aerothermal tests. Under radiant-heating conditions with a maximum surface temperature of 2050 R, the TPS performed as designed and limited the primary structure away from the support ribs to temperatures below 780 R. During the first attempt at aerothermal exposure, a failure in the panel-holder test fixture severely damaged the model. However, two radiant preheat/aerothermal tests were made with the damaged model to test its damage tolerance. During these tests, the damaged area did not enlarge; however, the rapidly increasing structural temperature measuring during these tests indicates that had the damaged area been exposed to aerodynamic heating for the entire trajectory, an aluminum burn-through would have occurred.

Best of both worlds: simultaneous high-light and shade-tolerance adaptations within individual leaves of the living stone Lithops aucampiae.

PubMed

Field, Katie J; George, Rachel; Fearn, Brian; Quick, W Paul; Davey, Matthew P

2013-01-01

"Living stones" (Lithops spp.) display some of the most extreme morphological and physiological adaptations in the plant kingdom to tolerate the xeric environments in which they grow. The physiological mechanisms that optimise the photosynthetic processes of Lithops spp. while minimising transpirational water loss in both above- and below-ground tissues remain unclear. Our experiments have shown unique simultaneous high-light and shade-tolerant adaptations within individual leaves of Lithops aucampiae. Leaf windows on the upper surfaces of the plant allow sunlight to penetrate to photosynthetic tissues within while sunlight-blocking flavonoid accumulation limits incoming solar radiation and aids screening of harmful UV radiation. Increased concentration of chlorophyll a and greater chlorophyll a:b in above-ground regions of leaves enable maximum photosynthetic use of incoming light, while inverted conical epidermal cells, increased chlorophyll b, and reduced chlorophyll a:b ensure maximum absorption and use of low light levels within the below-ground region of the leaf. High NPQ capacity affords physiological flexibility under variable natural light conditions. Our findings demonstrate unprecedented physiological flexibility in a xerophyte and further our understanding of plant responses and adaptations to extreme environments.

Differential responses of double petal and multi petal jasmine to shading: I. Photosynthetic characteristics and chloroplast ultrastructure.

PubMed

Deng, Yanming; Li, Congcong; Shao, Qingsong; Ye, Xiaoqing; She, Jianming

2012-06-01

A double petal (DP) and a multi petal (MP) type jasmine (Jasminum sambac Ait.) growth and flowering was known largely affected by different levels of irradiance. Here, our objective was to determine the effects of shade on photosynthesis related characteristics and chloroplast ultrastructure of these two types. In both types, net photosynthetic rate (Pn), stomatal conductance (g(s)) and transpiration rate increased with decreasing irradiance from 100% to 20%, while both maximum and variable fluorescence showed a steady increase, and photochemical and nonphotochemical quenching indexes declined. At each conducted time, chlorophyll a, b and carotenoids contents in DP type shaded leaves increased whereas those in MP type decreased at 5% irradiance (considered as extreme shade). The maximum photochemical efficiency of photosystem II of DP plants showed subtle changes but that of MP plants declined by shading thereafter 21 days of treatment. Observation of chloroplast ultrastructure showed its best development in the leaves of DP and MP types mostly from 50% to 20% irradiance (considered as weak and moderate shade, respectively). At each shade treatment, Pn, g(s) and water use efficiency of DP-jasmine were always higher than those of MP-jasmine, thus the shade tolerance ability of the former was higher than that of the latter. The results showed that full sunlight and 5% natural irradiance caused photoinhibition and light deficiency of jasmine plants respectively, and modulating chloroplast development by the more numbers of thylakoids and grana to contain more photosynthetic pigments is an important shade tolerance mechanism of DP type. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

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

Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu; Das, Shiva; Gu, Lin

2015-12-01

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standardmore » 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.« less

Oxygen dependence of upper thermal limits in fishes.

PubMed

Ern, Rasmus; Norin, Tommy; Gamperl, A Kurt; Esbaugh, Andrew J

2016-11-01

Temperature-induced limitations on the capacity of the cardiorespiratory system to transport oxygen from the environment to the tissues, manifested as a reduced aerobic scope (maximum minus standard metabolic rate), have been proposed as the principal determinant of the upper thermal limits of fishes and other water-breathing ectotherms. Consequently, the upper thermal niche boundaries of these animals are expected to be highly sensitive to aquatic hypoxia and other environmental stressors that constrain their cardiorespiratory performance. However, the generality of this dogma has recently been questioned, as some species have been shown to maintain aerobic scope at thermal extremes. Here, we experimentally tested whether reduced oxygen availability due to aquatic hypoxia would decrease the upper thermal limits (i.e. the critical thermal maximum, CT max ) of the estuarine red drum (Sciaenops ocellatus) and the marine lumpfish (Cyclopterus lumpus). In both species, CT max was independent of oxygen availability over a wide range of oxygen levels despite substantial (>72%) reductions in aerobic scope. These data show that the upper thermal limits of water-breathing ectotherms are not always linked to the capacity for oxygen transport. Consequently, we propose a novel metric for classifying the oxygen dependence of thermal tolerance; the oxygen limit for thermal tolerance (P CT max ), which is the water oxygen tension (Pw O 2 ) where an organism's CT max starts to decline. We suggest that this metric can be used for assessing the oxygen sensitivity of upper thermal limits in water-breathing ectotherms, and the susceptibility of their upper thermal niche boundaries to environmental hypoxia. © 2016. Published by The Company of Biologists Ltd.

Temperature and Leaf Osmotic Potential as Factors in the Acclimation of Photosynthesis to High Temperature in Desert Plants 1

PubMed Central

Seemann, Jeffrey R.; Downton, W. John S.; Berry, Joseph A.

1986-01-01

Seasonal changes in the high temperature limit for photosynthesis of desert winter annuals growing under natural conditions in Death Valley, California were studied using an assay based upon chlorophyll fluorescence. All species of this group were 6 to 9°C more tolerant of high temperature at the end of the growing season (May) than at its beginning (February). Over this same time period, the mean daily maximum air temperatures increased by 12°C. Laboratory studies have demonstrated that increases in thermal tolerance could be induced by increasing growth temperature alone. For plants growing under field conditions there was also a good correlation between the thermal tolerance of leaves and the osmotic potential of leaf water, indicating that increases in the concentrations of some small molecules might also confer increased thermal tolerance. Isolated chloroplast thylakoids subjected to increasing concentrations of sorbitol could be demonstrated to have increased thermal tolerance. PMID:16664743

Six-minute stepper test: a valid clinical exercise tolerance test for COPD patients

PubMed Central

Grosbois, JM; Riquier, C; Chehere, B; Coquart, J; Béhal, H; Bart, F; Wallaert, B; Chenivesse, C

2016-01-01

Introduction Exercise tolerance testing is an integral part of the pulmonary rehabilitation (PR) management of patients with chronic obstructive pulmonary disease (COPD). The 6-minute stepper test (6MST) is a new, well-tolerated, reproducible exercise test, which can be performed without any spatial constraints. Objective The aim of this study was to compare the results of the 6MST to those obtained during a 6-minute walk test (6MWT) and cardiopulmonary exercise testing (CPET) in a cohort of COPD patients. Methods Ninety-one COPD patients managed by outpatient PR and assessed by 6MST, 6MWT, and CPET were retrospectively included in this study. Correlations between the number of steps on the 6MST, the distance covered on the 6MWT, oxygen consumption, and power at the ventilatory threshold and at maximum effort during CPET were analyzed before starting PR, and the improvement on the 6MST and 6MWT was compared after PR. Results The number of steps on the 6MST was significantly correlated with the distance covered on the 6MWT (r=0.56; P<0.0001), the power at maximum effort (r=0.46; P<0.0001), and oxygen consumption at maximum effort (r=0.39; P<0.005). Performances on the 6MST and 6MWT were significantly improved after PR (570 vs 488 steps, P=0.001 and 448 vs 406 m, respectively; P<0.0001). Improvements of the 6MST and 6MWT after PR were significantly correlated (r=0.34; P=0.03). Conclusion The results of this study show that the 6MST is a valid test to evaluate exercise tolerance in COPD patients. The use of this test in clinical practice appears to be particularly relevant for the assessment of patients managed by home PR. PMID:27099483

Impact of glyphosate-tolerant soybean and glufosinate-tolerant corn production on herbicide losses in surface runoff.

PubMed

Shipitalo, Martin J; Malone, Robert W; Owens, Lloyd B

2008-01-01

Residual herbicides used in the production of soybean [Glycine max (L.) Merr] and corn (Zea mays L.) are often detected in surface runoff at concentrations exceeding their maximum contaminant levels (MCL) or health advisory levels (HAL). With the advent of transgenic, glyphosate-tolerant soybean and glufosinate-tolerant corn this concern might be reduced by replacing some of the residual herbicides with short half-life, strongly sorbed, contact herbicides. We applied both herbicide types to two chiseled and two no-till watersheds in a 2-yr corn-soybean rotation and at half rates to three disked watersheds in a 3-yr corn/soybean/wheat (Triticum aestivum L.)-red clover (Trifolium pratense L.) rotation and monitored herbicide losses in runoff water for four crop years. In soybean years, average glyphosate loss (0.07%) was approximately 1/7 that of metribuzin (0.48%) and about one-half that of alachlor (0.12%), residual herbicides it can replace. Maximum, annual, flow-weighted concentration of glyphosate (9.2 microg L(-1)) was well below its 700 microg L(-1) MCL and metribuzin (9.5 microg L(-1)) was well below its 200 microg L(-1) HAL, whereas alachlor (44.5 microg L(-1)) was well above its 2 microg L(-1) MCL. In corn years, average glufosinate loss (0.10%) was similar to losses of alachlor (0.07%) and linuron (0.15%), but about one-fourth that of atrazine (0.37%). Maximum, annual, flow-weighted concentration of glufosinate (no MCL) was 3.5 microg L(-1), whereas atrazine (31.5 microg L(-1)) and alachlor (9.8 microg L(-1)) substantially exceeded their MCLs of 3 and 2 microg L(-1), respectively. Regardless of tillage system, flow-weighted atrazine and alachlor concentrations exceeded their MCLs in at least one crop year. Replacing these herbicides with glyphosate and glufosinate can reduce the occurrence of dissolved herbicide concentrations in runoff exceeding drinking water standards.

An examination of the damage tolerance enhancement of carbon/epoxy using an outer lamina of spectra (R)

NASA Technical Reports Server (NTRS)

Lance, D. G.; Nettles, A. T.

1991-01-01

Low velocity instrumented impact testing was utilized to examine the effects of an outer lamina of ultra-high molecular weight polyethylene (Spectra) on the damage tolerance of carbon epoxy composites. Four types of 16-ply quasi-isotropic panels (0, +45, 90, -45) were tested. Some panels contained no Spectra, while others had a lamina of Spectra bonded to the top (impacted side), bottom, or both sides of the composite plates. The specimens were impacted with energies up to 8.5 J. Force time plots and maximum force versus impact energy graphs were generated for comparison purposes. Specimens were also subjected to cross-sectional analysis and compression after impact tests. The results show that while the Spectra improved the maximum load that the panels could withstand before fiber breakage, the Spectra seemingly reduced the residual strength of the composites.

Impact of Expiratory Strength Training in Amyotrophic Lateral Sclerosis

PubMed Central

Plowman, Emily K.; Watts, Stephanie A.; Tabor, Lauren; Robison, Raele; Gaziano, Joy; Domer, Amanda S.; Richter, Joel; Vu, Tuan; Gooch, Clifton

2016-01-01

Introduction We evaluated the feasibility and impact of Expiratory Muscle Strength Training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS). Methods 25 ALS patients participated in this delayed intervention open-label clinical trial. Following a lead-in period, patients completed a 5-week EMST protocol. Outcome measures included: maximum expiratory pressure (MEP), physiologic measures of swallow and cough, and Penetration-Aspiration Scale (PAS) scores. Results Of those participants who entered the active phase of the study (n=15), EMST was well tolerated and led to significant increases in MEPs and maximum hyoid displacement during swallowing post-EMST (P<0.05). No significant differences were observed for PAS scores or cough spirometry measures. Discussion EMST was feasible and well tolerated in this small cohort of ALS patients and led to improvements in expiratory force-generating pressures and swallow kinematics. Further investigation is warranted to confirm these preliminary findings. PMID:26599236

The effects of in-flight treadmill exercise on postflight orthostatic tolerance

NASA Technical Reports Server (NTRS)

Siconolfi, Steven F.; Charles, John B.

1992-01-01

In-flight aerobic exercise is thought to decrease the deconditioning effects of microgravity. Two deconditioning characteristics are the decreases in aerobic capacity (maximum O2 uptake) and an increased cardiovascular response to orthostatic stress (supine to standing). Changes in both parameters were examined after Shuttle flights of 8 to 11 days in astronauts who performed no in-flight exercise, a lower than normal volume of exercise, and a near-normal volume of exercise. The exercise regimen was a traditional continuous protocol. Maximum O2 uptake was maintained in astronauts who completed a near-normal exercise volume of in-flight exercise. Cardiovascular responses to stand test were equivocal among the groups. The use of the traditional exercise regimen as a means to maintain adequate orthostatic responses produced equivocal responses. A different exercise prescription may be more effective in maintaining both exercise capacity and orthostatic tolerance.

Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma.

PubMed

Hu, Wei; Wang, Wei; Yang, Peinong; Zhou, Chao; Yang, Weifang; Wu, Bo; Lu, Hongsheng; Yang, Haihua

2015-01-01

Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patients with NPC. Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated.

Deciphering adverse effects of heavy metals on diverse wheat germplasm on irrigation with urban wastewater of mixed municipal-industrial origin.

PubMed

Ali, Zeshan; Mujeeb-Kazi, Abdul; Quraishi, Umar Masood; Malik, Riffat Naseem

2018-04-25

The current study provides one of the first attempts to identify tolerant, moderately sensitive, and highly sensitive wheat genotypes on the basis of heavy metal accumulation, biochemical attributes, and human health risk assessments on urban wastewater (UW) irrigation. Mean heavy metals (Fe, Co, Ni, Cu, Zn, Pb, Cd, Cr, Mn) and macro-nutrients (Na, K, Ca, Mg) levels increased in the roots, stem, and grains of studied genotypes. Except K (stem > root > grain), all metals were accumulated in highest concentrations in roots followed by stem and grains. Principal component analyses (PCA) identified three groups of UW-irrigated genotypes which were confirmed by hierarchical agglomerative cluster analyses (HACA). Wheat genotypes with the lowest metal accumulation were regarded as tolerant, whereas those with maximum accumulation were considered highly sensitive. Tolerant genotypes showed the lowest hazard quotient for heavy metals, i.e., Co, Mn, Cd, Cu, Fe, Pb, and Cr, and hazard index (HI) values (adults, 2.04; children, 2.27) than moderately and highly sensitive genotypes. Higher health risks (HI) associated with moderate (adults 2.26; children 2.53) and highly sensitive (adults 2.52; children 2.82) genotypes revealed maximum uptake of heavy metals. The heatmap showed higher mean biochemical levels of chlorophyll, carotenoids, membrane stability index (MSI%), sugars, proteins, proline, superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in tolerant genotypes than remaining genotypes. With the lowest metal accumulation and advanced biochemical mechanisms to cope with the adverse effects of heavy metals in their plant bodies, tolerant genotypes present a better option for cultivation in areas receiving UW or similar type of wastewater.

Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.

PubMed

Axelrod, David E; Vedula, Sudeepti; Obaniyi, James

2017-05-01

The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.

Public tolerance to defoliation and flower distortion in a public horticulture garden.

PubMed

Sadof, Clifford S; Sclar, D Casey

2002-04-01

Surveys of visitor and grower perception of live potted plant quality were conducted in various locations in a large public display garden. Canna lily, Canna x generalis L.H.Bailey, was used to examine effects of defoliation by Japanese beetle, Popillia japonica Newman, on public perception. Chrysanthemums, Chrysanthemum x morifolium Ramat., were used to identify visitor and grower tolerance to flower distortion caused by western flower thrips, Frankliniella occidentalis (Pergande), on single and multiple flowered plants. On average, the maximum amount of defoliation or flower distortion tolerated by any respondent was low (< or = 10% for canna and < or = 25% for chrysanthemum). The level of acceptable injury was influenced by factors intrinsic to both the respondents and the plants themselves. Tolerance to injury was negatively associated with the risk aversion of the respondents. Visitors were less tolerant of injury on plants they considered for purchase than those that they would view at the garden. Similarly, grower tolerance was lower than that of visitors because producing substandard plants could put their professional reputation at risk. Factors that distracted visitor attention (e.g., presence of flowers and higher levels of background injury) increased their tolerance to plant injury. Visitors tolerated greater levels of flower distortion on multiple flowering chrysanthemum than on those with single flowers. We suggest that tolerance to insect pests can be increased by designing plantings that distract viewers from injured plant parts.

Effects of oxygen on responses to heating in two lizard species sampled along an elevational gradient.

PubMed

DuBois, P Mason; Shea, Tanner K; Claunch, Natalie M; Taylor, Emily N

2017-08-01

Thermal tolerance is an important variable in predictive models about the effects of global climate change on species distributions, yet the physiological mechanisms responsible for reduced performance at high temperatures in air-breathing vertebrates are not clear. We conducted an experiment to examine how oxygen affects three variables exhibited by ectotherms as they heat-gaping threshold, panting threshold, and loss of righting response (the latter indicating the critical thermal maximum)-in two lizard species along an elevational (and therefore environmental oxygen partial pressure) gradient. Oxygen partial pressure did not impact these variables in either species. We also exposed lizards at each elevation to severely hypoxic gas to evaluate their responses to hypoxia. Severely low oxygen partial pressure treatments significantly reduced the gaping threshold, panting threshold, and critical thermal maximum. Further, under these extreme hypoxic conditions, these variables were strongly and positively related to partial pressure of oxygen. In an elevation where both species overlapped, the thermal tolerance of the high elevation species was less affected by hypoxia than that of the low elevation species, suggesting the high elevation species may be adapted to lower oxygen partial pressures. In the high elevation species, female lizards had higher thermal tolerance than males. Our data suggest that oxygen impacts the thermal tolerance of lizards, but only under severely hypoxic conditions, possibly as a result of hypoxia-induced anapyrexia. Copyright © 2017. Published by Elsevier Ltd.

Heavy metals in rice samples on the Torbat-Heidarieh market, Iran.

PubMed

Roya, Amiri Qandashtani; Ali, Mohamadi Sani

2017-03-01

Levels of the heavy metals arsenic (As), cadmium (Cd) and lead (Pb) were determined in rice samples imported from India and Pakistan and marketed in Torbat-Heidarieh, Iran. To assess the safety of dietary intake of these metals by rice, the estimated weekly intake (EWI) was calculated and compared with the provisional tolerable weekly intake (PTWI). The results indicated that mean values for Pb and cadmium in imported rice were considerably higher than the safe limit as set by FAO/WHO. EWI for cadmium and As among the consumed types of imported rice was lower than the PTWI. The results also revealed that the weekly intake of Pb was higher than the maximum weekly intake recommended by WHO/FAO.

Cloning of organic solvent tolerance gene ostA that determines n-hexane tolerance level in Escherichia coli.

PubMed Central

Aono, R; Negishi, T; Nakajima, H

1994-01-01

A variety of genes are involved in determining the level of organic solvent tolerance of Escherichia coli K-12. Gene ostA is one of the genes contributing to the level of organic solvent tolerance. This gene was cloned from an n-hexane-tolerant strain of E. coli, JA300. A JA300-based n-hexane-sensitive strain, OST4251, was converted to the n-hexane-tolerant phenotype by transformation with DNA containing the ostA gene derived from JA300. Thus, the cloned ostA gene complemented the n-hexane-sensitive phenotype of OST4251. Images PMID:7811102

Enhancement of emulsifier production by Curvularia lunata in cadmium, zinc and lead presence.

PubMed

Paraszkiewicz, Katarzyna; Frycie, Aleksandra; Słaba, Mirosława; Długoński, Jerzy

2007-10-01

The influence of cadmium, zinc and lead on fungal emulsifier synthesis and on the growth of filamentous fungus Curvularia lunata has been studied. Tolerance to heavy metals established for C. lunata was additionally compared with the sensitivity exhibited by strains of Curvularia tuberculata and Paecilomyces marquandii-fungi which do not secrete compounds of emulsifying activity. Although C. lunata, as the only one out of all studied fungi, exhibited the lowest tolerance to heavy metals when grown on a solid medium (in conditions preventing emulsifier synthesis), it manifested the highest tolerance in liquid culture - in conditions allowing exopolymer production. Cadmium, zinc and lead presented in liquid medium up to a concentration of 15 mM had no negative effect on C. lunata growth and stimulated emulsifier synthesis. In the presence of 15 mM of heavy metals, both the emulsifier and 24-h-old growing mycelium exhibited maximum sorption capacities, which were determined as 18.2 +/- 2.67, 156.1 +/- 10.32 mg g(-1) for Cd2+, 22.2 +/- 3.40, 95.2 +/- 14.21 mg g(-1) for Zn2+ and 51.1 +/- 1.85, 230.0 +/- 28.47 mg g(-1) for Pb2+ respectively. The results obtained by us in this work indicate that the emulsifier acts as a protective compound increasing the ability of C. lunata to survive in heavy metal polluted environment. Enhancement of exopolymer synthesis in the presence of Cd2+, Zn2+ and Pb2+ may also suggest, at least to some extent, a metal-specific nature of emulsifier production in C. lunata. Due to accumulation capability and tolerance to heavy metals, C. lunata mycelium surrounded by the emulsifier could be applied for toxic metal removal.

Plasticity and stress tolerance override local adaptation in the responses of Mediterranean holm oak seedlings to drought and cold.

PubMed

Gimeno, Teresa E; Pías, Beatriz; Lemos-Filho, José P; Valladares, Fernando

2009-01-01

Plant populations of widely distributed species experience a broad range of environmental conditions that can be faced by phenotypic plasticity or ecotypic differentiation and local adaptation. The strategy chosen will determine a population's ability to respond to climate change. To explore this, we grew Quercus ilex (L.) seedlings from acorns collected at six selected populations from climatically contrasting localities and evaluated their response to drought and late season cold events. Maximum photosynthetic rate (A(max)), instantaneous water use efficiency (iWUE), and thermal tolerance to freeze and heat (estimated from chlorophyll fluorescence versus temperature curves) were measured in 5-month-old seedlings in control (no stress), drought (water-stressed), and cold (low suboptimal temperature) conditions. The observed responses were similar for the six populations: drought decreased A(max) and increased iWUE, and cold reduced A(max) and iWUE. All the seedlings maintained photosynthetic activity under adverse conditions (drought and cold), and rapidly increased their iWUE by closing stomata when exposed to drought. Heat and freeze tolerances were similarly high for seedlings from all the populations, and they were significantly increased by drought and cold, respectively; and were positively related to each other. Differences in seedling performance across populations were primarily induced by maternal effects mediated by seed size and to a lesser extent by idiosyncratic physiologic responses to drought and low temperatures. Tolerance to multiple stresses together with the capacity to physiologically acclimate to heat waves and cold snaps may allow Q. ilex to cope with the increasingly stressful conditions imposed by climate change. Lack of evidence of physiologic seedling adaptation to local climate may reflect opposing selection pressures to complex, multidimensional environmental conditions operating within the distribution range of this species.

The effect of metal pollution on the life history and insecticide resistance phenotype of the major malaria vector Anopheles arabiensis (Diptera: Culicidae)

PubMed Central

Brooke, Basil D.

2018-01-01

Metal exposure is one of the commonest anthropogenic pollutants mosquito larvae are exposed to, both in agricultural and urban settings. As members of the Anopheles gambiae complex, which contains several major malaria vector species including An. arabiensis, are increasingly adapting to polluted environments, this study examined the effects of larval metal exposure on various life history traits of epidemiological importance. Two laboratory strains of An. arabiensis, SENN (insecticide susceptible) and SENN DDT (insecticide resistant), were reared in maximum acceptable toxicity concentrations, (MATC—the highest legally accepted concentration) of cadmium chloride, lead nitrate and copper nitrate. Following these exposures, time to pupation, adult size and longevity were determined. Larvae reared in double the MATC were assessed for changes in malathion and deltamethrin tolerance, measured by lethal time bottle bioassay, as well as changes in detoxification enzyme activity. As defence against oxidative stress has previously been demonstrated to affect the expression of insecticide resistance, catalase, glutathione peroxidase and superoxide dismutase activity was assessed. The relative metal toxicity to metal naïve larvae was also assessed. SENN DDT larvae were more tolerant of metal pollution than SENN larvae. Pupation in SENN larvae was significantly reduced by metal exposure, while adult longevity was not affected. SENN DDT showed decreased adult size after larval metal exposure. Adult insecticide tolerance was increased after larval metal exposure, and this effect appeared to be mediated by increased β-esterase, cytochrome P450 and superoxide dismutase activity. These data suggest an enzyme-mediated positive link between tolerance to metal pollutants and insecticide resistance in adult mosquitoes. Furthermore, exposure of larvae to metal pollutants may have operational consequences under an insecticide-based vector control scenario by increasing the expression of insecticide resistance in adults. PMID:29408922

Wheat plant selection for high yields entailed improvement of leaf anatomical and biochemical traits including tolerance to non-optimal temperature conditions.

PubMed

Brestic, Marian; Zivcak, Marek; Hauptvogel, Pavol; Misheva, Svetlana; Kocheva, Konstantina; Yang, Xinghong; Li, Xiangnan; Allakhverdiev, Suleyman I

2018-05-01

Assessment of photosynthetic traits and temperature tolerance was performed on field-grown modern genotype (MG), and the local landrace (LR) of wheat (Triticum aestivum L.) as well as the wild relative species (Aegilops cylindrica Host.). The comparison was based on measurements of the gas exchange (A/c i , light and temperature response curves), slow and fast chlorophyll fluorescence kinetics, and some growth and leaf parameters. In MG, we observed the highest CO 2 assimilation rate [Formula: see text] electron transport rate (J max ) and maximum carboxylation rate [Formula: see text]. The Aegilops leaves had substantially lower values of all photosynthetic parameters; this fact correlated with its lower biomass production. The mesophyll conductance was almost the same in Aegilops and MG, despite the significant differences in leaf phenotype. In contrary, in LR with a higher dry mass per leaf area, the half mesophyll conductance (g m ) values indicated more limited CO 2 diffusion. In Aegilops, we found much lower carboxylation capacity; this can be attributed mainly to thin leaves and lower Rubisco activity. The difference in CO 2 assimilation rate between MG and others was diminished because of its higher mitochondrial respiration activity indicating more intense metabolism. Assessment of temperature response showed lower temperature optimum and a narrow ecological valence (i.e., the range determining the tolerance limits of a species to an environmental factor) in Aegilops. In addition, analysis of photosynthetic thermostability identified the LR as the most sensitive. Our results support the idea that the selection for high yields was accompanied by the increase of photosynthetic productivity through unintentional improvement of leaf anatomical and biochemical traits including tolerance to non-optimal temperature conditions.

Hotter nests produce hatchling lizards with lower thermal tolerance.

PubMed

Dayananda, Buddhi; Murray, Brad R; Webb, Jonathan K

2017-06-15

In many regions, the frequency and duration of summer heatwaves is predicted to increase in future. Hotter summers could result in higher temperatures inside lizard nests, potentially exposing embryos to thermally stressful conditions during development. Potentially, developmentally plastic shifts in thermal tolerance could allow lizards to adapt to climate warming. To determine how higher nest temperatures affect the thermal tolerance of hatchling geckos, we incubated eggs of the rock-dwelling velvet gecko, Amalosia lesueurii , at two fluctuating temperature regimes to mimic current nest temperatures (mean 23.2°C, range 10-33°C, 'cold') and future nest temperatures (mean 27.0°C, range 14-37°C, 'hot'). Hatchlings from the hot incubation group hatched 27 days earlier and had a lower critical thermal maximum (CT max 38.7°C) and a higher critical thermal minimum (CT min 6.2°C) than hatchlings from cold incubation group (40.2 and 5.7°C, respectively). In the field, hatchlings typically settle under rocks near communal nests. During the hatching period, rock temperatures ranged from 13 to 59°C, and regularly exceeded the CT max of both hot- and cold-incubated hatchlings. Because rock temperatures were so high, the heat tolerance of lizards had little effect on their ability to exploit rocks as retreat sites. Instead, the timing of hatching dictated whether lizards could exploit rocks as retreat sites; that is, cold-incubated lizards that hatched later encountered less thermally stressful environments than earlier hatching hot-incubated lizards. In conclusion, we found no evidence that CT max can shift upwards in response to higher incubation temperatures, suggesting that hotter summers may increase the vulnerability of lizards to climate warming. © 2017. Published by The Company of Biologists Ltd.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers

PubMed Central

Lee, Jieon; Lee, Howard; Jang, Kyungho; Lim, Kyoung Soo; Shin, Dongseong; Yu, Kyung-Sang

2014-01-01

Purpose Although cilnidipine and valsartan are widely coadministered to patients with hypertension, their drug–drug interaction potential has not been investigated. This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of cilnidipine and valsartan, both alone and in combination, in healthy male subjects. Patients and methods Fifty-four subjects, enrolled into an open-label, single-dose, three-treatment, three-period crossover study, randomly received cilnidipine (10 mg), valsartan (160 mg), or both according to one of six sequences. Blood samples were collected at baseline and up to 24 hours after drug administration in each period. Plasma concentrations of cilnidipine and valsartan were determined by liquid chromatography with tandem mass spectrometry. Maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time (AUClast) were estimated using a noncompartmental method. Tolerability was evaluated by assessing adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory tests. Blood pressure was also measured for PD assessment. Results A total of 51 subjects completed the study. The PK profile of cilnidipine was not significantly affected by coadministered valsartan; the geometric mean ratio and 90% confidence interval (90% CI) of AUClast for cilnidipine with and without valsartan was 1.04 (0.98–1.10). Likewise, cilnidipine did not affect the PK of valsartan; the geometric mean ratio (90% CI) of AUClast for valsartan with and without cilnidipine was 0.94 (0.83–1.07). Coadministration of cilnidipine and valsartan reduced blood pressure in an additive way. No serious AEs were reported, and both cilnidipine and valsartan were well tolerated. Conclusion Coadministered cilnidipine and valsartan do not cause a significant PK or PD interaction, and they are well tolerated. PMID:25336921

Do mitochondrial properties explain intraspecific variation in thermal tolerance?

PubMed

Fangue, Nann A; Richards, Jeffrey G; Schulte, Patricia M

2009-02-01

As global temperatures rise, there is a growing need to understand the physiological mechanisms that determine an organism's thermal niche. Here, we test the hypothesis that increases in mitochondrial capacity with cold acclimation and adaptation are associated with decreases in thermal tolerance using two subspecies of killifish (Fundulus heteroclitus) that differ in thermal niche. We assessed whole-organism metabolic rate, mitochondrial amount and mitochondrial function in killifish acclimated to several temperatures. Mitochondrial enzyme activities and mRNA levels were greater in fish from the northern subspecies, particularly in cold-acclimated fish, suggesting that the putatively cold-adapted northern subspecies has a greater capacity for increases in mitochondrial amount in response to cold acclimation. When tested at the fish's acclimation temperature, maximum ADP-stimulated (State III) rates of mitochondrial oxygen consumption in vitro were greater in cold-acclimated northern fish than in southern fish but did not differ between subspecies at higher acclimation temperatures. Whole-organism metabolic rate was greater in fish of the northern subspecies at all acclimation temperatures. Cold acclimation also changed the response of mitochondrial respiration to acute temperature challenge. Mitochondrial oxygen consumption was greater in cold-acclimated northern fish than in southern fish at low test temperatures, but the opposite was true at high test temperatures. These differences were reflected in whole-organism oxygen consumption. Our data indicate that the plasticity of mitochondrial function and amount differs between killifish subspecies, with the less high-temperature tolerant, and putatively cold adapted, northern subspecies having greater ability to increase mitochondrial capacity in the cold. However, there were few differences in mitochondrial properties between subspecies at warm acclimation temperatures, despite differences in both whole-organism oxygen consumption and thermal tolerance at these temperatures.

Thermal Tolerance of the Coffee Berry Borer Hypothenemus hampei: Predictions of Climate Change Impact on a Tropical Insect Pest

PubMed Central

Jaramillo, Juliana; Chabi-Olaye, Adenirin; Kamonjo, Charles; Jaramillo, Alvaro; Vega, Fernando E.; Poehling, Hans-Michael; Borgemeister, Christian

2009-01-01

Coffee is predicted to be severely affected by climate change. We determined the thermal tolerance of the coffee berry borer , Hypothenemus hampei, the most devastating pest of coffee worldwide, and make inferences on the possible effects of climate change using climatic data from Colombia, Kenya, Tanzania, and Ethiopia. For this, the effect of eight temperature regimes (15, 20, 23, 25, 27, 30, 33 and 35°C) on the bionomics of H. hampei was studied. Successful egg to adult development occurred between 20–30°C. Using linear regression and a modified Logan model, the lower and upper thresholds for development were estimated at 14.9 and 32°C, respectively. In Kenya and Colombia, the number of pest generations per year was considerably and positively correlated with the warming tolerance. Analysing 32 years of climatic data from Jimma (Ethiopia) revealed that before 1984 it was too cold for H. hampei to complete even one generation per year, but thereafter, because of rising temperatures in the area, 1–2 generations per year/coffee season could be completed. Calculated data on warming tolerance and thermal safety margins of H. hampei for the three East African locations showed considerably high variability compared to the Colombian site. The model indicates that for every 1°C rise in thermal optimum (Topt.), the maximum intrinsic rate of increase (r max) will increase by an average of 8.5%. The effects of climate change on the further range of H. hampei distribution and possible adaption strategies are discussed. Abstracts in Spanish and French are provided as supplementary material Abstract S1 and Abstract S2. PMID:19649255

A comparative study of a preservative-free latanoprost cationic emulsion (Catioprost) and a BAK-preserved latanoprost solution in animal models.

PubMed

Daull, Philippe; Buggage, Ronald; Lambert, Grégory; Faure, Marie-Odile; Serle, Janet; Wang, Rong-Fang; Garrigue, Jean-Sébastien

2012-10-01

Benzalkonium chloride (BAK), a common preservative in eye drops, can induce ocular surface toxicity that may decrease glaucoma therapy compliance. The ocular hypotensive effect, pharmacokinetic (PK) profiles, and local tolerance of a preservative-free latanoprost 0.005% cationic emulsion (Catioprost(®)), and a BAK-preserved latanoprost 0.005% solution (Xalatan(®)), were compared. The ocular hypotensive effect was evaluated in monkeys with elevated intraocular pressure (IOP) induced by laser photocoagulation of the trabecular meshwork. Each monkey (n=8) received both latanoprost formulations once daily for 5 consecutive treatment days in a crossover design with at least a 2-week washout period between treatments. IOP was measured at baseline (on day 1, no instillation), on vehicle treatment day (day 0), and on treatment days 1, 3, and 5 before drug instillation and then hourly for 6 h. In rabbits, the ocular and systemic concentrations of latanoprost free acid were determined following a single instillation and the local tolerance of twice daily instillations over 28 days was assessed. Both the preservative-free and BAK-preserved latanoprost formulations shared the same efficacy profile with the maximum IOP reduction occurring 2 h after each morning dose (-15%, -20%, and -26%; -15%, -23%, and -23% on days 1, 3, and 5, respectively) and lasting through 24 h. The equivalence in efficacy was confirmed by the PK data demonstrating similar area under the curves (AUCs). While both formulations were well tolerated, the incidence of conjunctival hyperemia was reduced by 42% with the BAK-free latanoprost cationic emulsion. In animal models, a preservative-free latanoprost cationic emulsion was as effective as Xalatan(®) for lowering IOP with an improved ocular tolerance profile.

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.

Steel test panel helps control additives in pyrophosphate copper plating

NASA Technical Reports Server (NTRS)

Hollar, W. T.

1967-01-01

Test panel helps control maximum tolerance level for plating solution contaminants. It provides low, medium, and high-current density areas such as exist in production plating, and plating is examined for uniformity of texture and ductility.

Impact Damage and Strain Rate Effects for Toughened Epoxy Composite Structures

NASA Technical Reports Server (NTRS)

Chamis, Christos C.; Minnetyan, Levon

2006-01-01

Structural integrity of composite systems under dynamic impact loading is investigated herein. The GENOA virtual testing software environment is used to implement the effects of dynamic loading on fracture progression and damage tolerance. Combinations of graphite and glass fibers with a toughened epoxy matrix are investigated. The effect of a ceramic coating for the absorption of impact energy is also included. Impact and post impact simulations include verification and prediction of (1) Load and Impact Energy, (2) Impact Damage Size, (3) Maximum Impact Peak Load, (4) Residual Strength, (5) Maximum Displacement, (6) Contribution of Failure Modes to Failure Mechanisms, (7) Prediction of Impact Load Versus Time, and (8) Damage, and Fracture Pattern. A computer model is utilized for the assessment of structural response, progressive fracture, and defect/damage tolerance characteristics. Results show the damage progression sequence and the changes in the structural response characteristics due to dynamic impact. The fundamental premise of computational simulation is that the complete evaluation of composite fracture requires an assessment of ply and subply level damage/fracture processes as the structure is subjected to loads. Simulation results for the graphite/epoxy composite were compared with the impact and tension failure test data, correlation and verification was obtained that included: (1) impact energy, (2) damage size, (3) maximum impact peak load, (4) residual strength, (5) maximum displacement, and (6) failure mechanisms of the composite structure.

The safety and pharmacokinetics of rapid iloprost aerosol delivery via the BREELIB nebulizer in pulmonary arterial hypertension

PubMed Central

Gessler, Tobias; Ghofrani, Hossein-Ardeschir; Held, Matthias; Klose, Hans; Leuchte, Hanno; Olschewski, Horst; Rosenkranz, Stephan; Fels, Lueder; Li, Na; Ren, Dawn; Kaiser, Andreas; Schultze-Mosgau, Marcus-Hillert; Müllinger, Bernhard; Rohde, Beate; Seeger, Werner

2017-01-01

The BREELIB nebulizer was developed for iloprost to reduce inhalation times for patients with pulmonary arterial hypertension (PAH). This multicenter, randomized, unblinded, four-part study compared inhalation time, pharmacokinetics, and acute tolerability of iloprost 5 µg at mouthpiece delivered via BREELIB versus the standard I-Neb nebulizer in 27 patients with PAH. The primary safety outcome was the proportion of patients with a maximum increase in heart rate (HR) ≥ 25% and/or a maximum decrease in systolic blood pressure ≥ 20% within 30 min after inhalation. Other safety outcomes included systolic, diastolic, and mean blood pressure, HR, oxygen saturation, and adverse events (AEs). Median inhalation times were considerably shorter with BREELIB versus I-Neb (2.6 versus 10.9 min; n = 24). Maximum iloprost plasma concentration and systemic exposure (area under the plasma concentration–time curve) were 77% and 42% higher, respectively, with BREELIB versus I-Neb. Five patients experienced a maximum systolic blood pressure decrease ≥ 20%, four with BREELIB (one mildly and transiently symptomatic), and one with I-Neb; none required medical intervention. AEs reported during the study were consistent with the known safety profile of iloprost. The BREELIB nebulizer offers reduced inhalation time, good tolerability, and may improve iloprost aerosol therapy convenience and thus compliance for patients with PAH. PMID:28597762

76 FR 22620 - Triflusulfuron-Methyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-22

... under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is effective April 22... Determination of Safety Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit... determination on aggregate exposure for triflusulfuron-methyl, including exposure resulting from the tolerances...

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Strong environmental tolerance of moss Venturiella under very high pressure

NASA Astrophysics Data System (ADS)

Ono, F.; Mori, Y.; Takarabe, K.; Nishihira, N.; Shindo, A.; Saigusa, M.; Matsushima, Y.; Saini, N. L.; Yamashita, M.

2010-03-01

It was shown by the present authors group that tardigrade can survive under high pressure of 7.5 GPa. In the case of land plants, however, no result of such experiment has been reported. We have extended our experiments to moss searching for lives under very high pressure. Spore placentas of moss Venturiella were sealed in a small Teflon capsule together with a liquid pressure medium. The capsule was put in the center of a pyrophillite cube, and the maximum pressure of 7.5 GPa was applied using a two-stage cubic anvil press. The pressure was kept constant at the maximum pressure for12, 24, 72 and 144 hours. After the pressure was released, the spores were seeded on a ager medium, and incubated for one week and more longer at 25°C with white light of 2000 lux. It was proved that 70-90% of the spores were alive and germinated after exposed to the maximum pressure of 7.5 GPa for up to 72 hours. However, after exposed to 7.5 GPa for 6 days, only 4 individuals in a hundred were germinated. The pressure tolerance of moss Venturiella is found to be stronger than a small animal, tardigrade.

Gasohol Quality Control for Real Time Applications by Means of a Multimode Interference Fiber Sensor

PubMed Central

Rodríguez Rodríguez, Adolfo J.; Baldovino-Pantaleón, Oscar; Domínguez Cruz, Rene F.; Zamarreño, Carlos R.; Matías, Ignacio R.; May-Arrioja, Daniel A.

2014-01-01

In this work we demonstrate efficient quality control of a variety of gasoline and ethanol (gasohol) blends using a multimode interference (MMI) fiber sensor. The operational principle relies on the fact that the addition of ethanol to the gasohol blend reduces the refractive index (RI) of the gasoline. Since MMI sensors are capable of detecting small RI changes, the ethanol content of the gasohol blend is easily determined by tracking the MMI peak wavelength response. Gasohol blends with ethanol contents ranging from 0% to 50% has been clearly identified using this device, which provides a linear response with a maximum sensitivity of 0.270 nm/% EtOH. The sensor can also distinguish when water incorporated in the blend has exceeded the maximum volume tolerated by the gasohol blend, which is responsible for phase separation of the ethanol and gasoline and could cause serious engine failures. Since the MMI sensor is straightforward to fabricate and does not require any special coating it is a cost effective solution for real time and in-situ monitoring of the quality of gasohol blends. PMID:25256111

Symmetrical solid oxide fuel cells with impregnated SrFe0.75Mo0.25O3-δ electrodes

NASA Astrophysics Data System (ADS)

Meng, Xie; Liu, Xuejiao; Han, Da; Wu, Hao; Li, Junliang; Zhan, Zhongliang

2014-04-01

Here we report nominally symmetrical solid oxide fuel cells that feature thin La0.9Sr0.1Ga0.8Mg0.2O3-δ (LSGM) electrolytes and impregnated SrFe0.75Mo0.25O3-δ (SFMO)-LSGM composite electrodes. Operation on hydrogen fuels and air oxidants can produce maximum power densities of 0.39 W cm-2 at 650 °C and 0.97 W cm-2 at 800 °C. Impedance measurements indicate that the anode and the cathode polarizations are 0.22 and 0.04 Ω cm2 at 800 °C, respectively. Hydrogen partial pressure and temperature dependence of impedance data in humidified hydrogen shows that hydrogen oxidation kinetics is largely determined by hydrogen adsorption on the SFMO catalysts at high temperatures and charge transfer reactions along the SFMO|LSGM interfaces at low temperatures. Carbon tolerance of the present fuel cells is also examined in iso-octane fuels balanced by nitrogen at 800 °C that yields stable maximum power densities of 0.39 W cm-2.

Changes in ABA and gene expression in cold-acclimated sugar maple.

PubMed

Bertrand, A; Robitaille, G; Castonguay, Y; Nadeau, P; Boutin, R

1997-01-01

To determine if cold acclimation of sugar maple (Acer saccharum Marsh.) is associated with specific changes in gene expression under natural hardening conditions, we compared bud and root translatable mRNAs of potted maple seedlings after cold acclimation under natural conditions and following spring dehardening. Cold-hardened roots and buds were sampled in January when tissues reached their maximum hardiness. Freezing tolerance, expressed as the lethal temperature for 50% of the tissues (LT(50)), was estimated at -17 degrees C for roots, and at lower than -36 degrees C for buds. Approximately ten transcripts were specifically synthesized in cold-acclimated buds, or were more abundant in cold-acclimated buds than in unhardened buds. Cold hardening was also associated with changes in translation. At least five translation products were more abundant in cold-acclimated buds and roots compared with unhardened tissues. Abscisic acid (ABA) concentration increased approximately tenfold in the xylem sap following winter acclimation, and the maximum concentration was reached just before maximal acclimation. We discuss the potential involvement of ABA in the observed modification of gene expression during cold hardening.

Field Quality from Tolerance Stack-up In R&D Quadrupoles for the Advanced Photon Source Upgrade

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

Liu, J.; Jaski, M.; Dejus, R.

2016-10-01

The Advanced Photon Source (APS) at Argonne National Laboratory (ANL) is considering upgrading the current double-bend, 7-GeV, 3rd generation storage ring to a 6-GeV, 4th generation storage ring with a Multibend Achromat (MBA) lattice. In this study, a novel method is proposed to determine fabrication and assembly tolerances through a combination of magnetic and mechanical tolerance analyses. Mechanical tolerance stackup analyses using Teamcenter Variation Analysis are carried out to determine the part and assembly level fabrication tolerances. Finite element analyses using OPERA are conducted to estimate the effect of fabrication and assembly errors on the magnetic field of a quadrupolemore » magnet and to determine the allowable tolerances to achieve the desired magnetic performance. Finally, results of measurements in R&D quadrupole prototypes are compared with the analysis results.« less

Inflammatory response and treatment tolerance of long-term infusion of the anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 in patients with high-risk neuroblastoma.

PubMed

Ceylan, Kiraz; Jahns, Luciana J; Lode, Bjoern N; Ehlert, Karoline; Kietz, Silke; Troschke-Meurer, Sascha; Siebert, Nikolai; Lode, Holger N

2018-06-01

The monoclonal anti-GD 2 antibody ch14.18/CHO in combination with IL-2 is active and effective in high-risk neuroblastoma (NB) patients. Here, we investigated the inflammatory response and treatment tolerance of long-term infusion (LTI) of ch14.18/CHO (10 × 10 mg/m 2 ; 24 hr) in combination with subcutaneous (s.c.) IL-2 in a single center program. Fifty-three NB patients received up to six cycles of 100 mg/m 2 ch14.18/CHO (d8-18, where d represents day(s)) as LTI combined with 6 × 10 6 IU/m 2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m 2 oral 13-cis retinoic acid (RA) (d19-32). Side effects of ch14.18/CHO and IL-2 treatment require hospitalization of patients on d8. Treatment tolerance was evaluated daily with clinical parameters (body temperature, vital signs, Lansky performance status, requirement of i.v. concomitant medication) to define an outpatient candidate status. sIL-2-R and C-reactive protein values were determined to assess the inflammatory response. LTI of ch14.18/CHO (d8-18) in combination with s.c.IL-2 (d8-12) showed an acceptable treatment tolerance that allowed all patients to receive part of the treatment as an outpatient (median time point of discharge: d15 for all cycles). The treatment tolerance improved from cycle to cycle and the time to become an outpatient candidate decreased from d15 to d13 in subsequent cycles. Clinical and laboratory parameters indicate a maximum inflammatory response at d11 of each cycle. Interestingly, the soluble IL-2 receptor remained increased at baseline of the next cycle indicating immune activation over the entire treatment period of 6 months. LTI of ch14.18/CHO combined with s.c.IL-2 shows an improved tolerance in subsequent cycles allowing outpatient treatment. © 2018 Wiley Periodicals, Inc.

A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours

PubMed Central

Nakagawa, K; Kudoh, S; Matsui, K; Negoro, S; Yamamoto, N; Latz, J E; Adachi, S; Fukuoka, M

2006-01-01

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB12) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0–2, and adequate organ function. Pemetrexed from 300 to 1200 mg m−2 was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB12. Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m−2, and infection and skin rash at 1200 mg m−2. The MTD/RD were determined to be 1200/1000 mg m−2, respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1200/1000 mg m−2, respectively, that is, a higher RD than without FA/VB12 (500 mg m−2). Pemetrexed with FA/VB12 showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study. PMID:16940981

Highly sensitive and selective spectrophotometric method for determination of trace gold in geological samples with 5-(2-hydroxy-5-nitrophenylazo)rhodanine.

PubMed

Zaijun, Li; Jiaomai, Pan; Jian, Tang

2003-02-01

A excellent sensitive and selective method for spectrophotometric determination of trace gold has been developed, the method is based on the color reaction of gold(III) with new reagent 5-(2-hydroxy-5-nitrophenylazo)rhodanine (HNAR). Under optimal conditions, HNAR reacts with gold(III) to form a 1:5 orange complex, which has an maximum absorption peak at 480 nm. Maximum enhancement of the absorbance of the complex was obtained in the presence of the mixed surfactant of Triton X-100 and CTMAB; the reaction completed rapidly and the absorbance is stable for 5 h at least at 20 degrees C; 0-48 microg L(-1) Au(III) obeyed Beer's law. The apparent molar absorptivity of the complex, Sandell's sensitivity, the limit of quantification, the limit of detection and relative standard deviation were found to be 2.0x10(6) L mol(-1) cm(-1), 0.000,098,483 micro g cm(-2), 1.02 ng mL(-1), 0.35 ng mL(-1) and 1.09%, respectively. The effect of co-existing ions was studied seriously; most metal ions can be tolerated in considerable amounts. Its sensitivity and selectivity are remarkably superior to other reagents in the literature. The proposed method was used successfully to determine trace gold in geological samples. Moreover, the synthesis, characteristics and analytical reaction of HNAR with gold are also described in detail.

Evolution of the climatic tolerance and postglacial range changes of the most primitive orchids (Apostasioideae) within Sundaland, Wallacea and Sahul.

PubMed

Kolanowska, Marta; Mystkowska, Katarzyna; Kras, Marta; Dudek, Magdalena; Konowalik, Kamil

2016-01-01

The location of possible glacial refugia of six Apostasioideae representatives is estimated based on ecological niche modeling analysis. The distribution of their suitable niches during the last glacial maximum (LGM) is compared with their current potential and documented geographical ranges. The climatic factors limiting the studied species occurrences are evaluated and the niche overlap between the studied orchids is assessed and discussed. The predicted niche occupancy profiles and reconstruction of ancestral climatic tolerances suggest high level of phylogenetic niche conservatism within Apostasioideae.

76 FR 36349 - Diethylene Glycol MonoEthyl Ether (DEGEE); Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-22

... use on growing crops and raw agricultural commodities, without limitation. Huntsman, Dow AgroSciences... a maximum permissible level for residues of DEGEE on growing crops and raw agricultural commodities... antifreeze [[Page 36350

Establishment of Maximum Voluntary Compressive Neck Tolerance Levels

DTIC Science & Technology

2011-07-01

Bridges Casey Pirnstill Chris Burneka John Plaga Grant Roush Biosciences and Performance Division Vulnerability Analysis Branch July 2011...S) Michael Cote, John Buhrman, Nathaniel Bridges, Casey Pirnstill, Chris Burneka, John Plaga , Grant Roush 5d. PROJECT NUMBER OSMS 5e. TASK

40 CFR 86.000-8 - Emission standards for 2000 and later model year light-duty vehicles.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Fueled, Natural Gas-Fueled, Liquefied Petroleum Gas-Fueled and Methanol-Fueled Heavy-Duty Vehicles § 86... mixture required to obtain maximum torque (lean best torque), plus a tolerance of six (6) percent. The...

40 CFR 86.000-8 - Emission standards for 2000 and later model year light-duty vehicles.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Fueled, Natural Gas-Fueled, Liquefied Petroleum Gas-Fueled and Methanol-Fueled Heavy-Duty Vehicles § 86... mixture required to obtain maximum torque (lean best torque), plus a tolerance of six (6) percent. The...

Dissipation of excess photosynthetic energy contributes to salinity tolerance: a comparative study of salt-tolerant Ricinus communis and salt-sensitive Jatropha curcas.

PubMed

Lima Neto, Milton C; Lobo, Ana K M; Martins, Marcio O; Fontenele, Adilton V; Silveira, Joaquim Albenisio G

2014-01-01

The relationships between salt tolerance and photosynthetic mechanisms of excess energy dissipation were assessed using two species that exhibit contrasting responses to salinity, Ricinus communis (tolerant) and Jatropha curcas (sensitive). The salt tolerance of R. communis was indicated by unchanged electrolyte leakage (cellular integrity) and dry weight in leaves, whereas these parameters were greatly affected in J. curcas. The leaf Na+ content was similar in both species. Photosynthesis was intensely decreased in both species, but the reduction was more pronounced in J. curcas. In this species biochemical limitations in photosynthesis were more prominent, as indicated by increased C(i) values and decreased Rubisco activity. Salinity decreased both the V(cmax) (in vivo Rubisco activity) and J(max) (maximum electron transport rate) more significantly in J. curcas. The higher tolerance in R. communis was positively associated with higher photorespiratory activity, nitrate assimilation and higher cyclic electron flow. The high activity of these alternative electron sinks in R. communis was closely associated with a more efficient photoprotection mechanism. In conclusion, salt tolerance in R. communis, compared with J. curcas, is related to higher electron partitioning from the photosynthetic electron transport chain to alternative sinks. Copyright © 2013 Elsevier GmbH. All rights reserved.

Ecological and physiological thermal niches to understand distribution of Chagas disease vectors in Latin America.

PubMed

DE LA Vega, G J; Schilman, P E

2018-03-01

In order to assess how triatomines (Hemiptera, Reduviidae), Chagas disease vectors, are distributed through Latin America, we analysed the relationship between the ecological niche and the limits of the physiological thermal niche in seven species of triatomines. We combined two methodological approaches: species distribution models, and physiological tolerances. First, we modelled the ecological niche and identified the most important abiotic factor for their distribution. Then, thermal tolerance limits were analysed by measuring maximum and minimum critical temperatures, upper lethal temperature, and 'chill-coma recovery time'. Finally, we used phylogenetic independent contrasts to analyse the link between limiting factors and the thermal tolerance range for the assessment of ecological hypotheses that provide a different outlook for the geo-epidemiology of Chagas disease. In triatomines, thermo-tolerance range increases with increasing latitude mainly due to better cold tolerances, suggesting an effect of thermal selection. In turn, physiological analyses show that species reaching southernmost areas have a higher thermo-tolerance than those with tropical distributions, denoting that thermo-tolerance is limiting the southern distribution. Understanding the latitudinal range along its physiological limits of disease vectors may prove useful to test ecological hypotheses and improve strategies and efficiency of vector control at the local and regional levels. © 2017 The Royal Entomological Society.

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

PubMed

Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

2014-04-01

The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

Thermopreference, tolerance and metabolic rate of early stages juvenile Octopus maya acclimated to different temperatures.

PubMed

Noyola, Javier; Caamal-Monsreal, Claudia; Díaz, Fernando; Re, Denisse; Sánchez, Adolfo; Rosas, Carlos

2013-01-01

Thermopreference, tolerance and oxygen consumption rates of early juveniles Octopus maya (O. maya; weight range 0.38-0.78g) were determined after acclimating the octopuses to temperatures (18, 22, 26, and 30°C) for 20 days. The results indicated a direct relationship between preferred temperature (PT) and acclimated temperature, the PT was 23.4°C. Critical Thermal Maxima, (CTMax; 31.8±1.2, 32.7±0.9, 34.8±1.4 and 36.5±1.0) and Critical Thermal Minima, (CTMin; 11.6±0.2, 12.8±0.6, 13.7±1.0, 19.00±0.9) increased significantly (P<0.05) with increasing acclimation temperatures. The endpoint for CTMax was ink release and for CTMin was tentacles curled, respectively. A thermal tolerance polygon over the range of 18-30°C resulted in a calculated area of 210.0°C(2). The oxygen consumption rate increased significantly α=0.05 with increasing acclimation temperatures between 18 and 30°C. Maximum and minimum temperature quotients (Q10) were observed between 26-30°C and 22-26°C as 3.03 and 1.71, respectively. These results suggest that O. maya has an increased capability for adapting to moderate temperatures, and suggest increased culture potential in subtropical regions southeast of México. Copyright © 2012 Elsevier Ltd. All rights reserved.

Chlorophyll fluorescence emission as a reporter on cold tolerance in Arabidopsis thaliana accessions

PubMed Central

Mishra, Anamika; Höermiller, Imke I; Heyer, Arnd G; Nedbal, Ladislav

2011-01-01

Non-invasive, high-throughput screening methods are valuable tools in breeding for abiotic stress tolerance in plants. Optical signals such as chlorophyll fluorescence emission can be instrumental in developing new screening techniques. In order to examine the potential of chlorophyll fluorescence to reveal plant tolerance to low temperatures, we used a collection of nine Arabidopsis thaliana accessions and compared their fluorescence features with cold tolerance quantified by the well established electrolyte leakage method on detached leaves. We found that, during progressive cooling, the minimal chlorophyll fluorescence emission rose strongly and that this rise was highly dependent on the cold tolerance of the accessions. Maximum quantum yield of PSII photochemistry and steady state fluorescence normalized to minimal fluorescence were also highly correlated to the cold tolerance measured by the electrolyte leakage method. In order to further increase the capacity of the fluorescence detection to reveal the low temperature tolerance, we applied combinatorial imaging that employs plant classification based on multiple fluorescence features. We found that this method, by including the resolving power of several fluorescence features, can be well employed to detect cold tolerance already at mild sub-zero temperatures. Therefore, there is no need to freeze the screened plants to the largely damaging temperatures of around −15°C. This, together with the method's easy applicability, represents a major advantage of the fluorescence technique over the conventional electrolyte leakage method. PMID:21427532

Evidence for a freezing tolerance-growth rate trade-off in the live oaks (Quercus series Virentes) across the tropical-temperate divide.

PubMed

Koehler, Kari; Center, Alyson; Cavender-Bares, Jeannine

2012-02-01

• It has long been hypothesized that species are limited to the north by minimum temperature and to the south by competition, resulting in a trade-off between freezing tolerance and growth rate. We investigated the extent to which the climatic origins of populations from four live oak species (Quercus series Virentes) were associated with freezing tolerance and growth rate, and whether species fitted a model of locally adapted populations, each with narrow climatic tolerances, or of broadly adapted populations with wide climatic tolerances. • Acorns from populations of four species across a tropical-temperate gradient were grown under common tropical and temperate conditions. Growth rate, seed mass, and leaf and stem freezing traits were compared with source minimum temperatures. • Maximum growth rates under tropical conditions were negatively correlated with freezing tolerance under temperate conditions. The minimum source temperature predicted the freezing tolerance of populations under temperate conditions. The tropical species Q. oleoides was differentiated from the three temperate species, and variation among species was greater than among populations. • The trade-off between freezing tolerance and growth rate supports the range limit hypothesis. Limited variation within species indicates that the distributions of species may be driven more strongly by broad climatic factors than by highly local conditions. © 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.

Hydraulics and life history of tropical dry forest tree species: coordination of species' drought and shade tolerance.

PubMed

Markesteijn, Lars; Poorter, Lourens; Bongers, Frans; Paz, Horacio; Sack, Lawren

2011-07-01

Plant hydraulic architecture has been studied extensively, yet we know little about how hydraulic properties relate to species' life history strategies, such as drought and shade tolerance. The prevailing theories seem contradictory. We measured the sapwood (K(s) ) and leaf (K(l) ) hydraulic conductivities of 40 coexisting tree species in a Bolivian dry forest, and examined associations with functional stem and leaf traits and indices of species' drought (dry-season leaf water potential) and shade (juvenile crown exposure) tolerance. Hydraulic properties varied across species and between life-history groups (pioneers vs shade-tolerant, and deciduous vs evergreen species). In addition to the expected negative correlation of K(l) with drought tolerance, we found a strong, negative correlation between K(l) and species' shade tolerance. Across species, K(s) and K(l) were negatively correlated with wood density and positively with maximum vessel length. Consequently, drought and shade tolerance scaled similarly with hydraulic properties, wood density and leaf dry matter content. We found that deciduous species also had traits conferring efficient water transport relative to evergreen species. Hydraulic properties varied across species, corresponding to the classical trade-off between hydraulic efficiency and safety, which for these dry forest trees resulted in coordinated drought and shade tolerance across species rather than the frequently hypothesized trade-off. © 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.

[Aquatic Ecological Index based on freshwater (ICE(RN-MAE)) for the Rio Negro watershed, Colombia].

PubMed

Forero, Laura Cristina; Longo, Magnolia; John Jairo, Ramirez; Guillermo, Chalar

2014-04-01

Aquatic Ecological Index based on freshwater (ICE(RN-MAE)) for the Rio Negro watershed, Colombia. Available indices to assess the ecological status of rivers in Colombia are mostly based on subjective hypotheses about macroinvertebrate tolerance to pollution, which have important limitations. Here we present the application of a method to establish an index of ecological quality for lotic systems in Colombia. The index, based on macroinvertebrate abundance and physicochemical variables, was developed as an alternative to the BMWP-Col index. The method consists on determining an environmental gradient from correlations between physicochemical variables and abundance. The scores obtained in each sampling point are used in a standardized correlation for a model of weighted averages (WA). In the WA model abundances are also weighted to estimate the optimum and tolerance values of each taxon; using this information we estimated the index of ecological quality based also on macroinvertebrate (ICE(RN-MAE)) abundance in each sampling site. Subsequently, we classified all sites using the index and concentrations of total phosphorus (TP) in a cluster analysis. Using TP and ICE(RN-MAE), mean, maximum, minimum and standard deviation, we defined threshold values corresponding to three categories of ecological status: good, fair and critical.

Hydraulic acclimation to shading in boreal conifers of varying shade tolerance.

PubMed

Schoonmaker, Amanda L; Hacke, Uwe G; Landhäusser, Simon M; Lieffers, Victor J; Tyree, Melvin T

2010-03-01

The purpose of this study was to determine how shading affects the hydraulic and wood-anatomical characteristics of four boreal conifers (Pinus banksiana, Pinus contorta, Picea glauca and Picea mariana) that differ in shade tolerance. Plants were grown in an open field and under a deciduous-dominated overstory for 6 years. Sapwood- and leaf-area specific conductivity, vulnerability curves, and anatomical measurements (light and scanning electron microscopy) were made on leading shoots from six to nine trees of each treatment combination. There was no difference in sapwood-area specific conductivity between open-grown and understory conifers, although two of four species had larger tracheid diameters in the open. Shaded conifers appeared to compensate for small diameter tracheids by changes in pit membrane structure. Scanning electron microscopy revealed that understory conifers had thinner margo strands, greater maximum pore size in the margo, and more torus extensions. All of these trends may contribute to inadequate sealing of the torus. This is supported by the fact that all species showed increased vulnerability to cavitation when grown in the understory. Although evaporative demand in an understory environment is low, a rapid change into fully exposed conditions could be detrimental for shaded conifers.

40 CFR 180.505 - Emamectin; tolerances for residues.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Emamectin; tolerances for residues... § 180.505 Emamectin; tolerances for residues. (a) General. (1) Tolerances are established for emamectin... tolerance levels specified below is to be determined by measuring only the sum of emamectin (a mixture of a...

40 CFR 180.505 - Emamectin; tolerances for residues.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Emamectin; tolerances for residues... § 180.505 Emamectin; tolerances for residues. (a) General. (1) Tolerances are established for emamectin... tolerance levels specified below is to be determined by measuring only the sum of emamectin (a mixture of a...

Compatibility Flight Profile and Internal Environment Characterization for the RASCAL Pod. Project: Senior RASCAL

DTIC Science & Technology

2008-12-01

pod at increasing angles of attack. An overall vertical acceleration maximum of 7.5 g RMS occurred while in a transonic wind-up turn at 15,000 ft and...landings, level accelerations, and specific maneuver blocks of varying sideslip, load factor, and angle of attack (AOA). The flight conditions...0g 10s maximum Angle of Attack (deg) ±1 ±1 16 Table A1: Data Bands and Tolerances for the Vibroacoustic Tests Table A2 summarizes the conditions

A new concept of feature-based gauge for coordinate measuring arm evaluation

NASA Astrophysics Data System (ADS)

Cuesta, E.; González-Madruga, D.; Alvarez, B. J.; Barreiro, J.

2014-06-01

Articulated arm coordinate measuring machines (AACMM or CMA) have conquered a market share in the actual dimensional metrology field, overall when their role implies the inspection of geometrical and dimensional tolerances in an accurate 3D environment for medium-size parts. However, the unavoidable fact of AACMM manual operation constrains its reliability to a great extent, avoiding rigorous evaluation and casting doubt upon the usefulness of external calibration. In this research, a dimensional gauge especially aimed at AACMM evaluation has been developed. Furthermore, the operator skill will be revealed through the use of this gauge. A set of geometrical features, some of them oriented to evaluate the operator and others the equipment, have been collected for the gauge. The proposed evaluation methodology clearly distinguishes between dimensional and geometrical tolerances (with or without datum references), whereas actual verification standards only consider the former. Next, quality indicators deduced from the measurement results are proposed in order to compare AACMM versus coordinate measuring machine (CMM) performance, assuming that CMM possess the maximum accuracy that AACMM could reach, because CMM combines maximum contact accuracy with minimum operator influence. As a result, AACMM evaluation time could be significantly reduced since this gauge allows us to perform a customized evaluation of only those specific tolerances of interest to the user.

High tolerance of and removal of cefazolin sodium in single-chamber microbial fuel cells operation.

PubMed

Zhang, Enren; Yu, Qingling; Zhai, Wenjing; Wang, Feng; Scott, Keith

2018-02-01

Single-chamber microbial fuel cells (MFCs) have been shown to be a promising approach for cefazolin sodium (CFZS)-contaminated wastewater treatment, in terms of electricity production, high CFZS tolerance and effective CFZS removal. MFCs exposed to CFZS loadings up to 100 mg L -1 , produced stable power of 18.2 ± 1.1 W m -3 and a maximum power of 30.4 ± 2.1 W m -3 , similar to that of CFZS-free MFCs (stable power 19.4 ± 0.8 W m -3 and maximum power 32.5 ± 1.6 W m -3 ), notwithstanding a longer acclimitisation MFC activation. More anodophilic genera (i.e. Acinetobacter, Stenotrophomonas, Lysinibacillus) and antibiotic-resisting genera (i.e. Dysgonomonas) were enriched in CFZS acclimitised anodes. Both the thickness of biofilms and the duration of CFZS acclimitisation were essential for the development of high CFZS tolerance (e.g. 450 mg L -1 ). The inhibition of MFCs by CFZS was reversible. The present MFCs generated a CFZS removal rate of 1.2-6.8 mg L -1  h -1 without any apparent inhibition of electricity production. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integration of a vision-based tracking platform, visual instruction, and error analysis models for an efficient billiard training system

NASA Astrophysics Data System (ADS)

Shih, Chihhsiong; Hsiung, Pao-Ann; Wan, Chieh-Hao; Koong, Chorng-Shiuh; Liu, Tang-Kun; Yang, Yuanfan; Lin, Chu-Hsing; Chu, William Cheng-Chung

2009-02-01

A billiard ball tracking system is designed to combine with a visual guide interface to instruct users for a reliable strike. The integrated system runs on a PC platform. The system makes use of a vision system for cue ball, object ball and cue stick tracking. A least-squares error calibration process correlates the real-world and the virtual-world pool ball coordinates for a precise guidance line calculation. Users are able to adjust the cue stick on the pool table according to a visual guidance line instruction displayed on a PC monitor. The ideal visual guidance line extended from the cue ball is calculated based on a collision motion analysis. In addition to calculating the ideal visual guide, the factors influencing selection of the best shot among different object balls and pockets are explored. It is found that a tolerance angle around the ideal line for the object ball to roll into a pocket determines the difficulty of a strike. This angle depends in turn on the distance from the pocket to the object, the distance from the object to the cue ball, and the angle between these two vectors. Simulation results for tolerance angles as a function of these quantities are given. A selected object ball was tested extensively with respect to various geometrical parameters with and without using our integrated system. Players with different proficiency levels were selected for the experiment. The results indicate that all players benefit from our proposed visual guidance system in enhancing their skills, while low-skill players show the maximum enhancement in skill with the help of our system. All exhibit enhanced maximum and average hit-in rates. Experimental results on hit-in rates have shown a pattern consistent with that of the analysis. The hit-in rate is thus tightly connected with the analyzed tolerance angles for sinking object balls into a target pocket. These results prove the efficiency of our system, and the analysis results can be used to attain an efficient game-playing strategy.

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.

40 CFR 180.2010 - Threshold of regulation determinations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Threshold of regulation determinations... Requiring a Tolerance or an Exemption From a Tolerance § 180.2010 Threshold of regulation determinations... on EPA's determination that the uses are below the threshold of regulation. Pesticide Chemical CAS...

40 CFR 180.2010 - Threshold of regulation determinations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Threshold of regulation determinations... Requiring a Tolerance or an Exemption From a Tolerance § 180.2010 Threshold of regulation determinations... on EPA's determination that the uses are below the threshold of regulation. Pesticide Chemical CAS...

40 CFR 180.2010 - Threshold of regulation determinations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Threshold of regulation determinations... Requiring a Tolerance or an Exemption From a Tolerance § 180.2010 Threshold of regulation determinations... on EPA's determination that the uses are below the threshold of regulation. Pesticide Chemical CAS...

Tolerance of snakes to hypergravity

NASA Technical Reports Server (NTRS)

Lillywhite, H. B.; Ballard, R. E.; Hargens, A. R.

1996-01-01

Sensitivity of carotid blood flow to increased gravitational force acting in the head-to-tail direction(+Gz) was studied in diverse species of snakes hypothesized to show adaptive variation of response. Tolerance to increased gravity was measured red as the maximum graded acceleration force at which carotid blood flow ceased and was shown to vary according to gravitational adaptation of species defined by their ecology and behavior. Multiple regression analysis showed that gravitational habitat, but not body length, had a significant effect on Gz tolerance. At the extremes, carotid blood flow decreased in response to increasing G force and approached zero near +1 Gz in aquatic and ground-dwelling species, whereas in climbing species carotid flow was maintained at forces in excess of +2 Gz. Tolerant (arboreal) species were able to withstand hypergravic forces of +2 to +3 Gz for periods up to 1 h without cessation of carotid blood flow or loss of body movement and tongue flicking. Data suggest that the relatively tight skin characteristic of tolerant species provides a natural antigravity suit and is of prime importance in counteracting Gz stress on blood circulation.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

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

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

Deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation: multicenter phase I study (KSGCT1302).

PubMed

Tachibana, Takayoshi; Kanda, Junya; Machida, Shinichiro; Saito, Takeshi; Tanaka, Masatsugu; Najima, Yuho; Koyama, Satoshi; Miyazaki, Takuya; Yamamoto, Eri; Takeuchi, Masahiro; Morita, Satoshi; Kanda, Yoshinobu; Kanamori, Heiwa; Okamoto, Shinichiro

2018-05-01

The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22-68). Median time from HCT to deferasirox administration was 9 months (range 6-84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient. UMIN000011251.

A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.

PubMed

Duong, Janna K; Griffin, Melanie J; Hargrave, Darren; Vormoor, Josef; Edwards, David; Boddy, Alan V

2017-08-01

AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. Data from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children. The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h -1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg -1  72 h -1 . For adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg -1  72 h -1 children with leukaemia. © 2017 The British Pharmacological Society.

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer.

PubMed

Fakih, Marwan G; Pendyala, Lakshmi; Fetterly, Gerald; Toth, Karoli; Zwiebel, James A; Espinoza-Delgado, Igor; Litwin, Alan; Rustum, Youcef M; Ross, Mary Ellen; Holleran, Julianne L; Egorin, Merrill J

2009-05-01

We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX). Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied. Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR. The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.

A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.

PubMed

Dy, Grace K; Bruzek, Laura M; Croghan, Gary A; Mandrekar, Sumithra; Erlichman, Charles; Peethambaram, Prema; Pitot, Henry C; Hanson, Lorelei J; Reid, Joel M; Furth, Alfred; Cheng, Shinta; Martell, Robert E; Kaufmann, Scott H; Adjei, Alex A

2005-03-01

This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

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

Tada, Takuhito, E-mail: tada@msic.med.osaka-cu.ac.jp; Department of Radiology, Izumi Municipal Hospital, Izumi; Chiba, Yasutaka

2012-05-01

Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m{sup 2}) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m{sup 2}). Total doses were 54 Gy in 36 fractions, 60 Gymore » in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade {>=}4 esophagitis and neutropenic fever and Grade {>=}3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.« less

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

21 CFR 526.313 - Ceftiofur.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) Related tolerances. See § 556.113 of this chapter. (d) Conditions of use in cattle—(1) Lactating cows—(i... lactating dairy cattle associated with coagulase-negative staphylococci, Streptococcus dysgalactiae, and Escherichia coli. (iii) Limitations. Milk taken from cows during treatment (a maximum of eight daily infusions...

UNITED STATES DEPARTMENT OF TRANSPORTATION GLOBAL POSITIONING SYSTEM (GPS) ADJACENT BAND COMPATIBILITY ASSESSMENT

DOT National Transportation Integrated Search

2018-04-01

The goal of the U.S. Department of Transportation (DOT) Global Positioning System (GPS) Adjacent Band Compatibility Assessment is to evaluate the maximum transmitted power levels of adjacent band radiofrequency (RF) systems that can be tolerated by G...

Variation in temperature tolerance among families of Atlantic salmon (Salmo salar) is associated with hypoxia tolerance, ventricle size and myoglobin level.

PubMed

Anttila, Katja; Dhillon, Rashpal S; Boulding, Elizabeth G; Farrell, Anthony P; Glebe, Brian D; Elliott, Jake A K; Wolters, William R; Schulte, Patricia M

2013-04-01

In fishes, performance failure at high temperature is thought to be due to a limitation on oxygen delivery (the theory of oxygen and capacity limited thermal tolerance, OCLTT), which suggests that thermal tolerance and hypoxia tolerance might be functionally associated. Here we examined variation in temperature and hypoxia tolerance among 41 families of Atlantic salmon (Salmo salar), which allowed us to evaluate the association between these two traits. Both temperature and hypoxia tolerance varied significantly among families and there was a significant positive correlation between critical maximum temperature (CTmax) and hypoxia tolerance, supporting the OCLTT concept. At the organ and cellular levels, we also discovered support for the OCLTT concept as relative ventricle mass (RVM) and cardiac myoglobin (Mb) levels both correlated positively with CTmax (R(2)=0.21, P<0.001 and R(2)=0.17, P=0.003, respectively). A large RVM has previously been shown to be associated with high cardiac output, which might facilitate tissue oxygen supply during elevated oxygen demand at high temperatures, while Mb facilitates the oxygen transfer from the blood to tissues, especially during hypoxia. The data presented here demonstrate for the first time that RVM and Mb are correlated with increased upper temperature tolerance in fish. High phenotypic variation between families and greater similarity among full- and half-siblings suggests that there is substantial standing genetic variation in thermal and hypoxia tolerance, which could respond to selection either in aquaculture or in response to anthropogenic stressors such as global climate change.

Specific oral desensitization in children with IgE-mediated cow's milk allergy. Evolution in one year.

PubMed

Alvaro, Montserrat; Giner, Ma Teresa; Vázquez, Marta; Lozano, Jaime; Domínguez, Olga; Piquer, Mónica; Días, Marcia; Jiménez, Rosa; Martín, Ma Anunciación; Alsina, Laia; Plaza, Ana Ma

2012-09-01

Cow's milk allergy is the most frequent childhood food allergy. Children older than 5 who have not become tolerant have less probabilities of natural tolerance. Specific oral desensitization methods are being investigated in reference centres. The aims of our study were to assess the efficacy of our guideline of specific oral desensitization to cow's milk in children and to know its suitability for anaphylactic children. Both clinical and specific IgE outcomes were evaluated. Eighty-seven children aged 5 to 16 years with a history of cow's milk allergy were included. Prior to desensitization, skin prick test, specific IgE to cow's milk proteins and a double-blind placebo control food challenge were performed in all. Of the 87 patients, 21 had a negative challenge; they were considered tolerant, and they were told to follow a free diet. Of the positive, 44 were anaphylactic and 22 non-anaphylactic. All of them were included. In non-anaphylactic patients, 6 achieved partial and 16 maximum desensitization after 23.1 weeks. In the anaphylactic group, 7 achieved partial and 35 maximum desensitization after 26.4 weeks. Cow's milk-specific IgE levels and casein-specific IgE levels were significantly lower in the tolerant patients at baseline. One year after desensitization, the medium specific cow's milk levels and casein IgE levels had dropped significantly. Our guideline for specific oral desensitization to cow's milk is efficacious even in patients with anaphylactic reactions to cow's milk and represents a significant life change. Immunological changes in 1 year show a drop in cow's milk protein-specific IgE.

Noise tolerant dendritic lattice associative memories

NASA Astrophysics Data System (ADS)

Ritter, Gerhard X.; Schmalz, Mark S.; Hayden, Eric; Tucker, Marc

2011-09-01

Linear classifiers based on computation over the real numbers R (e.g., with operations of addition and multiplication) denoted by (R, +, x), have been represented extensively in the literature of pattern recognition. However, a different approach to pattern classification involves the use of addition, maximum, and minimum operations over the reals in the algebra (R, +, maximum, minimum) These pattern classifiers, based on lattice algebra, have been shown to exhibit superior information storage capacity, fast training and short convergence times, high pattern classification accuracy, and low computational cost. Such attributes are not always found, for example, in classical neural nets based on the linear inner product. In a special type of lattice associative memory (LAM), called a dendritic LAM or DLAM, it is possible to achieve noise-tolerant pattern classification by varying the design of noise or error acceptance bounds. This paper presents theory and algorithmic approaches for the computation of noise-tolerant lattice associative memories (LAMs) under a variety of input constraints. Of particular interest are the classification of nonergodic data in noise regimes with time-varying statistics. DLAMs, which are a specialization of LAMs derived from concepts of biological neural networks, have successfully been applied to pattern classification from hyperspectral remote sensing data, as well as spatial object recognition from digital imagery. The authors' recent research in the development of DLAMs is overviewed, with experimental results that show utility for a wide variety of pattern classification applications. Performance results are presented in terms of measured computational cost, noise tolerance, classification accuracy, and throughput for a variety of input data and noise levels.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

[The antigravity suit, chamberless type, as a means of increasing orthostatic tolerance after water immersion hypokinesis and acceleration].

PubMed

Shul'zhenko, E B; Kozlova, V G; Kurdin, K A; Iarov, A S; Plokhova, V G

1983-01-01

Orthostatic tolerance after 7-day dry immersion and head-to-feet acceleration was investigated on test subjects with and without an antigravity suit of bladderless type. With the suit on, the 20 min tilt test at 70 degrees prior to immersion induced less marked changes than without the suit. When the suit was on, cardiovascular reactions to tilt tests after immersion and acceleration improved. The maximum heart rate decreased from 135 +/- 4 to 101 +/- 5 beats/min (p less than 0.01), minimum stroke volume increased from 29 +/- 2 to 41 +/- 3 ml (p less than 0.05), and pulse pressure grew. Thus, an antigravity suit may help increase initial orthostatic tolerance and maintain it after the combined effect of simulated hypogravity and acceleration.

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

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

Noise-margin limitations on gallium-arsenide VLSI

NASA Technical Reports Server (NTRS)

Long, Stephen I.; Sundaram, Mani

1988-01-01

Two factors which limit the complexity of GaAs MESFET VLSI circuits are considered. Power dissipation sets an upper complexity limit for a given logic circuit implementation and thermal design. Uniformity of device characteristics and the circuit configuration determines the electrical functional yield. Projection of VLSI complexity based on these factors indicates that logic chips of 15,000 gates are feasible with the most promising static circuits if a maximum power dissipation of 5 W per chip is assumed. While lower power per gate and therefore more gates per chip can be obtained by using a popular E/D FET circuit, yields are shown to be small when practical device parameter tolerances are applied. Further improvements in materials, devices, and circuits wil be needed to extend circuit complexity to the range currently dominated by silicon.

A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia☆

PubMed Central

Maddocks, Kami; Ruppert, Amy S.; Browning, Rebekah; Jones, Jeffrey; Flynn, Joseph; Kefauver, Cheryl; Gao, Yue; Jiang, Yao; Rozewski, Darlene M.; Poi, Ming; Phelps, Mitch A.; Harper, Erica; Johnson, Amy J.; Byrd, John C.; Andritsos, Leslie A.

2015-01-01

Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5 mg followed by 5.0 mg continuous. In Cohort A, tumor flare grade 1–2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD. PMID:25082342

Interference-Fit Life Factors for Ball Bearings

NASA Technical Reports Server (NTRS)

Oswald, Fred B.; Zaretsky, Erwin V.; Poplawski, Joseph V.

2010-01-01

The effect of hoop stresses on the rolling-element fatigue life of angular-contact and deep-groove ball bearings was determined for common inner-ring interference fits at the ABEC-5 tolerance level. The analysis was applied to over 1150 bearing configurations and load cases. Hoop stresses were superimposed on the Hertzian principal stresses created by the applied bearing load to calculate the inner-race maximum shearing stress. The resulting fatigue life of the bearing was recalculated through a series of equations. The reduction in the fatigue life is presented as life factors that are applied to the unfactored bearing life. The life factors found in this study ranged from 1.00 (no life reduction)--where there was no net interface pressure--to a worst case of 0.38 (a 62-percent life reduction). For a given interference fit, the reduction in life is different for angular-contact and deep-groove ball bearings. Interference fits also affect the maximum Hertz stress-life relation. Experimental data of Czyzewski, showing the effect of interference fit on rolling-element fatigue life, were reanalyzed to determine the shear stress-life exponent. The Czyzewski data shear stress-life exponent c equals 8.77, compared with the assumed value of 9. Results are presented as tables and charts of life factors for angular-contact and deep-groove ball bearings with light, normal, and heavy loads and interference fits ranging from extremely light to extremely heavy.

Estimating Long-Term Survival Temperatures at the Assemblage Level in the Marine Environment: Towards Macrophysiology

PubMed Central

Richard, Joëlle; Morley, Simon Anthony; Thorne, Michael A. S.; Peck, Lloyd Samuel

2012-01-01

Defining ecologically relevant upper temperature limits of species is important in the context of environmental change. The approach used in the present paper estimates the relationship between rates of temperature change and upper temperature limits for survival in order to evaluate the maximum long-term survival temperature (Ts). This new approach integrates both the exposure time and the exposure temperature in the evaluation of temperature limits. Using data previously published for different temperate and Antarctic marine environments, we calculated Ts in each environment, which allowed us to calculate a new index: the Warming Allowance (WA). This index is defined as the maximum environmental temperature increase which an ectotherm in a given environment can tolerate, possibly with a decrease in performance but without endangering survival over seasonal or lifetime time-scales. It is calculated as the difference between maximum long-term survival temperature (Ts) and mean maximum habitat temperature. It provides a measure of how close a species, assemblage or fauna are living to their temperature limits for long-term survival and hence their vulnerability to environmental warming. In contrast to data for terrestrial environments showing that warming tolerance increases with latitude, results here for marine environments show a less clear pattern as the smallest WA value was for the Peru upwelling system. The method applied here, relating upper temperature limits to rate of experimental warming, has potential for wide application in the identification of faunas with little capacity to survive environmental warming. PMID:22509340

7 CFR 1493.40 - Application for payment guarantee.

Code of Federal Regulations, 2011 CFR

2011-01-01

... CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Export Credit Guarantee Program (GSM-102) and CCC Intermediate Export Credit Guarantee Program..., contract loading tolerance and, if necessary, a request for CCC to reserve coverage up to the maximum...

7 CFR 1493.40 - Application for payment guarantee.

Code of Federal Regulations, 2010 CFR

2010-01-01

... CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Export Credit Guarantee Program (GSM-102) and CCC Intermediate Export Credit Guarantee Program..., contract loading tolerance and, if necessary, a request for CCC to reserve coverage up to the maximum...

Intraspecific individual variation of temperature tolerance associated with oxygen demand in the European sea bass (Dicentrarchus labrax)

PubMed Central

Ozolina, Karlina; Shiels, Holly A; Ollivier, Hélène; Claireaux, Guy

2016-01-01

Abstract The European sea bass (Dicentrarchus labrax) is an economically important fish native to the Mediterranean and Northern Atlantic. Its complex life cycle involves many migrations through temperature gradients that affect the energetic demands of swimming. Previous studies have shown large intraspecific variation in swimming performance and temperature tolerance, which could include deleterious and advantageous traits under the evolutionary pressure of climate change. However, little is known of the underlying determinants of this individual variation. We investigated individual variation in temperature tolerance in 30 sea bass by exposing them to a warm temperature challenge test. The eight most temperature-tolerant and eight most temperature-sensitive fish were then studied further to determine maximal swimming speed (UCAT), aerobic scope and post-exercise oxygen consumption. Finally, ventricular contractility in each group was determined using isometric muscle preparations. The temperature-tolerant fish showed lower resting oxygen consumption rates, possessed larger hearts and initially recovered from exhaustive exercise faster than the temperature-sensitive fish. Thus, whole-animal temperature tolerance was associated with important performance traits. However, the temperature-tolerant fish also demonstrated poorer maximal swimming capacity (i.e. lower UCAT) than their temperature-sensitive counterparts, which may indicate a trade-off between temperature tolerance and swimming performance. Interestingly, the larger relative ventricular mass of the temperature-tolerant fish did not equate to greater ventricular contractility, suggesting that larger stroke volumes, rather than greater contractile strength, may be associated with thermal tolerance in this species. PMID:27382468

Intraspecific individual variation of temperature tolerance associated with oxygen demand in the European sea bass (Dicentrarchus labrax).

PubMed

Ozolina, Karlina; Shiels, Holly A; Ollivier, Hélène; Claireaux, Guy

2016-01-01

The European sea bass (Dicentrarchus labrax) is an economically important fish native to the Mediterranean and Northern Atlantic. Its complex life cycle involves many migrations through temperature gradients that affect the energetic demands of swimming. Previous studies have shown large intraspecific variation in swimming performance and temperature tolerance, which could include deleterious and advantageous traits under the evolutionary pressure of climate change. However, little is known of the underlying determinants of this individual variation. We investigated individual variation in temperature tolerance in 30 sea bass by exposing them to a warm temperature challenge test. The eight most temperature-tolerant and eight most temperature-sensitive fish were then studied further to determine maximal swimming speed (U CAT), aerobic scope and post-exercise oxygen consumption. Finally, ventricular contractility in each group was determined using isometric muscle preparations. The temperature-tolerant fish showed lower resting oxygen consumption rates, possessed larger hearts and initially recovered from exhaustive exercise faster than the temperature-sensitive fish. Thus, whole-animal temperature tolerance was associated with important performance traits. However, the temperature-tolerant fish also demonstrated poorer maximal swimming capacity (i.e. lower U CAT) than their temperature-sensitive counterparts, which may indicate a trade-off between temperature tolerance and swimming performance. Interestingly, the larger relative ventricular mass of the temperature-tolerant fish did not equate to greater ventricular contractility, suggesting that larger stroke volumes, rather than greater contractile strength, may be associated with thermal tolerance in this species.

Noise tolerance in optical waveguide circuits for recognition of optical 16 quadrature amplitude modulation codes

NASA Astrophysics Data System (ADS)

Inoshita, Kensuke; Hama, Yoshimitsu; Kishikawa, Hiroki; Goto, Nobuo

2016-12-01

In photonic label routers, various optical signal processing functions are required; these include optical label extraction, recognition of the label, optical switching and buffering controlled by signals based on the label information and network routing tables, and label rewriting. Among these functions, we focus on photonic label recognition. We have proposed two kinds of optical waveguide circuits to recognize 16 quadrature amplitude modulation codes, i.e., recognition from the minimum output port and from the maximum output port. The recognition function was theoretically analyzed and numerically simulated by finite-difference beam-propagation method. We discuss noise tolerance in the circuit and show numerically simulated results to evaluate bit-error-rate (BER) characteristics against optical signal-to-noise ratio (OSNR). The OSNR required to obtain a BER less than 1.0×10-3 for the symbol rate of 2.5 GBaud was 14.5 and 27.0 dB for recognition from the minimum and maximum output, respectively.

+Gz tolerance after 14 days bed rest and the effects of rehydration.

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Van Beaumont, W.; Bernauer, E. M.; Haines, R. F.; Sandler, H.; Young, H. L.; Yusken, J. W.

1972-01-01

Measurement of the reduction in centrifugation tolerance after two weeks of bedrest with moderate daily exercise, with an attempt to determine if rehydration improves +Gz tolerance. There were significant reductions in +Gz tolerance during bedrest periods at three acceleration levels. Rehydration resulted in a significant increase in tolerance at 2.1G but it did not restore tolerance to control levels. Rehydration did not affect tolerance at 3.2G and 3.8G.

Long-term safety, tolerability, and efficacy of α1-adrenergic blocker in young men with primary bladder neck obstruction: results from a single centre in China.

PubMed

Li, Bing; Gao, Wansheng; Dong, Chuanjiang; Han, Xiaomin; Li, Shuqiang; Jia, Renfeng; Xiao, Chuanguo

2012-06-01

Primary bladder neck obstruction (PBNO) is a nonneurogenic voiding disorder and frequently overlooked in young men. Prior studies have reported the efficacy of α-blockers only in the short-term for male patients with PBNO. We hereby report our long-term results using α1-blocker therapy in young men with PBNO. Between January 2005 and December 2009, PBNO was diagnosed in 30 young men (mean age 27.3 years, range 18-35) at our institution. Doxazosin 4 mg once daily was administered for at least 12 months. Safety and tolerability were assessed, and efficacy was evaluated from International Prostate Symptom Score (I-PSS), Quality of Life (QOL), uroflowmetry, and post-void residual following 3- and 12-month treatment. Successful treatment was defined as at least 3 ml per second increase in the maximum flow rate and more than a 40% decrease in I-PSS. In all 30 patients, Mean symptom duration was 26.4 (3-65) months. The most common symptoms were hesitancy (93.3%), weak stream (76.7%), and frequency (66.7%). A total of 24 patients (80%, 24/30) successfully completed the 12 month of treatment. The medication period was 15.2 months, and follow-up duration was 16.3 months. Doxazosin was safe and well tolerated. The efficacy of doxazosin was maintained over the 12-month treatment period. Relative to baseline, there were reductions in the number of mean I-PSS (from 17.7 ± 4.2 to 10.4 ± 4.8), mean QOL (from 4.2 ± 1.1 to 2.4 ± 1.3), and mean post-void residual urine (from 79.3 ± 33.4 to 47.1 ± 21.3), and an increase in mean maximum flow rate (from 11.4 ± 2.9 to 15.1 ± 3.2 ml) after 12-month treatment. Treatment was successful in 16 patients (66.7%, 16/24) according to the improvement in both symptoms and maximum urine flow. α1-blocker therapy displayed a favorable safety, tolerability, and efficacy profile during 12-month treatment in young male patients with PBNO.

Acetone, butanol, and ethanol production from gelatinized cassava flour by a new isolates with high butanol tolerance.

PubMed

Li, Han-Guang; Ofosu, Fred Kwame; Li, Kun-Tai; Gu, Qiu-Ya; Wang, Qiang; Yu, Xiao-Bin

2014-11-01

To obtain native strains resistant to butanol toxicity, a new isolating method and serial enrichment was used in this study. With this effort, mutant strain SE36 was obtained, which could withstand 35g/L (compared to 20g/L of the wild-type strain) butanol challenge. Based on 16s rDNA comparison, the mutant strain was identified as Clostridium acetobutylicum. Under the optimized condition, the phase shift was smoothly triggered and fermentation performances were consequently enhanced. The maximum total solvent and butanol concentration were 23.6% and 24.3%, respectively higher than that of the wild-type strain. Furthermore, the correlation between butanol produced and the butanol tolerance was investigated, suggesting that enhancing butanol tolerance could improve butanol production. These results indicate that the simple but effective isolation method and acclimatization process are a promising technique for isolation and improvement of butanol tolerance and production. Copyright © 2014 Elsevier Ltd. All rights reserved.

Stress response in medically important Mucorales.

PubMed

Singh, Pankaj; Paul, Saikat; Shivaprakash, M Rudramurthy; Chakrabarti, Arunaloke; Ghosh, Anup K

2016-10-01

Mucorales are saprobes, ubiquitously distributed and able to infect a heterogeneous population of human hosts. The fungi require robust stress responses to survive in human host. We tested the growth of Mucorales in the presence of different abiotic stress. Eight pathogenic species of Mucorales, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Apophysomyces elegans, Licthemia corymbifera, Cunninghamella bertholletiae, Syncephalastrum racemosum and Mucor racemosus, were exposed to different stress inducers: osmotic (sodium chloride and d-sorbitol), oxidative (hydrogen peroxide and menadione), pH, cell wall and metal ions (Cu, Zn, Fe and Mg). Wide variation in stress responses was noted: R. arrhizus showed maximum resistance to both osmotic and oxidative stresses, whereas R. pusillus and M. indicus were relatively sensitive. Rhizopus arrhizus and R. microsporus showed maximum resistance to alkaline pH, whereas C. bertholletiae, L. corymbifera, M. racemosus and A. elegans were resistant to acidic pH. Maximum tolerance was noted in R. microsporus to Cu, R. microsporus and R. arrhizus to Fe and C. bertholletiae to Zn. In contrast, L. corymbifera, A. elegans and M. indicus were sensitive to Cu, Zn and Fe respectively. In conclusion, R. arrhizus showed high stress tolerance in comparison to other species of Mucorales, and this could be the possible reason for high pathogenic potential of this fungi. © 2016 Blackwell Verlag GmbH.

Effects of Surface Electrical Stimulation Both at Rest and During Swallowing in Chronic Pharyngeal Dysphagia§

PubMed Central

Ludlow, Christy L.; Humbert, Ianessa; Saxon, Keith; Poletto, Christopher; Sonies, Barbara; Crujido, Lisa

2006-01-01

We tested two hypotheses using surface electrical stimulation in chronic pharyngeal dysphagia: that stimulation 1) lowered the hyoid bone and/or larynx when applied at rest, and 2) increased aspiration, penetration or pharyngeal pooling during swallowing. Bipolar surface electrodes were placed on the skin overlying the submandibular and laryngeal regions. Maximum tolerated levels of stimulation were applied while patients held their mouth closed at rest. Videofluoroscopic recordings were used to measure hyoid movements in the superior-inferior (s-i) and anterior-posterior (a-p) dimensions and the subglottic air column (s-i) position while stimulation was on and off. Patients swallowed 5 ml liquid when stimulation was off, at low sensory stimulation levels, and at maximum tolerated levels (motor). Speech pathologists blinded to condition, tallied the frequency of aspiration, penetration, pooling and esophageal entry from videofluorographic recordings of swallows. Only significant (p=0.0175) hyoid depression occurred during stimulation at rest. Aspiration and pooling were significantly reduced only with low sensory threshold levels of stimulation (p=0.025) and not during maximum levels of surface electrical stimulation. Those patients who had reduced aspiration and penetration during swallowing with stimulation had greater hyoid depression during stimulation at rest (p= 0.006). Stimulation may have acted to resist patients’ hyoid elevation during swallowing. PMID:16718620

Image fusion using sparse overcomplete feature dictionaries

DOEpatents

Brumby, Steven P.; Bettencourt, Luis; Kenyon, Garrett T.; Chartrand, Rick; Wohlberg, Brendt

2015-10-06

Approaches for deciding what individuals in a population of visual system "neurons" are looking for using sparse overcomplete feature dictionaries are provided. A sparse overcomplete feature dictionary may be learned for an image dataset and a local sparse representation of the image dataset may be built using the learned feature dictionary. A local maximum pooling operation may be applied on the local sparse representation to produce a translation-tolerant representation of the image dataset. An object may then be classified and/or clustered within the translation-tolerant representation of the image dataset using a supervised classification algorithm and/or an unsupervised clustering algorithm.

Evolution of the climatic tolerance and postglacial range changes of the most primitive orchids (Apostasioideae) within Sundaland, Wallacea and Sahul

PubMed Central

Mystkowska, Katarzyna; Kras, Marta; Dudek, Magdalena

2016-01-01

The location of possible glacial refugia of six Apostasioideae representatives is estimated based on ecological niche modeling analysis. The distribution of their suitable niches during the last glacial maximum (LGM) is compared with their current potential and documented geographical ranges. The climatic factors limiting the studied species occurrences are evaluated and the niche overlap between the studied orchids is assessed and discussed. The predicted niche occupancy profiles and reconstruction of ancestral climatic tolerances suggest high level of phylogenetic niche conservatism within Apostasioideae. PMID:27635348

Automated determination of bromide in waters by ion chromatography with an amperometric detector

USGS Publications Warehouse

Pyen, G.S.; Erdmann, D.E.

1983-01-01

An automated ion chromatograph, including a program controller, an automatic sampler, an integrator, and an amperometric detector, was used to develop a procedure for the determination of bromide in rain water and many ground waters. Approximately 10 min is required to obtain a chromatogram. The detection limit for bromide is 0.01 mg l-1 and the relative standard deivation is <5% for bromide concentrations between 0.05 and 0.5 mg l-1. Chloride interferes if the chloride-to-bromide ratio is greater than 1 000:1 for a range of 0.01-0.1 mg l-1 bromide; similarly, chloride interferes in the 0.1-1.0 mg l-1 range if the ratio is greater than 5 000:1. In the latter case, a maximum of 2 000 mg l-1 of chloride can be tolerated. Recoveries of known concentrations of bromide added to several samples, ranged from 97 to 110%. ?? 1983.

77 FR 48899 - Flutriafol; Pesticide Tolerances for Emergency Exemptions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-15

... cotton, undelinted seed; cotton, meal; cotton, refined oil; and cotton gin byproducts. This action is in..., and Rodenticide Act (FIFRA) authorizing use of the pesticide on cotton. This regulation establishes a maximum permissible level for residues of flutriafol in or on cotton commodities. The time-limited...

Automatic, nondestructive test monitors in-process weld quality

NASA Technical Reports Server (NTRS)

Deal, F. C.

1968-01-01

Instrument automatically and nondestructively monitors the quality of welds produced in microresistance welding. It measures the infrared energy generated in the weld as the weld is made and compares this energy with maximum and minimum limits of infrared energy values previously correlated with acceptable weld-strength tolerances.

7 CFR 1493.430 - Application for a payment guarantee.

Code of Federal Regulations, 2010 CFR

2010-01-01

... CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Supplier Credit Guarantee Program Operations § 1493.430 Application for a payment guarantee... request for CCC to reserve coverage up to the maximum quantity permitted by the contract loading tolerance...

7 CFR 1493.430 - Application for a payment guarantee.

Code of Federal Regulations, 2011 CFR

2011-01-01

... CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS CCC EXPORT CREDIT GUARANTEE PROGRAMS CCC Supplier Credit Guarantee Program Operations § 1493.430 Application for a payment guarantee... request for CCC to reserve coverage up to the maximum quantity permitted by the contract loading tolerance...

Electronic modification of Pt via Ti and Se as tolerant cathodes in air-breathing methanol microfluidic fuel cells.

PubMed

Ma, Jiwei; Habrioux, Aurélien; Morais, Cláudia; Alonso-Vante, Nicolas

2014-07-21

We reported herein on the use of tolerant cathode catalysts such as carbon supported Pt(x)Ti(y) and/or Pt(x)Se(y) nanomaterials in an air-breathing methanol microfluidic fuel cell. In order to show the improvement of mixed-reactant fuel cell (MRFC) performances obtained with the developed tolerant catalysts, a classical Pt/C nanomaterial was used for comparison. Using 5 M methanol concentration in a situation where the fuel crossover is 100% (MRFC-mixed reactant fuel cell application), the maximum power density of the fuel cell with a Pt/C cathodic catalyst decreased by 80% in comparison with what is observed in the laminar flow fuel cell (LFFC) configuration. With Pt(x)Ti(y)/C and Pt(x)Se(y)/C cathode nanomaterials, the performance loss was only 55% and 20%, respectively. The evaluation of the tolerant cathode catalysts in an air-breathing microfluidic fuel cell suggests the development of a novel nanometric system that will not be size restricted. These interesting results are the consequence of the high methanol tolerance of these advanced electrocatalysts via surface electronic modification of Pt. Herein we used X-ray photoelectron and in situ FTIR spectroscopies to investigate the origin of the high methanol tolerance on modified Pt catalysts.

Heavy metal tolerance and accumulation of Triarrhena sacchariflora, a large amphibious ornamental grass.

PubMed

Tian, R N; Yu, S; Wang, S G; Zhang, Y; Tang, J Y; Liu, Y L; Nie, Y H

2013-01-01

In this study, we report the tolerance and accumulation of Triarrhena sacchariflora to copper (Cu) and cadmium (Cd). The results show that T. sacchariflora had strong tolerance to Cu and Cd stress. The tolerance indexes (TI) were greater than 0.5 for all treatments. The bioconcentration factors (BCFs) to Cu and Cd were both above 1.0. The accumulation ability of roots was stronger than that of shoots, and ranges of BCF to Cu and Cd in roots were 37.89-79.08 and 83.96-300.57, respectively. However, the translocation ability to Cu and Cd was weak, with more than 86% of Cu or Cd accumulated in roots, suggesting an exclusion strategy for heavy metal tolerance. The uptake efficiency (UE) and translocation efficiency (TE) to Cu and Cd increased linearly as the Cu and Cd concentration in the substrate increased. UE was higher than TE, with a maximum of 2,118.90 μg g(-1) root dry weight (DW) (50 mg L(-1) Cu) and 1,847.51 μg g(-1) root DW (20 mg L(-1)Cd), respectively. The results indicate that T. sacchariflora is a Cu- and Cd-tolerant non-hyperaccumulator plant, suggesting that T. sacchariflora could play an important role in phytoremediation in areas contaminated with Cu and Cd.

Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.

PubMed

He, Xiao-Tao; Zhou, Kai-Xiang; Zhao, Wen-Jun; Zhang, Chen; Deng, Jian-Ping; Chen, Fa-Ming; Gu, Ze-Xu; Li, Yun-Qing; Dong, Yu-Lin

2018-01-01

The easily developed morphine tolerance in bone cancer pain (BCP) significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs) regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI), we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT) and percentage maximum possible effects (MPEs) decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

PubMed Central

2010-01-01

Background YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. Methods This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. Results Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. Conclusions The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. Trial registration ClinicalTrials.gov unique identifier: NCT00633490 PMID:20923544

Spinal Cord Tolerance to Single-Fraction Partial-Volume Irradiation: A Swine Model

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

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed; Foster, Ryan D.; Kogel, Albert J. van der

2011-01-01

Purpose: To determine the spinal cord tolerance to single-fraction, partial-volume irradiation in swine. Methods and Materials: A 5-cm-long cervical segment was irradiated in 38-47-week-old Yucatan minipigs using a dedicated, image-guided radiosurgery linear accelerator. The radiation was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter that was positioned lateral to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10% isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. The dose was prescribed to the 90% isodose line. A total of 26 pigs were stratified into eightmore » dose groups of 12-47 Gy. The mean maximum spinal cord dose was 16.9 {+-} 0.1, 18.9 {+-} 0.1, 21.0 {+-} 0.1, 23.0 {+-} 0.2, and 25.3 {+-} 0.3 Gy in the 16-, 18-, 20-, 22-, and 24-Gy dose groups, respectively. The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 43% {+-} 3%, 48% {+-} 4%, 51% {+-} 2%, 57% {+-} 2%, and 59% {+-} 4%. The study endpoint was motor neurologic deficit determined by a change in gait during a 1-year follow-up period. Results: A steep dose-response curve was observed with a median effective dose for the maximum dose point of 20.0 Gy (95% confidence interval, 18.3-21.7). Excellent agreement was observed between the occurrence of neurologic change and the presence of histologic change. All the minipigs with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of the gray matter. The histologic findings were unremarkable in the minipigs with normal neurologic status. Conclusions: Our results have indicated that for a dose distribution with a steep lateral gradient, the pigs had a lower median effective dose for paralysis than has been observed in rats and more closely resembles that for rats, mice, and guinea pigs receiving uniform spinal cord irradiation.« less

Spinal Cord Tolerance to Reirradiation With Single-Fraction Radiosurgery: A Swine Model

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

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.edu; Foster, Ryan D.; Kogel, Albert J. van der

2012-07-01

Purpose: This study was performed to determine swine spinal cord tolerance to single-fraction, partial-volume irradiation 1 year after receiving uniform irradiation to 30 Gy in 10 fractions. Methods and Materials: A 10-cm length of spinal cord (C3-T1) was uniformly irradiated to 30 Gy in 10 consecutive fractions and reirradiated 1 year later with a single radiosurgery dose centered within the previously irradiated segment. Radiosurgery was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter, which was positioned laterally to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10%more » isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. Twenty-three pigs were stratified into six dose groups with mean maximum spinal cord doses of 14.9 {+-} 0.1 Gy (n = 2), 17.1 {+-} 0.3 Gy (n = 3), 19.0 {+-} 0.1 Gy (n = 5), 21.2 {+-} 0.1 Gy (n = 5), 23.4 {+-} 0.2 Gy (n = 5), and 25.4 {+-} 0.4 Gy (n = 3). The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 34% {+-} 1%, 40% {+-} 1%, 46% {+-} 3%, 52% {+-} 1%, 56 {+-} 3%, and 57% {+-} 1%. The study endpoint was motor neurologic deficit as determined by a change in gait during a 1- year follow-up period. Results: A steep dose-response curve was observed with a 50% incidence of paralysis (ED{sub 50}) for the maximum point dose of 19.7 Gy (95% confidence interval, 17.4-21.4). With two exceptions, histology was unremarkable in animals with normal neurologic status, while all animals with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of gray matter. Histologic comparison with a companion study of de novo irradiated animals revealed that retreatment responders had more extensive tissue damage, including infarction of gray matter, only at prescription doses >20 Gy. Conclusion: Pigs receiving spinal radiosurgery 1 year after receiving 30 Gy in 10 fractions were not at significantly higher risk of developing motor deficits than pigs that received radiosurgery alone.« less

Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

PubMed Central

Yeo, Winnie; Chung, Hyun C.; Chan, Stephen L.; Wang, Ling Z.; Lim, Robert; Picus, Joel; Boyer, Michael; Mo, Frankie K.F.; Koh, Jane; Rha, Sun Y.; Hui, Edwin P.; Jeung, Hei C.; Roh, Jae K.; Yu, Simon C.H.; To, Ka F.; Tao, Qian; Ma, Brigette B.; Chan, Anthony W.H.; Tong, Joanna H.M.; Erlichman, Charles; Chan, Anthony T.C.; Goh, Boon C.

2012-01-01

Purpose Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). Conclusion Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization. PMID:22915658

Determination of the optimal tolerance for MLC positioning in sliding window and VMAT techniques

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

Hernandez, V., E-mail: vhernandezmasgrau@gmail.com; Abella, R.; Calvo, J. F.

2015-04-15

Purpose: Several authors have recommended a 2 mm tolerance for multileaf collimator (MLC) positioning in sliding window treatments. In volumetric modulated arc therapy (VMAT) treatments, however, the optimal tolerance for MLC positioning remains unknown. In this paper, the authors present the results of a multicenter study to determine the optimal tolerance for both techniques. Methods: The procedure used is based on dynalog file analysis. The study was carried out using seven Varian linear accelerators from five different centers. Dynalogs were collected from over 100 000 clinical treatments and in-house software was used to compute the number of tolerance faults as amore » function of the user-defined tolerance. Thus, the optimal value for this tolerance, defined as the lowest achievable value, was investigated. Results: Dynalog files accurately predict the number of tolerance faults as a function of the tolerance value, especially for low fault incidences. All MLCs behaved similarly and the Millennium120 and the HD120 models yielded comparable results. In sliding window techniques, the number of beams with an incidence of hold-offs >1% rapidly decreases for a tolerance of 1.5 mm. In VMAT techniques, the number of tolerance faults sharply drops for tolerances around 2 mm. For a tolerance of 2.5 mm, less than 0.1% of the VMAT arcs presented tolerance faults. Conclusions: Dynalog analysis provides a feasible method for investigating the optimal tolerance for MLC positioning in dynamic fields. In sliding window treatments, the tolerance of 2 mm was found to be adequate, although it can be reduced to 1.5 mm. In VMAT treatments, the typically used 5 mm tolerance is excessively high. Instead, a tolerance of 2.5 mm is recommended.« less

75 FR 29969 - Environmental Impact Statement; Determination of Nonregulated Status of Sugar Beet Genetically...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-28

... Tolerance to the Herbicide Glyphosate AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION... genetically engineered for tolerance to the herbicide glyphosate. The petition stated that this article should...-tolerant sugar beet systems. What are the impacts of weeds, herbicide-tolerant weeds, weed management...

40 CFR 180.444 - Sulfur dioxide; tolerances for residues.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Sulfur dioxide; tolerances for... § 180.444 Sulfur dioxide; tolerances for residues. A tolerance is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) in or on the following raw agricultural...

40 CFR 180.444 - Sulfur dioxide; tolerances for residues.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 25 2012-07-01 2012-07-01 false Sulfur dioxide; tolerances for... § 180.444 Sulfur dioxide; tolerances for residues. (a) General. A tolerance is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) in or on the following raw...

40 CFR 180.444 - Sulfur dioxide; tolerances for residues.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Sulfur dioxide; tolerances for... § 180.444 Sulfur dioxide; tolerances for residues. (a) General. A tolerance is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) in or on the following raw...

40 CFR 180.444 - Sulfur dioxide; tolerances for residues.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Sulfur dioxide; tolerances for... § 180.444 Sulfur dioxide; tolerances for residues. (a) General. A tolerance is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) in or on the following raw...

40 CFR 180.444 - Sulfur dioxide; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Sulfur dioxide; tolerances for... § 180.444 Sulfur dioxide; tolerances for residues. A tolerance is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) in or on the following raw agricultural...

Change in blood coagulation indices as a function of the incubation period of plasma in a constant magnetic field. [considering heparin tolerance and recalcification

NASA Technical Reports Server (NTRS)

Yepishina, S. G.

1974-01-01

The influence of a constant magnetic field (CMF) with a strength of 250 and 2500 oersteds on the recalcification reaction and the tolerance of plasma to heparin was studied as a function of the exposure time of the plasma to the CMF. The maximum and reliable change in the activation of the coagulatory system of the blood was observed after a 20-hour incubation of the plasma in a CMF. As the exposure time increased, the recalcification reaction changed insigificantly; the difference between the mean arithmetic of the experiment and control values was not statistically reliable. The tolerance of the plasma to heparin as a function of the exposure time to the CMF of the plasma was considerably modified, an was statistically reliable.

Low velocity instrumented impact testing of four new damage tolerant carbon/epoxy composite systems

NASA Technical Reports Server (NTRS)

Lance, D. G.; Nettles, A. T.

1990-01-01

Low velocity drop weight instrumented impact testing was utilized to examine the damage resistance of four recently developed carbon fiber/epoxy resin systems. A fifth material, T300/934, for which a large data base exists, was also tested for comparison purposes. A 16-ply quasi-isotropic lay-up configuration was used for all the specimens. Force/absorbed energy-time plots were generated for each impact test. The specimens were cross-sectionally analyzed to record the damage corresponding to each impact energy level. Maximum force of impact versus impact energy plots were constructed to compare the various systems for impact damage resistance. Results show that the four new damage tolerant fiber/resin systems far outclassed the T300/934 material. The most damage tolerant material tested was the IM7/1962 fiber/resin system.

Intraspecific variability of Steinernema feltiae strains from Cemoro Lawang, eastern Java, Indonesia.

PubMed

Addis, T; Mulawarman, M; Waeyenberge, L; Moens, M; Viaene, N; Ehlers, R U

2010-01-01

Four strains of Steinernema feltiae from Eastern Java, Indonesia were characterized based on morphometric, morphological and molecular data. In addition, their virulence against last instar Tenebrio molitor and heat tolerance was tested. Infective juvenile have a mean body length ranging from 749 to 792 microm. The maximum sequence difference among the four strains was 7 bp (8.8%) in the ITS and 2 bp (0.3%) in D2D3 regions of the rDNA. All the strains are not reproductively isolated and can reproduce with European strain S. feltiae Owiplant. The lowest LC50 was observed for strain SCM (373) and the highest for S. feltiae strain Owiplant (458) IJs/40 T. molitor. All four strains showed relatively better mean heat tolerance when compared with S. feltiae Owiplant, both in adapted and non-adapted heat tolerance experiments.

Some low homogenization pressures improve certain probiotic characteristics of yogurt culture bacteria and Lactobacillus acidophilus LA-K.

PubMed

Muramalla, T; Aryana, K J

2011-08-01

Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus salivarius ssp. thermophilus, and Lactobacillus acidophilus are dairy cultures widely used in the manufacture of cultured dairy products. Commonly used homogenization pressures in the dairy industry are 13.80 MPa or less. It is not known whether low homogenization pressures can stimulate bacteria to improve their probiotic characteristics. Objectives were to determine the effect of homogenization at 0, 3.45, 6.90, 10.34, and 13.80 MPa on acid tolerance, bile tolerance, protease activity, and growth of L. delbrueckii ssp. bulgaricus LB-12, S. salivarius ssp. thermophilus ST-M5, and L. acidophilus LA-K. The cultures were individually inoculated in cool autoclaved skim milk (4°C) and homogenized for 5 continuous passes. Growth and bile tolerance of samples were determined hourly for 10h of incubation. Acid tolerance was determined every 20 min for 120 min of incubation. Protease activity was determined at 0, 12, and 24h of incubation. All homogenization pressures studied improved acid tolerance of L. delbrueckii ssp. bulgaricus LB-12 but had no beneficial effect on protease activity and had negative effects on growth and bile tolerance. A pressure of 6.90 MPa improved acid tolerance, bile tolerance, and protease activity of S. salivarius ssp. thermophilus ST-M5, but none of the homogenization pressures studied had an effect on its growth. Homogenization pressures of 13.80 and 6.90 MPa improved acid tolerance and bile tolerance, respectively, of L. acidophilus LA-K but had no effect on protease activity and its growth. Some low homogenization pressures positively influenced some characteristics of yogurt culture bacteria and L. acidophilus LA-K. Culture pretreatment with some low homogenization pressures can be recommended for improvement of certain probiotic characteristics. Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Overexpression of spinach non-symbiotic hemoglobin in Arabidopsis resulted in decreased NO content and lowered nitrate and other abiotic stresses tolerance

PubMed Central

Bai, Xuegui; Long, Juan; He, Xiaozhao; Yan, Jinping; Chen, Xuanqin; Tan, Yong; Li, Kunzhi; Chen, Limei; Xu, Huini

2016-01-01

A class 1 non-symbiotic hemoglobin family gene, SoHb, was isolated from spinach. qRT-PCR showed that SoHb was induced by excess nitrate, polyethylene glycol, NaCl, H2O2, and salicylic acid. Besides, SoHb was strongly induced by application of nitric oxide (NO) donor, while was suppressed by NO scavenger, nitrate reductase inhibitor, and nitric oxide synthase inhibitor. Overexpression of SoHb in Arabidopsis resulted in decreased NO level and sensitivity to nitrate stress, as shown by reduced root length, fresh weight, the maximum photosystem II quantum ratio of variable to maximum fluorescence (Fv/Fm), and higher malondialdehyde contents. The activities and gene transcription of superoxide dioxidase, and catalase decreased under nitrate stress. Expression levels of RD22, RD29A, DREB2A, and P5CS1 decreased after nitrate treatment in SoHb-overexpressing plants, while increased in the WT plants. Moreover, SoHb-overexpressing plants showed decreased tolerance to NaCl and osmotic stress. In addition, the SoHb-overexpression lines showed earlier flower by regulating the expression of SOC, GI and FLC genes. Our results indicated that the decreasing NO content in Arabidopsis by overexpressing SoHb might be responsible for lowered tolerance to nitrate and other abiotic stresses. PMID:27211528

Studying DDT Susceptibility at Discriminating Time Intervals Focusing on Maximum Limit of Exposure Time Survived by DDT Resistant Phlebotomus argentipes (Diptera: Psychodidae): an Investigative Report.

PubMed

Rama, Aarti; Kesari, Shreekant; Das, Pradeep; Kumar, Vijay

2017-07-24

Extensive application of routine insecticide i.e., dichlorodiphenyltrichloroethane (DDT) to control Phlebotomus argentipes (Diptera: Psychodidae), the proven vector of visceral leishmaniasis in India, had evoked the problem of resistance/tolerance against DDT, eventually nullifying the DDT dependent strategies to control this vector. Because tolerating an hour-long exposure to DDT is not challenging enough for the resistant P. argentipes, estimating susceptibility by exposing sand flies to insecticide for just an hour becomes a trivial and futile task.Therefore, this bioassay study was carried out to investigate the maximum limit of exposure time to which DDT resistant P. argentipes can endure the effect of DDT for their survival. The mortality rate of laboratory-reared DDT resistant strain P. argentipes exposed to DDT was studied at discriminating time intervals of 60 min and it was concluded that highly resistant sand flies could withstand up to 420 min of exposure to this insecticide. Additionally, the lethal time for female P. argentipes was observed to be higher than for males suggesting that they are highly resistant to DDT's toxicity. Our results support the monitoring of tolerance limit with respect to time and hence points towards an urgent need to change the World Health Organization's protocol for susceptibility identification in resistant P. argentipes.

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

PubMed

Egle, Alexander; Steurer, Michael; Melchardt, Thomas; Weiss, Lukas; Gassner, Franz Josef; Zaborsky, Nadja; Geisberger, Roland; Catakovic, Kemal; Hartmann, Tanja Nicole; Pleyer, Lisa; Voskova, Daniela; Thaler, Josef; Lang, Alois; Girschikofsky, Michael; Petzer, Andreas; Greil, Richard

2018-06-04

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).

Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer.

PubMed

Narayan, Vivek; Mamtani, Ronac; Keefe, Stephen; Guzzo, Thomas; Malkowicz, S Bruce; Vaughn, David J

2016-07-01

We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

Evaluation of air pollution tolerance index and anticipated performance index of plants and their application in development of green space along the urban areas.

PubMed

Kaur, Mandeep; Nagpal, Avinash Kaur

2017-08-01

Air pollution due to vehicular emissions has become one of the most serious problems in the whole world and has resulted in huge threat to both the environment and the health of living organisms (plants, humans, animals, microorganisms). Plants growing along the roadsides get affected at the maximum as they are the primary recipients to different air pollutants and show varied levels of tolerance and sensitivity. Taking this into account, the present work was based on assessment of seasonal variation in air pollution tolerance index (APTI) and anticipated performance index (API) of four roadside plants, namely, Alstonia scholaris, Nerium oleander, Tabernaemontana coronaria, and Thevetia peruviana belonging to family Apocynaceae. APTI was calculated by the determination of four important biochemical parameters, viz., pH, relative water content (RWC), total chlorophyll (TChl), and ascorbic acid (AsA) content of leaves. The leaf samples were collected from plants growing at seven different sites of Amritsar (Punjab), India, for pre-monsoon and post-monsoon seasons. Highest APTI (82.14) was reported in N. oleander during the pre-monsoon season while the lowest was recorded in T. coronaria (18.59) in the post-monsoon season. On the basis of API score, A. scholaris was anticipated to be an excellent performer during the pre-monsoon and post-monsoon seasons followed by N. oleander, T. coronaria, and T. peruviana. Linear regression analysis and Pearson's correlation coefficient depicted significant positive correlation between APTI and ascorbic acid content during the pre-monsoon and post-monsoon seasons.

Fungal Traits That Drive Ecosystem Dynamics on Land

PubMed Central

Lennon, Jay T.

2015-01-01

SUMMARY Fungi contribute extensively to a wide range of ecosystem processes, including decomposition of organic carbon, deposition of recalcitrant carbon, and transformations of nitrogen and phosphorus. In this review, we discuss the current knowledge about physiological and morphological traits of fungi that directly influence these processes, and we describe the functional genes that encode these traits. In addition, we synthesize information from 157 whole fungal genomes in order to determine relationships among selected functional genes within fungal taxa. Ecosystem-related traits varied most at relatively coarse taxonomic levels. For example, we found that the maximum amount of variance for traits associated with carbon mineralization, nitrogen and phosphorus cycling, and stress tolerance could be explained at the levels of order to phylum. Moreover, suites of traits tended to co-occur within taxa. Specifically, the genetic capacities for traits that improve stress tolerance—β-glucan synthesis, trehalose production, and cold-induced RNA helicases—were positively related to one another, and they were more evident in yeasts. Traits that regulate the decomposition of complex organic matter—lignin peroxidases, cellobiohydrolases, and crystalline cellulases—were also positively related, but they were more strongly associated with free-living filamentous fungi. Altogether, these relationships provide evidence for two functional groups: stress tolerators, which may contribute to soil carbon accumulation via the production of recalcitrant compounds; and decomposers, which may reduce soil carbon stocks. It is possible that ecosystem functions, such as soil carbon storage, may be mediated by shifts in the fungal community between stress tolerators and decomposers in response to environmental changes, such as drought and warming. PMID:25971588

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer.

PubMed

Takahashi, Shunji; Kobayashi, Takayuki; Tomomatsu, Junichi; Ito, Yoshinori; Oda, Hisanobu; Kajitani, Tatsuhiro; Kakizume, Tomoyuki; Tajima, Takeshi; Takeuchi, Hiromi; Maacke, Heiko; Esaki, Taito

2017-01-01

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. ClinicalTrials.gov NCT01911936.

Finger cold-induced vasodilation of older Korean female divers, haenyeo: effects of chronic cold exposure and aging

NASA Astrophysics Data System (ADS)

Lee, Joo-Young; Park, Joonhee; Koh, Eunsook; Cha, Seongwon

2017-07-01

The aim of the present study was to evaluate the local cold tolerance of older Korean female divers, haenyeo ( N = 22) in terms of cold acclimatization and ageing. As control groups, older non-diving females ( N = 25) and young females from a rural area ( N = 15) and an urban area ( N = 51) participated in this study. To evaluate local cold tolerance, finger cold-induced vasodilation (CIVD) during finger immersion of 4 °C water was examined. As a result, older haenyeos showed greater minimum finger temperature and recovery finger temperature than older non-diving females ( P < 0.05), but similar responses in onset time, peak time, maximum finger temperature, frequency of CIVD, heart rate, blood pressure, and thermal and pain sensations as those of older non-diving females. Another novel finding was that young urban females showed more vulnerable responses to local cold in CIVD variables and subjective sensations when compared to older females, whereas young rural females had the most excellent cold tolerance in terms of maximum temperature and frequency of CIVD among the four groups ( P < 0.05). The present results imply that older haenyeos still retain cold acclimatized features on the periphery even though they changed their cotton diving suits to wet suits in the early 1980s. However, cardiovascular responses and subjective sensations to cold reflect aging effects. In addition, we suggest that young people who have been adapted to highly insulated clothing and indoor heating systems in winter should be distinguished from young people who were exposed to less modern conveniences when compared to the aged in terms of cold tolerance.

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis ▿ §

PubMed Central

Cornely, O. A.; Vehreschild, J. J.; Vehreschild, M. J. G. T.; Würthwein, G.; Arenz, D.; Schwartz, S.; Heussel, C. P.; Silling, G.; Mahne, M.; Franklin, J.; Harnischmacher, U.; Wilkens, A.; Farowski, F.; Karthaus, M.; Lehrnbecher, T.; Ullmann, A. J.; Hallek, M.; Groll, A. H.

2011-01-01

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin. PMID:21911573

Finger cold-induced vasodilation of older Korean female divers, haenyeo: effects of chronic cold exposure and aging.

PubMed

Lee, Joo-Young; Park, Joonhee; Koh, Eunsook; Cha, Seongwon

2017-07-01

The aim of the present study was to evaluate the local cold tolerance of older Korean female divers, haenyeo (N = 22) in terms of cold acclimatization and ageing. As control groups, older non-diving females (N = 25) and young females from a rural area (N = 15) and an urban area (N = 51) participated in this study. To evaluate local cold tolerance, finger cold-induced vasodilation (CIVD) during finger immersion of 4 °C water was examined. As a result, older haenyeos showed greater minimum finger temperature and recovery finger temperature than older non-diving females (P < 0.05), but similar responses in onset time, peak time, maximum finger temperature, frequency of CIVD, heart rate, blood pressure, and thermal and pain sensations as those of older non-diving females. Another novel finding was that young urban females showed more vulnerable responses to local cold in CIVD variables and subjective sensations when compared to older females, whereas young rural females had the most excellent cold tolerance in terms of maximum temperature and frequency of CIVD among the four groups (P < 0.05). The present results imply that older haenyeos still retain cold acclimatized features on the periphery even though they changed their cotton diving suits to wet suits in the early 1980s. However, cardiovascular responses and subjective sensations to cold reflect aging effects. In addition, we suggest that young people who have been adapted to highly insulated clothing and indoor heating systems in winter should be distinguished from young people who were exposed to less modern conveniences when compared to the aged in terms of cold tolerance.

40 CFR 1042.840 - Application requirements for remanufactured engines.

Code of Federal Regulations, 2013 CFR

2013-07-01

... other basic parameters of the engine's design and emission controls. List the fuel type on which your engines are designed to operate (for example, ultra low-sulfur diesel fuel). List each distinguishable... and the range of values for maximum engine power resulting from production tolerances, as described in...

40 CFR 1042.840 - Application requirements for remanufactured engines.

Code of Federal Regulations, 2012 CFR

2012-07-01

... other basic parameters of the engine's design and emission controls. List the fuel type on which your engines are designed to operate (for example, ultra low-sulfur diesel fuel). List each distinguishable... and the range of values for maximum engine power resulting from production tolerances, as described in...

7 CFR 201.55 - Retests.

Code of Federal Regulations, 2010 CFR

2010-01-01

..., Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.55 Retests. Retests shall be made as follows: (a) When the range of 100-seed replicates of a given test exceeds the maximum tolerated range in the table...

7 CFR 201.55 - Retests.

Code of Federal Regulations, 2011 CFR

2011-01-01

..., Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.55 Retests. Retests shall be made as follows: (a) When the range of 100-seed replicates of a given test exceeds the maximum tolerated range in the table...

Influence of G-forces and hypodynamia on the portal system of the liver

NASA Technical Reports Server (NTRS)

Drozdova, A. V.

1975-01-01

Longitudinally and transversely applied g-forces as intolerable levels cause damage to the interlobular veins of the liver, with maximum damage caused by dorso-ventral g-force application. The portal vein system is more resilient with respect to g-forces at the limit of tolerance.

75 FR 28155 - Acephate, Cacodylic acid, Dicamba, Dicloran et al.; Proposed Tolerance Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

... (NAICS code 112). Food manufacturing (NAICS code 311). Pesticide manufacturing (NAICS code 32532). This..., including food service, manufacturing and processing establishments, such as restaurants, cafeterias... concentration shall be limited to a maximum of 1.0 percent active ingredient. Contamination of food or food...

Determination of industrial color tolerance limits: case studies in the textile industry

NASA Astrophysics Data System (ADS)

Gay, Jennifer; Hirschler, Robert

2002-06-01

The approach and findings during the application of instrumental color quality control in industry are described, where the best tolerance formulae and tolerance limits were determined by correlating visual and instrumental evaluations. A panel of previously tested observers evaluated a collection of samples taken from production and color measurements are then compared to these assessments, according to different color difference formulae. T he formula and the limit giving the best agreement with visual evaluations were determined with two different methods. For a large variety of textile substrates, processes and market situations the CMC(2:1) formula was always the best or one of the bests, but the limits varied widely, according to the individual application. Additional shade sorting, based on the tolerance limit, was also applied in several companies. The ideal box size was also determined by comparing visual and instrumental evaluations. The application as logistical tools was established according to individual necessities.

Method and apparatus for faulty memory utilization

DOEpatents

Cher, Chen-Yong; Andrade Costa, Carlos H.; Park, Yoonho; Rosenburg, Bryan S.; Ryu, Kyung D.

2016-04-19

A method for faulty memory utilization in a memory system includes: obtaining information regarding memory health status of at least one memory page in the memory system; determining an error tolerance of the memory page when the information regarding memory health status indicates that a failure is predicted to occur in an area of the memory system affecting the memory page; initiating a migration of data stored in the memory page when it is determined that the data stored in the memory page is non-error-tolerant; notifying at least one application regarding a predicted operating system failure and/or a predicted application failure when it is determined that data stored in the memory page is non-error-tolerant and cannot be migrated; and notifying at least one application regarding the memory failure predicted to occur when it is determined that data stored in the memory page is error-tolerant.

Trace Metal Levels in Rainbow Trout (Oncorhynchus mykiss) Cultured in Net Cages in a Reservoir and Evaluation of Human Health Risks from Consumption.

PubMed

Varol, Memet; Kaya, Gülderen Kurt; Alp, Sumru Anık; Sünbül, Muhammet Raşit

2017-09-19

Although fish consumption has positive health effects, metals accumulated in fish can cause human health risks. In this study, the levels of ten metals in rainbow trout (Oncorhynchus mykiss) farmed in the Keban Dam Reservoir, which has the biggest rainbow trout production capacity in Turkey, were determined and compared with the maximum permissible levels (MPLs). Also, human health risks associated with rainbow trout consumption were assessed. The metal concentrations in rainbow trout were found below the MPLs. The estimated daily intake of each metal was much lower than the respective tolerable daily intake. The target hazard quotient (THQ) for individual metal and total THQ for combined metals did not exceed 1, indicating no health risk for consumers. The cancer risk (CR) value for inorganic arsenic was within the acceptable lifetime risk range of 10 -6 and 10 -4 . For carcinogenic and non-carcinogenic effects, the maximum allowable fish consumption rates were high enough to ensure the human health. According to these results, the consumption of rainbow trout farmed in the Keban Dam Reservoir does not pose a risk on human health.

[Determination of insulin in saliva and its correlation with plasma insulin. Assessment of the possible participation++ of the salivary glands in the production of the hormone].

PubMed

Sánchez García, P; de Portugal Alvarez, J; Alonso Gutiérrez, D; Cruz Hernández, J J

1989-01-01

The finding of immunoreactive insulin (IRI) in saliva and an insulin-like protein, similar to pancreatic insulin and with the same biological activities, suggest that both products are pancreatic insulin stored and/or eliminated in the salival manner or an extrapancreatic hormone synthesis, bearing in mind the features which both glands share. The aim of this study is to ascertain whether the amount of insulin from saliva depends on plasmatic insulin and, if so, whether this is a form of elimination. Our results pointed out that the amount of insulin in saliva is similar to the plasmatic insulin in those patients with normal pancreatic function. The oral glucose tolerance test was carried out on 20 patients. The maximum insulin level was produced at the same time as maximum serum glucose level, taking place 60 minutes later. These data, support the concept that salival insulin is a product of the elimination more than synthesis by salival glands, however we can not exclude the possibility of synthesis by the salival gland without direct studies, the ideal test being the immunocytochemist.

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.

PubMed

LoRusso, Patricia M; Infante, Jeffrey R; Kim, Kevin B; Burris, Howard A; Curt, Gregory; Emeribe, Ugochi; Clemett, Delyth; Tomkinson, Helen K; Cohen, Roger B

2017-03-06

The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors. This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m 2 or dacarbazine 1000 mg/m 2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A. A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine. The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors. ClinicalTrials.gov NCT00600496; registered 8 July 2009.

Switchgrass (Panicum virgatum L.) Intraspecific Variation and Thermotolerance Classification Using in Vitro Seed Germination Assay

DOE PAGES

Seepaul, Ramdeo; Macoon, Bisoondat; Reddy, K. Raja; ...

2011-01-01

Cardinal temperatures for plant processes have been used for thermotolerance screening of genotypes, geoclimatic adaptability determination and phenological prediction. Current simulation models for switchgrass (Panicum virgatum L.) utilize single cardinal temperatures across genotypes for both vegetative and reproductive processes although in-tra-specific variation exists among genotypes. An experiment was conducted to estimate the cardinal temperatures for seed germination of 14 diverse switchgrass genotypes and to classify genotypes for temperature tolerance. Stratified seeds of each genotype were germinated at eight constant temperatures from 10 °C to 45 °C under a constant light intensity of 35 μmol m -2s -1 for 12 hdmore » -1. Germination was recorded at 6-h intervals in all treatments. Maximum seed germination (MSG) and germination rate (GR), estimated by fitting Sigmoidal function to germination-time series data, varied among genotypes. Quadratic and bilinear models best described the MSG and GR responses to temperature, respectively. The mean cardinal temperatures, T min, T opt, and T max, were 8.1, 26.6, and 45.1 °C for MSG and 11.1, 33.1, and 46.0 °C for GR, respectively. Cardinal temperatures for MSG and GR; however, varied significantly among genotypes. Genotypes were classified as sensitive (Cave-in-Rock, Dacotah, Expresso, Forestburg, Kanlow, Sunburst, Trailblazer, and Tusca), intermediate (Alamo, Blackwell, Carthage, Shawnee, and Shelter) and tolerant (Summer) to high temperature based on cumulative temperature response index (CTRI) estimated by summing individual response indices estimated from the MSG and GR cardinal temperatures. Similarly, genotypes were also classified as sensitive (Alamo, Blackwell, Carthage, Dacotah, Shawnee, Shelter and Summer), moderately sensitive (Cave-in-rock, Forestburg, Kanlow, Sunburst, and Tusca), moderately tolerant (Trailblazer), and tolerant (Expresso) to low temperatures. The cardinal temperature estimates would be useful to improve switchgrass models for field applications. Additionally, the identified cold- and heat-tolerant genotypes can be selected for niche environments and in switchgrass breeding programs to develop new genotypes for low and high temperature environments.« less

Microbial Diversity of Emalahleni Mine Water in South Africa and Tolerance Ability of the Predominant Organism to Vanadium and Nickel

PubMed Central

Kamika, Ilunga; Momba, Maggie N. B.

2014-01-01

The present study aims firstly at determining the microbial diversity of mine-water collected in Emalahleni, South Africa and secondly isolating and characterizing the most dominant bacterial species found in the mine water in terms of its resistance to both V5+ and Ni2+ in a modified wastewater liquid media. The results revealed a microbial diversity of 17 orders, 27 families and 33 genera were found in the mine-water samples with Marinobacteria (47.02%) and Anabaena (17.66%) being the most abundant genera. Considering their abundance in the mine-water samples, a species of the Marinobacter genera was isolated, identified, and characterised for metal tolerance and removal ability. The MWI-1 isolate (Marinobacter sp. MWI-1 [AB793286]) was found to be closely related to Marinobacter goseongensis at 97% of similarity. The isolate was exposed to various concentrations of Ni2+ and V5+ in wastewater liquid media and its tolerance to metals was also assessed. The MWI-1 isolate could tolerate V5+ and Ni2+ separately at concentrations (in terms of MIC) up to 13.41±0.56 mM and 5.39±0.5 mM at pH 7, whereas at pH 3, the tolerance limit decrease to 11.45±0.57 mM and 2.67±0.1 mM, respectively. The removal of V5+ and Ni2+ in liquid media was noted to gradually decrease with a gradual increase of the test metals. A significant difference (p<0.05) between V5+ and Ni2+ removal was noted. Marinobacter sp. MWI-1 achieved the maximum permissible limit of 0.1 mg-V5+/L prescribed by UN-FAO at 100 mg/L, while at 200 mg/L only V5+ was removed at approximately 95% and Ni2+ at 47%. This study suggests that mine-water indigenous microorganisms are the best solution for the remediation of polluted mine water. PMID:24465951

78 FR 13305 - Syngenta Seeds, Inc., and Bayer CropScience AG; Availability of Petition for Determination of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

... Status of Soybean Genetically Engineered for Herbicide Tolerance AGENCY: Animal and Plant Health... SYHTOH2, which has been genetically engineered for tolerance to the herbicides glufosinate and mesotrione... engineered to tolerate exposure to the herbicides glufosinate and mesotrione. Glufosinate tolerance is not a...

Intradetrusor Injections of Onabotulinum Toxin-A in Children With Urinary Incontinence due to Neurogenic Detrusor Overactivity Refractory to Antimuscarinic Treatment.

PubMed

Tarcan, Tufan; Akbal, Cem; Sekerci, Cağri A; Top, Tuncay; Simşek, Ferruh

2014-04-01

This was a prospective single-arm study to assess the efficacy and safety of intradetrusor injections of onabotulinum toxin-A in children with urinary incontinence associated with neurogenic detrusor overactivity due to myelomeningocele. All patients had failed the first-line treatment of a combination of oral antimuscarinics and intermittent catheterization. The study group consisted of 31 children with myelomeningocele with a mean age of 7.95 years (range, 5-3 years) who were followed up for a mean of 29 weeks. The amount of onabotulinum toxin A injected was 10 U/kg with a maximal dose of 300 U. There were 20 to 30 injection sites with rigid cystoscopic guidance under general anesthesia. Thirty of 31 patients reported dryness between intermittent catheterization intervals. The mean reduction in maximum detrusor pressure and the mean increase in maximum cystometric capacity from baseline were 53% and 51.5%, respectively, 6 weeks after injection. We found a 324% increase in mean bladder compliance and a 57% increase in mean intermittent catheterization volumes. The mean duration of efficacy was 28 weeks with a single injection and 36 weeks for repeated injections (minimum, 16 weeks; maximum, 52 weeks). The mean time interval between repeated onabotulinum toxin-A injections was 7 months (maximum, 13 months). Intradetrusor injections of onabotulinum toxin-A were well tolerated. Onabotulinum toxin-A injections into the bladder wall provide a significant symptomatic and urodynamic improvement in children with neurogenic detrusor overactivity due to myelomeningocele who are on intermittent catheterization. The treatment seems to be safe and very well tolerated.

Estimated exposure to zearalenone, ochratoxin A and aflatoxin B1 through the consume of bakery products and pasta considering effects of food processing.

PubMed

Bol, Emilli Keller; Araujo, Letícia; Veras, Flávio Fonseca; Welke, Juliane Elisa

2016-03-01

The objective of this research was to estimate the processing effect on mycotoxins levels and the exposure to zearalenone (ZEA), ochratoxin (OTA) and aflatoxin B1 (AFB1) through the consumption of pasta and bakery products. The higher reduction percentage of mycotoxins was observed in cake production (95, 90 and 70% for ZEA, OTA and AFB1, respectively). Bread and biscuit showed similar reduction in mycotoxins levels (89 and 90% for ZEA; 80 and 85% for OTA; 36 and 40% for AFB1, respectively). The lower reduction in the levels of mycotoxins has been observed for pasta (75, 65 and 10% for ZEA, OTA and AFB1, respectively). The consumption of these products could represent 12.6% of the maximum tolerable daily intake of ZEA and 30.5% of the tolerable weekly intake of OTA. The margin of exposure value related to the exposure to AFB1 was 24.6. The exposure to ZEA and OTA through the consumption of bakery products and pasta would not represent risk for consumer health, (although conjugated forms were not determined). However, the exposure to AFB1 represents a risk (even without considering the AFB1-conjugated forms). Copyright © 2016 Elsevier Ltd. All rights reserved.

Tolerance and biosorption of copper (Cu) and lead (Pb) by filamentous fungi isolated from a freshwater ecosystem.

PubMed

Iskandar, Nur Liyana; Zainudin, Nur Ain Izzati Mohd; Tan, Soon Guan

2011-01-01

Filamentous fungi are able to accumulate significant amount of metals from their environment. The potential of fungal biomass as agents for biosorption of heavy metals from contaminated sediments is currently receiving attention. In the present study, a total of 41 isolates of filamentous fungi obtained from the sediment of the Langat River, Selangor, Malaysia were screened for their tolerance and uptake capability of copper (Cu) and lead (Pb). The isolates were identified as Aspergillus niger, A. fumigatus, Trichoderma asperellum, Penicillium simplicissimum and P. janthinellum. A. niger and P. simplicissimum, were able to survive at 1000 mg/L of Cu(II) concentration on Potato Dextrose Agar (PDA) while for Pb, only A. niger survived at 5000 mg/L concentration. The results showed that A. niger, P. simplicissimum and T. asperellum have a better uptake capacity for Pb compared to Cu and the findings indicated promising biosorption of Cu and Pb by these filamentous fungi from aqueous solution. The present study was also determined the maximum removal of Cu(II) and Pb(II) that was performed by A. niger. The metal removal which occurred at Cu(II) 200 mg/L was (20.910 +/- 0.581) mg/g and at 250 mg/L of Pb(II) was (54.046 +/- 0.328) mg/g.

Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit.

PubMed

Leonardi, Antonio; Bucolo, Claudio; Drago, Filippo; Salomone, Salvatore; Pignatello, Rosario

2015-01-15

The study was aimed at evaluating whether the ocular hypotensive effect of melatonin (MEL) was enhanced by its encapsulation in cationic solid lipid nanoparticles (cSLN), as well as at determining the tolerability of these formulations on the ocular surface. MEL was loaded in cSLN that had already been shown to be suitable for ophthalmic use. The formulations were prepared using Softisan(®) 100 as the main lipid matrix, with the presence of either stearic (SA) or palmitic acid (PA) as lipid modifiers. A fixed positive charge was provided by the addition of a cationic lipid (didecyldimethylammonium bromide). The ocular hypotensive effect was evaluated by measuring the intraocular pressure (IOP) during 24h in albino rabbits. MEL elicited a significant (p<0.01) IOP reduction in rabbit eye. All the formulations tested in vivo demonstrated a good tolerability. The nanocarrier containing SA was the most effective in terms of IOP reduction (maximum IOP reduction: -7 mmHg), and its effect lasted approximately 24h. The experimental data indicate that the new formulations based on cSLN loaded with MEL represent a potent anti-glaucoma treatment with a safe profile, warranting further clinical evaluation of the proposed nanotechnological strategy. Copyright © 2014. Published by Elsevier B.V.

Health risk assessment of zinc, chromium, and nickel from cow meat consumption in an urban Nigerian population

PubMed Central

Ihedioha, Janefrances N; Okoye, Chukwuma O B; Onyechi, Uchenna A

2014-01-01

Background: Meat consumption is increasingly becoming a larger part of diets worldwide. However, the bioaccumulation of toxic metals from anthropogenic pollution is a potential health risk to human health. Objective: To measure the daily intake of zinc, chromium, and nickel from cow meat consumption and assess the possible health risks in an urban population in Nigeria. Methods: Dried meat samples were digested with 3 : 2HNO3 : HClO4 v/v. Zinc, chromium, and nickel concentrations were determined with atomic absorption spectrophotometer. Daily intakes of meat were obtained using a food frequency questionnaire (FFQ). Results: The estimated daily intakes (EDI) (μg/person/day) ranges were: zinc (10 496–13 459), chromium (310.90–393.73), and nickel (26.72–34.87). Estimated daily intake for zinc was 15–30% of provisional maximum tolerable daily intake (PMTDI) and for nickel it was 8–15% of tolerable daily intake (TDI). Conclusion: Chromium intakes were above recommended daily intake (RDI). Target hazard quotient (THQ) for nickel and zinc were within WHO/FAO limit. There was no evidence of possible health risk to consumers with regard to zinc and nickel. However, chromium intake should be of utmost concern, while disposal of tanning waste should be checked. PMID:25078345

Modafinil in the treatment of excessive sleepiness

PubMed Central

Schwartz, Jonathan RL

2008-01-01

The wake-promoting agent modafinil is approved for the treatment of excessive sleepiness associated with obstructive sleep apnea (OSA), shift work disorder (SWD), and narcolepsy. In OSA, modafinil is recommended for use as an adjunct to standard therapies that treat the underlying airway obstruction. This article reviews the literature on modafinil (pharmacology, pharmacokinetics, efficacy, tolerability, and abuse potential), with emphasis on use of modafinil in the treatment of excessive sleepiness in patients with OSA, SWD, and narcolepsy. In large-scale, double-blind, placebo-controlled studies, modafinil improved objectively determined sleep latency, improved overall clinical condition related to severity of sleepiness, and reduced patient-reported sleepiness. Improvements in wakefulness were accompanied by improvements in behavioral alertness, functional status, and health-related quality of life. In patients with SWD, diary data showed modafinil reduced the maximum level of sleepiness during night shift work, level of sleepiness during the commute home, and incidence of accidents or near-accidents during the commute home when compared with placebo. Modafinil was well tolerated, without adversely affecting cardiovascular parameters or scheduled sleep. These findings and those of extension studies which reported improvements were maintained suggest modafinil has a beneficial effect on daily life and well-being in patients with excessive sleepiness associated with OSA, SWD, or narcolepsy. PMID:19920895

Study of the effects of neutron irradiation on silicon strip detectors

NASA Astrophysics Data System (ADS)

Guibellino, P.; Panizza, G.; Hall, G.; Sotthibandhu, S.; Ziock, H. J.; Ferguson, P.; Sommer, W. F.; Edwards, M.; Cartiglia, N.; Hubbard, B.; Lesloe, J.; Pitzl, D.; O'Shaughnessy, K.; Rowe, W.; Sadoziski, H. F.-W.; Seiden, A.; Spencer, E.

1992-05-01

Silicon strip detectors and test structures were exposed to neutron fluences up to Φ = 6.1 × 10 14 n/cm 2, using the ISIS neutron source at the Rutherford Appleton Laboratory (UK). In this paper we report some of our results concerning the effects of displacement damage, with a comparison of devices made of silicon of different resistivity. The various samples exposed showed a very similar dependence of the leakage current on the fluence received. We studied the change of effective doping concentration, and observed a behaviour suggesting the onset of type inversion at a fluence of ˜ 2.0 × 10 13 n/cm 2, a value which depends on the initial doping concentration. The linear increase of the depletion voltage for fluences higher than the inversion point could eventually determine the maximum fluence tolerable by silicon detectors.

SU-F-T-113: Inherent Functional Dependence of Spinal Cord Doses of Variable Irradiated Volumes in Spine SBRT

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

Ma, L; Braunstein, S; Chiu, J

2016-06-15

Purpose: Spinal cord tolerance for SBRT has been recommended for the maximum point dose level or at irradiated volumes such as 0.35 mL or 10% of contoured volumes. In this study, we investigated an inherent functional relationship that associates these dose surrogates for irradiated spinal cord volumes of up to 3.0 mL. Methods: A hidden variable termed as Effective Dose Radius (EDR) was formulated based on a dose fall-off model to correlate dose at irradiated spinal cord volumes ranging from 0 mL (point maximum) to 3.0 mL. A cohort of 15 spine SBRT cases was randomly selected to derive anmore » EDR-parameterized formula. The mean prescription dose for the studied cases was 21.0±8.0 Gy (range, 10–40Gy) delivered in 3±1 fractions with target volumes of 39.1 ± 70.6 mL. Linear regression and variance analysis were performed for the fitting parameters of variable EDR values. Results: No direct correlation was found between the dose at maximum point and doses at variable spinal cord volumes. For example, Pearson R{sup 2} = 0.643 and R{sup 2}= 0.491 were obtained when correlating the point maximum dose with the spinal cord dose at 1 mL and 3 mL, respectively. However, near perfect correlation (R{sup 2} ≥0.99) was obtained when corresponding parameterized EDRs. Specifically, Pearson R{sup 2}= 0.996 and R{sup 2} = 0.990 were obtained when correlating EDR (maximum point dose) with EDR (dose at 1 mL) and EDR(dose at 3 mL), respectively. As a result, high confidence level look-up tables were established to correlate spinal cord doses at the maximum point to any finite irradiated volumes. Conclusion: An inherent functional relationship was demonstrated for spine SBRT. Such a relationship unifies dose surrogates at variable cord volumes and proves that a single dose surrogate (e.g. point maximum dose) is mathematically sufficient in constraining the overall spinal cord dose tolerance for SBRT.« less

Influence of muscle pain tolerance on muscle pain threshold in experimental tooth clenching in man.

PubMed

Christensen, L V

1979-07-01

Ten adults and ten children exercised maximal voluntary tooth clenching until pains appeared in the jaw muscles, i.e. the muscle pain threshold of tooth clenching was determined. Subsequently, the subjects were instructed to exercise tooth clenching until they were forced to stop because of intolerable pains and exhaustion of the contracting muscles, i.e. the muscle pain tolerance of tooth clenching was recorded, and during these bouts of clenching the pain tolerance of tooth clenching was recorded, and during these bouts of clenching the pain threshold was also determined. In adults, determination of the pain tolerance decreased the pain threshold by 19%, and in children it either decreased the pain threshold by 20% or increased it by 56%. It is proposed to introduce the muscle pain tolerance of tooth clenching as an adjunct in the clinical examination of cases of facial pains presumed to originate from the jaw muscles, but the test should be interpreted with caution.

In the queue for total joint replacement: patients' perspectives on waiting times. Ontario Hip and Knee Replacement Project Team.

PubMed

Llewellyn-Thomas, H A; Arshinoff, R; Bell, M; Williams, J I; Naylor, C D

1998-02-01

We assessed patients on the waiting lists of a purposive sample of orthopaedic surgeons in Ontario, Canada, to determine patients' attitudes towards time waiting for hip or knee replacement. We focused on 148 patients who did not have a definite operative date, obtaining complete information on 124 (84%). Symptom severity was assessed with the Western Ontario/McMaster Osteoarthritis Index and a disease-specific standard gamble was used to elicit patients' overall utility for their arthritic state. Next, in a trade-off task, patients considered a hypothetical choice between a 1-month wait for a surgeon who could provide a 2% risk of post-operative mortality, or a 6-month wait for joint replacement with a 1% risk of post-operative mortality. Waiting times were then shifted systematically until the patient abandoned his/her initial choice, generating a conditional maximal acceptable wait time. Patients were divided in their attitudes, with 57% initially choosing a 6-month wait with a 1% mortality risk. The overall distribution of conditional maximum acceptable wait time scores ranged from 1 to 26 months, with a median of 7 months. Utility values were independently but weakly associated with patients' tolerance of waiting times (adjusted R-square = 0.059, P = 0.004). After splitting the sample along the median into subgroups with a relatively 'low' and 'high' tolerance for waiting, the subgroup with the apparently lower tolerance for waiting reported lower utility scores (z = 2.951; P = 0.004) and shorter times since their surgeon first advised them of the need for surgery (z = 3.014; P = 0.003). These results suggest that, in the establishment and monitoring of a queue management system for quality-of-life-enhancing surgery, patients' own perceptions of their overall symptomatic burden and ability to tolerate delayed relief should be considered along with information derived from clinical judgements and pre-weighted health status instruments.

Itopride for gastric volume, gastric emptying and drinking capacity in functional dyspepsia

PubMed Central

Abid, Shahab; Jafri, Wasim; Zaman, Maseeh Uz; Bilal, Rakhshanda; Awan, Safia; Abbas, Aamir

2017-01-01

AIM To study the effect of itopride on gastric accommodation, gastric emptying and drinking capacity in functional dyspepsia (FD). METHODS Randomized controlled trial was conducted to check the effect of itopride on gastric accommodation, gastric emptying, capacity of tolerating nutrient liquid and symptoms of FD. We recruited a total of 31 patients having FD on the basis of ROME III criteria. After randomization, itopride was received by 15 patients while 16 patients received placebo. Gastric accommodation was determined using Gastric Scintigraphy. 13C labeled octanoic breadth test was performed to assess gastric emptying. Capacity of tolerating nutrient liquid drink was checked using satiety drinking capacity test. The intervention group comprised of 150 mg itopride. Patients in both arms were followed for 4 wk. RESULTS Mean age of the recruited participant 33 years (SD = 7.6) and most of the recruited individuals, i.e., 21 (67.7%) were males. We found that there was no effect of itopride on gastric accommodation as measured at different in volumes in the itopride and control group with the empty stomach (P = 0.14), at 20 min (P = 0.38), 30 min (P = 0.30), 40 min (P = 0.43), 50 min (P = 0.50), 60 min (P = 0.81), 90 min (P = 0.25) and 120 min (P = 0.67). Gastric emptying done on a sub sample (n = 11) showed no significant difference (P = 0.58) between itopride and placebo group. There was no significant improvement in the capacity to tolerate liquid in the itopride group as compared to placebo (P = 0.51). Similarly there was no significant improvement of symptoms as assessed through a composite symptom score (P = 0.74). The change in QT interval in itopride group was not significantly different from placebo (0.10). CONCLUSION Our study found no effect of itopride on gastric accommodation, gastric emptying and maximum tolerated volume in patients with FD. PMID:28217377

Itopride for gastric volume, gastric emptying and drinking capacity in functional dyspepsia.

PubMed

Abid, Shahab; Jafri, Wasim; Zaman, Maseeh Uz; Bilal, Rakhshanda; Awan, Safia; Abbas, Aamir

2017-02-06

To study the effect of itopride on gastric accommodation, gastric emptying and drinking capacity in functional dyspepsia (FD). Randomized controlled trial was conducted to check the effect of itopride on gastric accommodation, gastric emptying, capacity of tolerating nutrient liquid and symptoms of FD. We recruited a total of 31 patients having FD on the basis of ROME III criteria. After randomization, itopride was received by 15 patients while 16 patients received placebo. Gastric accommodation was determined using Gastric Scintigraphy. 13 C labeled octanoic breadth test was performed to assess gastric emptying. Capacity of tolerating nutrient liquid drink was checked using satiety drinking capacity test. The intervention group comprised of 150 mg itopride. Patients in both arms were followed for 4 wk. Mean age of the recruited participant 33 years (SD = 7.6) and most of the recruited individuals, i.e ., 21 (67.7%) were males. We found that there was no effect of itopride on gastric accommodation as measured at different in volumes in the itopride and control group with the empty stomach ( P = 0.14), at 20 min ( P = 0.38), 30 min ( P = 0.30), 40 min ( P = 0.43), 50 min ( P = 0.50), 60 min ( P = 0.81), 90 min ( P = 0.25) and 120 min ( P = 0.67). Gastric emptying done on a sub sample ( n = 11) showed no significant difference ( P = 0.58) between itopride and placebo group. There was no significant improvement in the capacity to tolerate liquid in the itopride group as compared to placebo ( P = 0.51). Similarly there was no significant improvement of symptoms as assessed through a composite symptom score ( P = 0.74). The change in QT interval in itopride group was not significantly different from placebo (0.10). Our study found no effect of itopride on gastric accommodation, gastric emptying and maximum tolerated volume in patients with FD.

Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads

PubMed Central

Liem, Edwin B.; Joiner, Teresa V.; Tsueda, Kentaro; Sessler, Daniel I.

2005-01-01

Background: Anesthetic requirement in redheads is exaggerated, suggesting that redheads may be especially sensitive to pain. We therefore tested the hypotheses that women with natural red hair are more sensitive to pain, and that redheads are resistant to topical and subcutaneous lidocaine. Methods: We evaluated pain sensitivity in red-haired (n=30) or dark-haired (n=30) women by determining the electrical current perception threshold, pain perception, and maximum pain tolerance with a Neurometer CPT/C (Neurotron, Inc., Baltimore, MD). We evaluated the analogous warm and cold temperature thresholds with the TSA-II Neurosensory Analyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested with both devices at baseline and with the Neurometer after 1-hour exposure to 4% liposomal lidocaine and after subcutaneous injection of 1% lidocaine. Data are presented as medians [interquartile ranges]. Results: Current perception, pain perception, and pain tolerance thresholds were similar in the red-haired and dark-haired women at 2000, 250, and 5 Hz. In contrast, redheads were more sensitive to cold pain perception (22.6°C [15.1, 26.1] vs. 12.6°C [0, 20], P=0.004), cold pain tolerance (6.0°C [0, 9.7] vs. 0.0°C [0.0, 2.0], P=0.001), and heat pain (46.3°C [45.7, 47.5] vs. 47.7°C [46.6, 48.7], P=0.009). Subcutaneous, lidocaine was significantly less effective in redheads, e.g., pain tolerance threshold at 2000 Hz stimulation in redheads was 11.0 mA [8.5, 16.5] vs. >20.0 mA [14.5, >20] in others, P=0.005). Conclusion: Red hair is the phenotype for mutations of the melanocortin 1 receptor. Our results indicate that redheads are more sensitive to thermal pain and are resistant to the analgesic effects of subcutaneous lidocaine. Mutations of the melanocortin 1 receptor, or a consequence thereof, thus modulate pain sensitivity. PMID:15731586

On the Compliance of Simbol-X Mirror Roughness with its Effective Area Requirements

NASA Astrophysics Data System (ADS)

Spiga, D.; Basso, S.; Cotroneo, V.; Pareschi, G.; Tagliaferri, G.

2009-05-01

Surface microroughness of X-ray mirrors is a key issue for the angular resolution of Simbol-X to comply with the required one (<20 arcsec at 30 keV). The maximum tolerable microroughness for Simbol-X mirrors, in order to satisfy the required imaging capability, has already been derived in terms of its PSD (Power Spectral Density). However, also the Effective Area of the telescope is affected by the mirror roughness. In this work we will show how the expected effective area of the Simbol-X mirror module can be computed from the roughness PSD tolerance, checking its compliance with the requirements.

Difference in oxidative stress tolerance between rice cultivars estimated with chlorophyll fluorescence analysis.

PubMed

Kasajima, Ichiro

2017-04-26

Oxidative stress is considered to be involved in growth retardation of plants when they are exposed to a variety of biotic and abiotic stresses. Despite its potential importance in improving crop production, comparative studies on oxidative stress tolerance between rice (Oryza sativa L.) cultivars are limited. This work describes the difference in term of oxidative stress tolerance between 72 rice cultivars. 72 rice cultivars grown under naturally lit greenhouse were used in this study. Excised leaf discs were subjected to a low concentration of methyl viologen (paraquat), a chemical reagent known to generate reactive oxygen species in chloroplast. Chlorophyll fluorescence analysis using a two-dimensional fluorescence meter, ion leakage analysis as well as the measurement of chlorophyll contents were used to evaluate the oxidative stress tolerance of leaf discs. Furthermore, fluorescence intensities were finely analyzed based on new fluorescence theories that we have optimized. Treatment of leaf discs with methyl viologen caused differential decrease of maximum quantum yield of photosystem II (Fv/Fm) between cultivars. Decrease of Fv/Fm was also closely correlated with increase of ion leakage and decrease of chlorophyll a/b ratio. Fv/Fm was factorized into photochemical and non-photochemical parameters to classify rice cultivars into sensitive and tolerant ones. Among the 72 compared rice cultivars, the traditional cultivar Co13 was identified as the most tolerant to oxidative stress. Koshihikari, a dominant modern Japonica cultivar in Japan as well as IR58, one of the modern Indica breeding lines exhibited a strong tolerance to oxidative stress. Close correlation between Fv/Fm and chlorophyll a/b ratio provides a simple method to estimate oxidative stress tolerance, without measurement of chlorophyll fluorescence with special equipment. The fact that modern cultivars, especially major cultivars possessed tolerance to oxidative stress suggests that oxidative stress tolerance is one of the agricultural traits prerequisite for improvement of modern rice cultivars. Data presented in this study would enable breeding of rice cultivars having strong tolerance to oxidative stress.

Fault-tolerant clock synchronization validation methodology. [in computer systems

NASA Technical Reports Server (NTRS)

Butler, Ricky W.; Palumbo, Daniel L.; Johnson, Sally C.

1987-01-01

A validation method for the synchronization subsystem of a fault-tolerant computer system is presented. The high reliability requirement of flight-crucial systems precludes the use of most traditional validation methods. The method presented utilizes formal design proof to uncover design and coding errors and experimentation to validate the assumptions of the design proof. The experimental method is described and illustrated by validating the clock synchronization system of the Software Implemented Fault Tolerance computer. The design proof of the algorithm includes a theorem that defines the maximum skew between any two nonfaulty clocks in the system in terms of specific system parameters. Most of these parameters are deterministic. One crucial parameter is the upper bound on the clock read error, which is stochastic. The probability that this upper bound is exceeded is calculated from data obtained by the measurement of system parameters. This probability is then included in a detailed reliability analysis of the system.

Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs.

PubMed Central

Turnbull, M J; Watkins, J W

1976-01-01

A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypertensive rats awakened with lower brain halothane concentrations and were also hypersensitivity to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may be indicative of a drug's potential to produce dependence is discussed. PMID:987820

Stem carbohydrate dynamics and expression of genes involved in fructan accumulation and remobilization during grain growth in wheat (Triticum aestivum L.) genotypes with contrasting tolerance to water stress.

PubMed

Yáñez, Alejandra; Tapia, Gerardo; Guerra, Fernando; Del Pozo, Alejandro

2017-01-01

The genetic and physiological mechanisms underlying the relationship between water-soluble carbohydrates (WSC) and water stress tolerance are scarcely known. This study aimed to evaluate the main WSC in stems, and the expression of genes involved in fructan metabolism in wheat genotypes growing in a glasshouse with water stress (WS; 50% field capacity from heading) and full irrigation (FI; 100% field capacity). Eight wheat genotypes (five tolerant and three susceptible to water stress) were evaluated initially (experiment 1) and the two most contrasting genotypes in terms of WSC accumulation were evaluated in a subsequent experiment (experiment 2). Maximum accumulation of WSC occurred 10-20 days after anthesis. Under WS, the stress-tolerant genotype exhibited higher concentrations of WSC, glucose, fructose and fructan in the stems, compared to FI. In addition, the stress-tolerant genotype exhibited higher up-regulation of the fructan 1-fructosyltransferase B (1-FFTB) and fructan 1-exohydrolase w2 (1-FEHw2) genes, whereas the susceptible cultivar presented an up-regulation of the fructan 6-fructosyltransferase (6-SFT) and fructan 1-exohydrolase w3 (1-FEHw3) genes. Our results indicated clear differences in the pattern of WSC accumulation and the expression of genes regulating fructan metabolism between the tolerant and susceptible genotypes under WS.

Stem carbohydrate dynamics and expression of genes involved in fructan accumulation and remobilization during grain growth in wheat (Triticum aestivum L.) genotypes with contrasting tolerance to water stress

PubMed Central

Yáñez, Alejandra; Tapia, Gerardo; Guerra, Fernando

2017-01-01

The genetic and physiological mechanisms underlying the relationship between water-soluble carbohydrates (WSC) and water stress tolerance are scarcely known. This study aimed to evaluate the main WSC in stems, and the expression of genes involved in fructan metabolism in wheat genotypes growing in a glasshouse with water stress (WS; 50% field capacity from heading) and full irrigation (FI; 100% field capacity). Eight wheat genotypes (five tolerant and three susceptible to water stress) were evaluated initially (experiment 1) and the two most contrasting genotypes in terms of WSC accumulation were evaluated in a subsequent experiment (experiment 2). Maximum accumulation of WSC occurred 10–20 days after anthesis. Under WS, the stress-tolerant genotype exhibited higher concentrations of WSC, glucose, fructose and fructan in the stems, compared to FI. In addition, the stress-tolerant genotype exhibited higher up-regulation of the fructan 1-fructosyltransferase B (1-FFTB) and fructan 1-exohydrolase w2 (1-FEHw2) genes, whereas the susceptible cultivar presented an up-regulation of the fructan 6-fructosyltransferase (6-SFT) and fructan 1-exohydrolase w3 (1-FEHw3) genes. Our results indicated clear differences in the pattern of WSC accumulation and the expression of genes regulating fructan metabolism between the tolerant and susceptible genotypes under WS. PMID:28552955

Production, purification and characterization of halophilic organic solvent tolerant protease from marine crustacean shell wastes and its efficacy on deproteinization.

PubMed

Maruthiah, Thirumalai; Somanath, Beena; Jasmin, Jebamonydhas Vijila; Immanuel, Grasian; Palavesam, Arunachalam

2016-12-01

The quantum of marine fish wastes produced by fish processing industries has necessitated to search new methods for its disposal. Hence, this study is focused on production and purification of halophilic organic solvent tolerant protease (HOSP) from marine Alcaligenes faecalis APCMST-MKW6 using marine shell wastes as substrate. The candidate bacterium was isolated from the marine sediment of Manakudi coast and identified as A. faecalis APCMST-MKW6. The purified protease showed 16.39-fold purity, 70.34 U/mg specific activity with 21.67 % yield. The molecular weight of the purified alkaline protease was 49 kDa. This purified protease registered maximum activity at pH 9 and it was stable between pH 8-9 after 1.30 h of incubation. The optimum temperature registered was 60 °C and it was stable between 50 and 60 °C even after 1.30 h of incubation. This enzyme also showed maximum activity at 20 % NaCl concentration. Further, manganese chloride, magnesium chloride, calcium chloride and barium chloride influenced this enzyme activity remarkably and it was also found to be enhanced by many of the tested surfactants and solvents. The candidate bacterium effectively deproteinized the shrimp shell waste compared to the other tested crustaceans shell wastes and also attained maximum antioxidant activity.

Effect of salt-tolerant plant growth-promoting rhizobacteria on wheat plants and soil health in a saline environment.

PubMed

Upadhyay, S K; Singh, D P

2015-01-01

Salt-tolerant plant growth-promoting rhizobacteria (ST-PGPR) significantly influence the growth and yield of wheat crops in saline soil. Wheat growth improved in pots with inoculation of all nine ST-PGPR (ECe = 4.3 dS·m(-1) ; greenhouse experiment), while maximum growth and dry biomass was observed in isolate SU18 Arthrobacter sp.; simultaneously, all ST-PGPR improved soil health in treated pot soil over controls. In the field experiment, maximum wheat root dry weight and shoot biomass was observed after inoculation with SU44 B. aquimaris, and SU8 B. aquimaris, respectively, after 60 and 90 days. Isolate SU8 B. aquimaris, induced significantly higher proline and total soluble sugar accumulation in wheat, while isolate SU44 B. aquimaris, resulted in higher accumulation of reducing sugars after 60 days. Percentage nitrogen (N), potassium (K) and phosphorus (P) in leaves of wheat increased significantly after inoculation with ST-PGPR, as compared to un-inoculated plants. Isolate SU47 B. subtilis showed maximum reduction of sodium (Na) content in wheat leaves of about 23% at both 60 and 90 days after sowing, and produced the best yield of around 17.8% more than the control. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

Tannic acid degradation by Klebsiella strains isolated from goat feces

PubMed Central

Tahmourespour, Arezoo; Tabatabaee, Nooroldin; Khalkhali, Hossein; Amini, Imane

2016-01-01

Background and Objectives: Tannins are toxic polyphenols that either bind and precipitate or condense proteins. The high tannin content of some plants is the preliminary limitation of using them as a ruminant feed. So, the aim of this study was the isolation and characterization of tannic acid degrading bacterial strains from goat feces before and after feeding on Pistachio-Soft Hulls as tannin rich diet (TRD). Materials and Methods: Bacterial strains capable of utilizing tannic acid as sole carbon and energy source were isolated and characterized from goat feces before and after feeding on TRD. Tannase activity, maximum tolerable concentration and biodegradation potential were assessed. Results: Four tannase positive isolates were identified as Klebsiella pneumoniae. Isolated strains showed the maximum tolerable concentration of 64g/L of tannin. The tannic acid degradation percentage at a concentration of 15.0 g/L reached a maximum of 68% after 24 h incubation, and more than 98% after 72 h incubation. The pH of the medium also decreased along with tannic acid utilization. Conclusions: It is obvious that TRD induced adaptive responses. Thus, while the bacteria were able to degrade and detoxify the tannic acids, they had to adapt in the presence of high concentrations of tannic acid. So, these isolates have an amazing potential for application in bioremediation, waste water treatment, also reduction of tannins antinutritional effects in animal feeds. PMID:27092220

Standardized comparison of antiseptic efficacy of triclosan, PVP-iodine, octenidine dihydrochloride, polyhexanide and chlorhexidine digluconate.

PubMed

Koburger, T; Hübner, N-O; Braun, M; Siebert, J; Kramer, A

2010-08-01

This study presents a comparative investigation of the antimicrobial efficacy of the antiseptics PVP-iodine, triclosan, chlorhexidine, octenidine and polyhexanide used for pre-surgical antisepsis and antiseptic treatment of skin, wounds and mucous membranes based on internationally accepted standards. MICs and MBCs were determined in accordance with DIN 58940-7 and 58940-8 using Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus), Enterococcus faecalis (including vancomycin-resistant Enterococcus), Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Clostridium perfringens, Haemophilus influenzae and Candida albicans. The microbicidal efficacy was determined in accordance with DIN EN 1040 and 1275 using S. aureus, P. aeruginosa and C. albicans. For chlorhexidine, octenidine and polyhexanide, MIC(48) and MBC(24) ranged from 16 to 32 mg/L. Maximum values for triclosan ranged from 256 to 512 mg/L, with an efficacy gap against P. aeruginosa, while the maximum values of PVP-iodine were 1024 mg/L, with a gap against S. pneumoniae. Comparing the minimal effective concentrations, octenidine was most effective. After 1 min, only octenidine and PVP-iodine fulfil the requirements for antiseptics. Tests under standardized and harmonized conditions help to choose the most efficacious agent. When a prolonged contact time is feasible, ranking of agents would be polyhexanide = octenidine > chlorhexidine > triclosan > PVP-iodine. This is consistent with the recommendations for antisepsis of acute wounds. Polyhexanide seems to be preferable for chronic wounds due to its higher tolerability. If an immediate effect is required, ranking would be octenidine = PVP-iodine> polyhexanide > chlorhexidine > triclosan.

Upward ant distribution shift corresponds with minimum, not maximum, temperature tolerance

Treesearch

Robert J. Warren; Lacy Chick

2013-01-01

Rapid climate change may prompt species distribution shifts upward and poleward, but species movement in itself is not sufficient to establish climate causation. Other dynamics, such as disturbance history, may prompt species distribution shifts resembling those expected from rapid climate change. Links between species distributions, regional climate trends and...

Single-dose infusion of sodium butyrate, but not lactose, increases plasma ß-hydroxybutyrate and insulin in lactating dairy cows

USDA-ARS?s Scientific Manuscript database

Several previous studies have identified beneficial effects of butyrate on rumen development and intestinal health in pre-ruminants. These encouraging findings have led to further investigations related to butyrate supplementation in the mature ruminant. However, the maximum tolerable dosage rate of...

Investigation of the potential of Cyperus alternifolius in the phytoremediation of palm oil mill effluent

NASA Astrophysics Data System (ADS)

Sa'at, Siti Kamariah Md; Zaman, Nastaein Qamaruz; Yusoff, Suffian Mohd; Ismail, Hirun Azaman

2017-10-01

Phytoremediation is an emerging technology nowadays due to demand in environmental sustainability which requires cost-effective solutions in terms of capital and operational cost. The treatment gain attention due to their potential in wastewater treatment especially in organics, nutrients, and heavy metal removal of domestics, agricultural, and industrial wastewater treatment. Plant functions in phytoremediation make the plant selection as an essential element. The plant should have the ability to tolerate with the toxic effluent and able to uptake the contaminant. Cyperus alternifolius (umbrella grass) was chosen as aquatic plant due to the ability to tolerance in municipal and industrial effluent sources with strong and dense root systems. Thus, the objectives of this study are to determine the potential and effectiveness of Cyperus alternifolius in the palm oil mill effluent treatment especially in the removal of organics (COD), nutrients (NH3-N and TP) and suspended solid. The batch experiment was run using Cyperus alternifolius to determine their potential of aerobic pond effluent for 21 days of treatment. Cyperus alternifolius treatment shows the great removal of COD and TSS with 96% and 91%, respectively at the end of 21 days of treatment. Nutrients removal achieved the maximum removal of 92% NH3-N and 99% TP shows after 11 days of treatment and percentage slowly decrease until the end of 21 days of treatment. Cyperus alternifolius had shown potential in the palm oil mill effluent treatment and can be combined with ponding treatment to enhance to water quality prior discharge.

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer

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

Sudo, Kentaro; Yamaguchi, Taketo; Ishihara, Takeshi

Purpose: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m{sup 2}/day. Results: Sixteen patients were enrolled in this study. Three patients received S-1more » at 60 mg/m{sup 2}/day, 3 at 70 mg/m{sup 2}/day, and 10 at 80 mg/m{sup 2}/day. Though 1 patient at the final dose level (80 mg/m{sup 2}/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. Conclusions: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m{sup 2}/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.« less

Heavy metal tolerant halophilic bacteria from Vembanad Lake as possible source for bioremediation of lead and cadmium.

PubMed

Sowmya, M; Rejula, M P; Rejith, P G; Mohan, Mahesh; Karuppiah, Makesh; Hatha, A A Mohamed

2014-07-01

Microorganisms which can resist high concentration of toxic heavy metals are often considered as effective tools of bioremediation from such pollutants. In the present study, sediment samples from Vembanad Lake were screened for the presence of halophilic bacteria that are tolerant to heavy metals. A total of 35 bacterial strains belonging to different genera such as Alcaligenes, Vibrio, Kurthia, Staphylococcus and members of the family Enterobacteriaceae were isolated from 21 sediment samples during February to April, 2008. The salt tolerance and optimum salt concentrations of the isolates revealed that most of them were moderate halophiles followed by halotolerant and extremely halotolerant groups. The minimum inhibitory concentrations (MICs) against cadmium and lead for each isolate revealed that the isolates showed higher MIC against lead than cadmium. Based on the resistance limit concentration, most of them were more tolerant to lead than cadmium at all the three salt concentrations tested. Heavy metal removal efficiency of selected isolates showed a maximum reduction of 37 and 99% against cadmium and lead respectively. The study reveals the future prospects of halophilic microorganisms in the field of bioremediation.

Quantum money with nearly optimal error tolerance

NASA Astrophysics Data System (ADS)

Amiri, Ryan; Arrazola, Juan Miguel

2017-06-01

We present a family of quantum money schemes with classical verification which display a number of benefits over previous proposals. Our schemes are based on hidden matching quantum retrieval games and they tolerate noise up to 23 % , which we conjecture reaches 25 % asymptotically as the dimension of the underlying hidden matching states is increased. Furthermore, we prove that 25 % is the maximum tolerable noise for a wide class of quantum money schemes with classical verification, meaning our schemes are almost optimally noise tolerant. We use methods in semidefinite programming to prove security in a substantially different manner to previous proposals, leading to two main advantages: first, coin verification involves only a constant number of states (with respect to coin size), thereby allowing for smaller coins; second, the reusability of coins within our scheme grows linearly with the size of the coin, which is known to be optimal. Last, we suggest methods by which the coins in our protocol could be implemented using weak coherent states and verified using existing experimental techniques, even in the presence of detector inefficiencies.

Variation of photoautotrophic fatty acid production from a highly CO2 tolerant alga, Chlorococcum littorale, with inorganic carbon over narrow ranges of pH.

PubMed

Ota, Masaki; Takenaka, Motohiro; Sato, Yoshiyuki; Smith, Richard L; Inomata, Hiroshi

2015-01-01

Photoautotrophic fatty acid production of a highly CO2 -tolerant green alga Chlorococcum littorale in the presence of inorganic carbon at 295 K and light intensity of 170 µmol-photon m(-2) s(-1) was investigated. CO2 concentration in the bubbling gas was adjusted by mixing pure gas components of CO2 and N2 to avoid photorespiration and β-oxidation of fatty acids under O2 surrounding conditions. Maximum content of total fatty acid showed pH-dependence after nitrate depletion of the culture media and increased with the corresponding inorganic carbon ratio. Namely, [HCO3 (-) ]/([CO2 ]+n[ CO32-]) ratio in the culture media was found to be a controlling factor for photoautotrophic fatty acid production after the nitrate limitation. At a CO2 concentration of 5% (vol/vol) and a pH of 6.7, the fatty acid content was 47.8 wt % (dry basis) at its maximum that is comparable with land plant seed oils. © 2015 American Institute of Chemical Engineers.

Efficacy and safety of a new intravenous immunoglobulin 10% formulation (octagam® 10%) in patients with immune thrombocytopenia.

PubMed

Robak, Tadeusz; Mainau, Claudia; Pyringer, Barbara; Chojnowski, Krzysztof; Warzocha, Krzysztof; Dmoszynska, Anna; Straub, Jan; Imbach, Paul

2010-10-01

Intravenous immunoglobulin (IVIg) has an established role in the treatment of immune thrombocytopenia (ITP). The safety and efficacy of a new ready-to-use IVIg 10% formulation (octagam(®) 10%) were investigated in a prospective phase III study in 116 adult patients with ITP (platelet count ≤20×10(9)/l). Sixty-six patients had chronic ITP and 49 were newly diagnosed. Patients received octagam 10% 1 g/kg/day on two consecutive days; infusion rate was adjusted according to tolerability to a maximum of 0·12 ml/kg/minute. Eighty per cent of patients attained the primary efficacy endpoint of clinical response (platelet count ≥50×10(9)/l within 6 days of dosing). The median time to response was 2 days and the median duration of response was 12 days; mean response duration was 24·1 days. octagam 10% was well tolerated and effective in this population representative of adult patients with ITP, even at the maximum infusion rate of 0·12 ml/kg/minute, without unexpected safety issues.

Fuel freeze-point investigations. Final report, September 1982-March 1984

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

Desmarais, L.A.; Tolle, F.F.

1984-07-01

The objective of this program was to conduct a detailed assessment of the low-temperature environment to which USAF aircraft are exposed for the purpose of defining a maximum acceptable fuel freeze-point and also to define any operational changes required with the use of a high freeze-point fuel. A previous study of B-52, C-141, and KC-135 operational missions indicated that the -58 C freeze point specification was too conservative. Based on recommendations resulting from the previous program, several improvements in the method of analysis were made, such as: expansion of the atmospheric temperature data base, the addition of ground temperature analysis,more » the addition of fuel-freezing analysis to the one-dimensional fuel-temperature computer program, and the examination of heat transfer in external fuel tanks, such as pylon or tip tanks. The B-52, C-141, and KC-135 mission were analyzed again, along with the operational missions of two tactical airplanes, the A-10 and F-15; -50C was determined to be the maximum allowable freeze point for a general-purpose USAF aviation turbine fuel. Higher freeze points can be tolerated if the probability of operational interference is acceptably low or if operational changes can be made. Study of atmospheric temperatures encountered for the missions of the five-study aircraft indicates that a maximum freeze point of -48 C would not likely create any operational difficulties in Northern Europe.« less

Utilising an LC-MS/MS-based multi-biomarker approach to assess mycotoxin exposure in the Bangkok metropolitan area and surrounding provinces.

PubMed

Warth, Benedikt; Petchkongkaew, Awanwee; Sulyok, Michael; Krska, Rudolf

2014-01-01

Human exposures to mycotoxins through dietary intake are a major health hazard and may result in various pathophysiological effects. Although Thailand is a country at increased risk due to its climatic conditions, no comprehensive dataset is available to perform proper exposure assessment of its population with regard to mycotoxins. Therefore, this pilot study was conducted to investigate and evaluate the exposure levels of major mycotoxins (aflatoxin B₁, ochratoxin A, fumonisins, zearalenone and trichothecenes). Sixty first-morning urine samples were collected from healthy volunteers who live in the Bangkok metropolitan area and surrounding provinces (Pathumthani, Nonthaburi, Samutprakarn and Samutsakorn). Urine samples were analysed by a LC-MS/MS-based multi-biomarker method following a so-called 'dilute and shoot' approach. Results generally indicated low mycotoxin exposures in most individuals through the determination of the four biomarkers that were detected in urine samples, i.e. aflatoxin M₁, ochratoxin A (OTA), as well as the deoxynivalenol (DON) metabolites DON-3-glucuronide and DON-15-glucuronide in 10 of 60 individuals. The maximum concentrations were used to estimate the daily intake confirming that none of the individuals exceeded the tolerable daily intake (TDI) of DON (maximum 26% of TDI) or OTA (maximum 22% of TDI). However, the maximum exposure of aflatoxin B₁, estimated to be 0.91 µg (kg bw)⁻¹ day⁻¹, should raise some concerns and suggests further studies utilising a more sensitive method. Low exposure to Fusarium toxins was also confirmed by the absence of zearalenone, α-zearalanol, β-zearalanol and zearalenone-14-glucuronide as well as T-2 toxin, HT-2 toxin, nivalenol and free DON. This is the first multi-mycotoxin biomarker study performed in Southeast Asia.

40 CFR 94.107 - Determination of maximum test speed.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Determination of maximum test speed... Determination of maximum test speed. (a) Overview. This section specifies how to determine maximum test speed from a lug curve. This maximum test speed is used in §§ 94.105, 94.106, and § 94.109 (including the...

40 CFR 94.107 - Determination of maximum test speed.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 20 2011-07-01 2011-07-01 false Determination of maximum test speed... Determination of maximum test speed. (a) Overview. This section specifies how to determine maximum test speed from a lug curve. This maximum test speed is used in §§ 94.105, 94.106, and § 94.109 (including the...

Removal of hydrogen sulfide by sulfate-resistant Acidithiobacillus thiooxidans AZ11.

PubMed

Lee, Eun Young; Lee, Nae Yoon; Cho, Kyung-Suk; Ryu, Hee Wook

2006-04-01

Toxic H2S gas is an important industrial pollutant that is applied to biofiltration. Here, we examined the effects of factors such as inlet concentration and space velocity on the removal efficiency of a bacterial strain capable of tolerating high sulfate concentrations and low pH conditions. We examined three strains of Acidithiobacillus thiooxidans known to have sulfur-oxidizing activity, and identified strain AZ11 as having the highest tolerance for sulfate. A. thiooxidans AZ11 could grow at pH 0.2 in the presence of 74 g l(-1) sulfate, the final oxidation product of elemental sulfur, in the culture broth. Under these conditions, the specific sulfur oxidation rate was 2.9 g-S g-DCW (dry cell weight)(-1) d(-1). The maximum specific sulfur oxidation rate of A. thiooxidans AZ11 was 21.2 g-S g-DCW(-1) d(-1), which was observed in the presence of 4.2 g-SO4(2-) l(-1) and pH 1.5, in the culture medium. To test the effects of various factors on biofiltration by this strain, A. thiooxidans AZ11 was inoculated into a porous ceramic biofilter. First, a maximum inlet loading of 670 g-S m(-3) h(-1) was applied with a constant space velocity (SV) of 200 h(-1) (residence time, 18 s) and the inlet concentration of H2S was experimentally increased from 200 ppmv to 2200 ppmv. Under these conditions, less than 0.1 ppmv H2S was detected at the biofilter outlet. When the inlet H2S was maintained at a constant concentration of 200 ppmv and the SV was increased from 200 h(-1) to 400 h(-1) (residence time, 9 s), an H2S removal of 99.9% was obtained. However, H2S removal efficiencies decreased to 98% and 94% when the SV was set to 500 h(-1) (residence time, 7.2 s) and 600 h(-1) (residence time, 6 s), respectively. The critical elimination capacity guaranteeing 96% removal of the inlet H2S was determined to be 160 g-S m(-3) h(-1) at a space velocity of 600 h(-1). Collectively, these findings show for the first time that a sulfur oxidizing bacterium has a high sulfate tolerance and a high sulfur oxidizing activity below pH 1.

Practical considerations of linear accelerator-based frameless extracranial radiosurgery for treatment of occipital neuralgia for nonsurgical candidates.

PubMed

Denton, Travis R; Shields, Lisa B E; Howe, Jonathan N; Shanks, Todd S; Spalding, Aaron C

2017-07-01

Occipital neuralgia generally responds to medical or invasive procedures. Repeated invasive procedures generate increasing complications and are often contraindicated. Stereotactic radiosurgery (SRS) has not been reported as a treatment option largely due to the extracranial nature of the target as opposed to the similar, more established trigeminal neuralgia. A dedicated phantom study was conducted to determine the optimum imaging studies, fusion matrices, and treatment planning parameters to target the C2 dorsal root ganglion which forms the occipital nerve. The conditions created from the phantom were applied to a patient with medically and surgically refractory occipital neuralgia. A dose of 80 Gy in one fraction was prescribed to the C2 occipital dorsal root ganglion. The phantom study resulted in a treatment achieved with an average translational magnitude of correction of 1.35 mm with an acceptable tolerance of 0.5 mm and an average rotational magnitude of correction of 0.4° with an acceptable tolerance of 1.0°. For the patient, the spinal cord was 12.0 mm at its closest distance to the isocenter and received a maximum dose of 3.36 Gy, a dose to 0.35 cc of 1.84 Gy, and a dose to 1.2 cc of 0.79 Gy. The brain maximum dose was 2.20 Gy. Treatment time was 59 min for 18, 323 MUs. Imaging was performed prior to each arc delivery resulting in 21 imaging sessions. The average deviation magnitude requiring a positional or rotational correction was 0.96 ± 0.25 mm, 0.8 ± 0.41°, whereas the average deviation magnitude deemed within tolerance was 0.41 ± 0.12 mm, 0.57 ± 0.28°. Dedicated quality assurance of the treatment planning and delivery is necessary for safe and accurate SRS to the cervical spine dorsal root ganglion. With additional prospective study, linear accelerator-based frameless radiosurgery can provide an accurate, noninvasive alternative for treating occipital neuralgia where an invasive procedure is contraindicated. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors

PubMed Central

Min, Chengchun; Zhang, Xiaohan; Zheng, Mei; Sun, Ningning; Acharya, Srijan; Zhang, Xiaowei; Kim, Kyeong-Man

2017-01-01

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the β-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and β-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ. PMID:27956717

Improved enteral tolerance following step procedure: systematic literature review and meta-analysis.

PubMed

Fernandes, Melissa A; Usatin, Danielle; Allen, Isabel E; Rhee, Sue; Vu, Lan

2016-10-01

Surgical management of children with short bowel syndrome (SBS) changed with the introduction of the serial transverse enteroplasty procedure (STEP). We conducted a systematic review and meta-analysis using MEDLINE and SCOPUS to determine if children with SBS had improved enteral tolerance following STEP. Studies were included if information about a child's pre- and post-STEP enteral tolerance was provided. A random effects meta-analysis provided a summary estimate of the proportion of children with enteral tolerance increase following STEP. From 766 abstracts, seven case series involving 86 children were included. Mean percent tolerance of enteral nutrition improved from 35.1 to 69.5. Sixteen children had no enteral improvement following STEP. A summary estimate showed that 87 % (95 % CI 77-95 %) of children who underwent STEP had an increase in enteral tolerance. Compilation of the literature supports the belief that SBS subjects' enteral tolerance improves following STEP. Enteral nutritional tolerance is a measure of efficacy of STEP and should be presented as a primary or secondary outcome. By standardizing data collection on children undergoing STEP procedure, better determination of nutritional benefit from STEP can be ascertained.

77 FR 58045 - Clopyralid; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

... Classification System (NAICS) codes have been provided to assist you and others in determining whether this... data supporting the petition, EPA has determined that the proposed tolerance on rapeseed subgroup 20A... exposure through drinking water and in residential settings, but does not include occupational exposure...

[ECS guidelines 2016 - dyslipidaemias].

PubMed

Sinning, D; Landmesser, U

2016-12-01

Dyslipidaemia is a major cause of atherosclerotic cardiovascular disease and its progression towards clinical complications, such as acute coronary syndromes and stroke. In August 2016 the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) issued new joint guidelines for the management of dyslipidaemias. In these new guidelines, the concept of treating patients to a risk-based low-density lipoprotein (LDL) cholesterol target is reinforced. The task force considers LDL cholesterol as the primary target for dyslipidaemia treatment, whereas high-density lipoprotein (HDL) cholesterol is not recommended as a treatment target (based on the failure of HDL cholesterol elevation treatment strategies to reduce cardiovascular risk in recent studies). In patients with a very high risk for cardiovascular events it is recommended to treat to an LDL cholesterol target of less than 70 mg/dl. Moreover, the new guidelines now additionally recommend a > 50% reduction of LDL cholesterol in patients with very high cardiovascular risk patients and baseline levels between 70 and 135 mg/dl as well as in patients with high cardiovascular risk and baseline LDL cholesterol levels between 100 and 200 mg/dl. Statins are recommended as first-line medicinal treatment and the LDL cholesterol goals given imply the more frequent use of maximum tolerated statin therapy, in particular for patients with very high cardiovascular risk. Treatment with ezetimibe in patients with substantially elevated LDL cholesterol levels despite maximum tolerated statin therapy has now received a stronger recommendation (currently IIa recommendation). The guidelines also now include the potential use of the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and a recent ESC/EAS consensus document provides more detailed information on which patients can be considered for treatment with PCSK9 inhibitors, i. e. in particular patients with familial hypercholesterolemia and patients at very high cardiovascular risk who have markedly elevated LDL cholesterol levels despite maximum tolerated statin and ezetimibe therapy.

Response of antioxidant system to drought stress and re-watering in Alfalfa during branching

NASA Astrophysics Data System (ADS)

Tina, R. R.; Shan, X. R.; Wang, Y.; Guo, S. Y.; Mao, B.; Wang, W.; Wu, H. Y.; Zhao, T. H.

2017-11-01

This paper aimed to reveal the response mechanism of active oxygen metabolism and antioxidant enzyme activities in Alfalfa under drought stress and re-watering, and the pot experiment was used, to explore the changes of H2O2, O2·-, electrolyte leakage conductivity and MDA, SOD, POD, CAT activity in Golden Empress (tolerant cultivar) and Sanditi (non-tolerant cultivar) under drought stress and re-watering during branching stage. Three water gradients were set up: CK (Maximum field capacity of 75%±5%), T1 (Maximum field capacity of 45%±5%), T2 (Maximum field capacity of 35%±5%) to compare, and the drought rehydration was also studied. Results: the results indicated that H2O2 content, O2·-production rate, relative conductivity and MDA content were higher than the control, and the increase extent of Golden Empress was higher than the Sanditi under drought stress and after re-watering the recovery capability of Golden Empress was also higher than the Sanditi. After 7 days of re-watering, all indexes were restored to the control level, indicating that the re-watering have compensation effect after drought. After drought stress, to weaken the damage of active oxygen Golden Empress was mainly by increasing the activity of POD and SOD, but Sanditi was mainly through the POD and CAT activity increased to effectively remove ROS. Under drought stress, active oxygen in leaves of Alfalfa increased, and thus the membrane system was damaged which lead to the increase of MDA content and relative electric conductivity. Plants play a defensive role by increasing the activity of antioxidant enzymes and scavenging reactive oxygen species. After re-watering, the stress effect was reduced, and the physiological indexes of plants were restored to the control level. In general, tolerant cultivar has stronger antioxidant properties under drought and re-watering.

SU-F-T-18: The Importance of Immobilization Devices in Brachytherapy Treatments of Vaginal Cuff

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

Shojaei, M; Dumitru, N; Pella, S

2016-06-15

Purpose: High dose rate brachytherapy is a highly localized radiation therapy that has a very high dose gradient. Thus one of the most important parts of the treatment is the immobilization. The smallest movement of the patient or applicator can result in dose variation to the surrounding tissues as well as to the tumor to be treated. We will revise the ML Cylinder treatments and their localization challenges. Methods: A retrospective study of 25 patients with 5 treatments each looking into the applicator’s placement in regard to the organs at risk. Motion possibilities for each applicator intra and inter fractionationmore » with their dosimetric implications were covered and measured in regard with their dose variance. The localization immobilization devices used were assessed for the capability to prevent motion before and during the treatment delivery. Results: We focused on the 100% isodose on central axis and a 15 degree displacement due to possible rotation analyzing the dose variations to the bladder and rectum walls. The average dose variation for bladder was 15% of the accepted tolerance, with a minimum variance of 11.1% and a maximum one of 23.14% on the central axis. For the off axis measurements we found an average variation of 16.84% of the accepted tolerance, with a minimum variance of 11.47% and a maximum one of 27.69%. For the rectum we focused on the rectum wall closest to the 120% isodose line. The average dose variation was 19.4%, minimum 11.3% and a maximum of 34.02% from the accepted tolerance values Conclusion: Improved immobilization devices are recommended. For inter-fractionation, localization devices are recommended in place with consistent planning in regards with the initial fraction. Many of the present immobilization devices produced for external radiotherapy can be used to improve the localization of HDR applicators during transportation of the patient and during treatment.« less

40 CFR 180.101 - Specific tolerances; general provisions.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances... per one million parts by weight of the raw agricultural commodity. (b) The poisonous and deleterious... used for determining whether pesticide residues, including negligible residues, in or on raw...

40 CFR 180.101 - Specific tolerances; general provisions.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Specific Tolerances... per one million parts by weight of the raw agricultural commodity. (b) The poisonous and deleterious... used for determining whether pesticide residues, including negligible residues, in or on raw...

Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial.

PubMed

Mulder, Gerit; Tallis, Arthur J; Marshall, V Tracy; Mozingo, David; Phillips, Laurie; Pierce, Glenn F; Chandler, Lois A; Sosnowski, Barbara K

2009-01-01

The results from a Phase 1/2 study of a replication-defective adenovirus encoding human platelet-derived growth factor (PDGF)-B formulated in a bovine collagen (Ad-5PDGF-B; 2.6% collagen; GAM501) gel for nonhealing neuropathic diabetic foot ulcers is reported. The primary objectives of the study were to evaluate the safety, maximum-tolerated dose, and preliminary biological activity of GAM501. Fifteen patients enrolled into the study with chronic, nonhealing ulcers received either a single administration of GAM501 at one of three dose levels, or up to four administrations of GAM501 at 1-week intervals. All patients received standard of care treatment including debridement and were required to wear an off-loading shoe. GAM501 was found to be safe and well tolerated with no evidence of systemic or local toxicity at all doses so no maximum-tolerated dose was reached. Serum antibody titers to platelet-derived growth factor-B homodimer and collagen were negative and adenoviral DNA was not detected in the blood. In the 12 patients that completed the study, ulcer closure was observed by Month 3 in 10 patients, seven of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.

Comparative of Quercus spp. and Salix spp. for phytoremediation of Pb/Zn mine tailings.

PubMed

Shi, Xiang; Wang, Shufeng; Sun, Haijing; Chen, Yitai; Wang, Dongxue; Pan, Hongwei; Zou, Yazhu; Liu, Jianfeng; Zheng, Linyu; Zhao, Xiulian; Jiang, Zeping

2017-02-01

A pot experiment was conducted to evaluate the feasibility of using tree seedlings for the phytoremediation of lead/zinc (Pb/Zn) mine tailings. Seedlings of three Quercus spp. (Q. shumardii, Q. phellos, and Q. virginiana) and rooted cuttings of two Salix spp. (S. matsudana and S. integra) were transplanted into pots containing 50 and 100 % Pb/Zn mine tailings to evaluate their tolerance of heavy metals. The five species showed different tolerance levels to the Pb/Zn tailings treatments. Q. virginiana was highly tolerant to heavy metals and grew normally in the Pb/Zn tailings. The root systems showed marked differences between the Quercus spp. and Salix spp., indicating that different mechanisms operated to confer tolerance of heavy metals. The maximum efficiency of photosystem II photochemistry value of the five species showed no differences among the treatments, except for Q. shumardii. All species showed low metal translocation factors (TFs). However, S. integra had significantly higher TF values for Zn (1.42-2.18) and cadmium (1.03-1.45) than did the other species. In this respect, Q. virginiana showed the highest tolerance and a low TF, implying that it is a candidate for phytostabilization of mine tailings in southern China. S. integra may be useful for phytoextraction of tailings in temperate regions.

Simulation of aspheric tolerance with polynomial fitting

NASA Astrophysics Data System (ADS)

Li, Jing; Cen, Zhaofeng; Li, Xiaotong

2018-01-01

The shape of the aspheric lens changes caused by machining errors, resulting in a change in the optical transfer function, which affects the image quality. At present, there is no universally recognized tolerance criterion standard for aspheric surface. To study the influence of aspheric tolerances on the optical transfer function, the tolerances of polynomial fitting are allocated on the aspheric surface, and the imaging simulation is carried out by optical imaging software. Analysis is based on a set of aspheric imaging system. The error is generated in the range of a certain PV value, and expressed as a form of Zernike polynomial, which is added to the aspheric surface as a tolerance term. Through optical software analysis, the MTF of optical system can be obtained and used as the main evaluation index. Evaluate whether the effect of the added error on the MTF of the system meets the requirements of the current PV value. Change the PV value and repeat the operation until the acceptable maximum allowable PV value is obtained. According to the actual processing technology, consider the error of various shapes, such as M type, W type, random type error. The new method will provide a certain development for the actual free surface processing technology the reference value.

[Indicators of dynamic work tolerability in healthy subjects].

PubMed

Capodaglio, E M; Capodaglio, P

1997-01-01

This paper reports a study on the dynamics of tolerability in performing dynamic cycling in healthy subjects. Data on individually tolerable levels (power x duration) was obtained from 9 subjects by means of three submaximal tests on an ergometric bicycle lasting < or = 40 minutes, with constant load (50%, 65% and 80% of maximum VO2 reached during a previous test of increasing difficulty within the limits of the symptoms). During performance of the test we monitored heart rate and subjective perception of fatigue (Borg's 10-point scale). We then defined the individual functions of "isoperception", which expressed the individual trend of the product "power x duration" at identical subjective perception score. On the basis of the metabolic parameters monitored, the individual isoperceptive functions at a "moderate" level of fatigue (3 on the Borg scale) were defined as "tolerability) threshold" for prolonged dynamic cycling. The product "power x duration" defined by the isoperceptive curves at a "moderate" level of fatigue does in fact reflect the individual aerobic capacity that can be sustained for prolonged dynamic activity (under 60 minutes). In order to validate the hypothesis of tolerability of the functions identified, three further short tests were performed (duration < or = 8.5 minutes) on an ergometric bicycle, with measurement of ventilatory and metabolic parameters.

Study on acute toxicity of anti-vertigo granule on mice

NASA Astrophysics Data System (ADS)

Wen, Zhonghua; Hao, Shaojun; Xie, Guoqi; Li, Jun; Su, Feng; Liu, Xiaobin; Wang, Xidong; Zhang, Zhengchen

2018-04-01

To observe the effect of anti - glare particles on acute toxicity of mice. Methods: 40 male and female mice weighing 18 - 21 g were randomly divided into anti - glare granule group and normal saline control group. The maximum volume of anti - glare particles (0.94 g/ml) was administered before the experiment. Results: the oral toxicity of the suspension was very small. The maximal concentration of mice was given at the maximum volume of gastric perfusion, and it was given three times in 1st. The cumulative maximum tolerance dose was 112.8g/kg per day. The dose was 226 times of clinical dosage and no death was found in mice. Conclusion: the toxicity of Kangxuan granules is very small and it can be considered safe in clinical use.

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

Variation in chilling tolerance for photosynthesis and leaf extension growth among genotypes related to the C-4 grass Miscanthus xgiganteus

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

Glowacka, K; Adhikari, S; Peng, JH

The goal of this study was to identify cold-tolerant genotypes within two species of Miscanthus related to the exceptionally chilling-tolerant C-4 biomass crop accession: M. xgiganteus 'Illinois' (Mxg) as well as in other Mxg genotypes. The ratio of leaf elongation at 10 degrees C/5 degrees C to that at 25 degrees C/25 degrees C was used to identify initially the 13 most promising Miscanthus genotypes out of 51 studied. Net leaf CO2 uptake (A(sat)) and the maximum operating efficiency of photosystem II (Phi(PSII)) were measured in warm conditions (25 degrees C/20 degrees C), and then during and following a chillingmore » treatment of 10 degrees C/5 degrees C for 11 d. Accessions of M. sacchariflorus (Msa) showed the smallest decline in leaf elongation on transfer to chilling conditions and did not differ significantly from Mxg, indicating greater chilling tolerance than diploid M. sinensis (Msi). Msa also showed the smallest reductions in A(sat) and Phi(PSII), and greater chilling-tolerant photosynthesis than Msi, and three other forms of Mxg, including new triploid accessions and a hexaploid Mxg 'Illinois'. Tetraploid Msa 'PF30153' collected in Gifu Prefecture in Honshu, Japan did not differ significantly from Mxg 'Illinois' in leaf elongation and photosynthesis at low temperature, but was significantly superior to all other forms of Mxg tested. The results suggested that the exceptional chilling tolerance of Mxg 'Illinois' cannot be explained simply by the hybrid vigour of this intraspecific allotriploid. Selection of chilling-tolerant accessions from both of Mxg's parental species, Msi and Msa, would be advisable for breeding new highly chilling-tolerant Mxg genotypes.« less

Variation in cassava germplasm for tolerance to post-harvest physiological deterioration.

PubMed

Venturini, M T; Santos, L R; Vildoso, C I A; Santos, V S; Oliveira, E J

2016-05-06

Tolerant varieties can effectively control post-harvest physiological deterioration (PPD) of cassava, although knowledge on the genetic variability and inheritance of this trait is needed. The objective of this study was to estimate genetic parameters and identify sources of tolerance to PPD and their stability in cassava accessions. Roots from 418 cassava accessions, grown in four independent experiments, were evaluated for PPD tolerance 0, 2, 5, and 10 days post-harvest. Data were transformed into area under the PPD-progress curve (AUP-PPD) to quantify tolerance. Genetic parameters, stability (Si), adaptability (Ai), and the joint analysis of stability and adaptability (Zi) were obtained via residual maximum likelihood (REML) and best linear unbiased prediction (BLUP) methods. Variance in the genotype (G) x environment (E) interaction and genotypic variance were important for PPD tolerance. Individual broad-sense heritability (hg(2)= 0.38 ± 0.04) and average heritability in accessions (hmg(2)= 0.52) showed high genetic control of PPD tolerance. Genotypic correlation of AUP-PPD in different experiments was of medium magnitude (ȓgA = 0.42), indicating significant G x E interaction. The predicted genotypic values o f G x E free of interaction (û + ĝi) showed high variation. Of the 30 accessions with high Zi, 19 were common to û + ĝi, Si, and Ai parameters. The genetic gain with selection of these 19 cassava accessions was -55.94, -466.86, -397.72, and -444.03% for û + ĝi, Si, Ai, and Zi, respectively, compared with the overall mean for each parameter. These results demonstrate the variability and potential of cassava germplasm to introduce PPD tolerance in commercial varieties.

Is sexual reproduction of high-mountain plants endangered by heat?

PubMed

Ladinig, Ursula; Pramsohler, Manuel; Bauer, Ines; Zimmermann, Sonja; Neuner, Gilbert; Wagner, Johanna

2015-04-01

Strong solar irradiation in combination with still air and dry soil can cause prostrate high-mountain plants to heat up considerably and ultimately suffer heat damage. Such heat damage has been repeatedly shown for vegetative structures, but not for reproductive structures, which we expected to be particularly vulnerable to heat. Heat effects on cold-adapted plants may increase with rising global temperatures and the predicted increase in heat waves. We have tested the heat tolerance of reproductive versus vegetative shoots at different reproductive stages, comparing ten common plant species from different elevation belts in the European Alps. Plant samples were exposed to temperatures in 2-K steps of 30 min each between 42 and 56 °C. Heat damage was assessed by visual rating and vital staining. Reproductive shoots were on average 2.5 K less heat tolerant (LT50, i.e. the mean temperature causing 50 % heat damage, 47.2 °C) than vegetative shoots (mean LT50 49.7 °C). Initial heat injuries (mean LT10) were observed at 43-45 °C in heat-susceptible species and at 45-47 °C in more heat-tolerant species, in at least one reproductive stage. Generally, heat tolerance was significantly higher during fruiting than during the bud stages and anthesis. Prostrate species with acaulescent buds and flowers tolerated heat better than those with caulescent buds and flowers. Petals were the most heat-susceptible plant structure and mature pollen the most heat tolerant. Based on these data, heat tolerance of reproductive structures appears to be adapted to the prevailing maximum temperatures which the plants experience during different reproductive stages in their environment. During hot spells, however, heat tolerance thresholds may be exceeded. More frequent heat waves would decrease the reproductive output and, consequently, the competitiveness of heat-susceptible species.

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

PubMed Central

Deming, Dustin A.; Cavalcante, Ludmila L.; Lubner, Sam J.; Mulkerin, Daniel L.; LoConte, Noelle K.; Eickhoff, Jens C.; Kolesar, Jill M.; Fioravanti, Suzanne; Greten, Tim F.; Compton, Kathryn; Doyle, Austin G.; Wilding, George; Duffy, Austin; Liu, Glenn

2015-01-01

Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes. PMID:26666244

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.

PubMed

Deming, Dustin A; Cavalcante, Ludmila L; Lubner, Sam J; Mulkerin, Daniel L; LoConte, Noelle K; Eickhoff, Jens C; Kolesar, Jill M; Fioravanti, Suzanne; Greten, Tim F; Compton, Kathryn; Doyle, Austin G; Wilding, George; Duffy, Austin; Liu, Glenn

2016-04-01

KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Developmental changes in the germinability, desiccation tolerance, hardseededness, and longevity of individual seeds of Trifolium ambiguum

PubMed Central

Hay, F. R.; Smith, R. D.; Ellis, R. H.; Butler, L. H.

2010-01-01

Background and Aims Using two parental clones of outcrossing Trifolium ambiguum as a potential model system, we examined how during seed development the maternal parent, number of seeds per pod, seed position within the pod, and pod position within the inflorescence influenced individual seed fresh weight, dry weight, water content, germinability, desiccation tolerance, hardseededness, and subsequent longevity of individual seeds. Methods Near simultaneous, manual reciprocal crosses were carried out between clonal lines for two experiments. Infructescences were harvested at intervals during seed development. Each individual seed was weighed and then used to determine dry weight or one of the physiological behaviour traits. Key Results Whilst population mass maturity was reached at 33–36 days after pollination (DAP), seed-to-seed variation in maximum seed dry weight, when it was achieved, and when maturation drying commenced, was considerable. Individual seeds acquired germinability between 14 and 44 DAP, desiccation tolerance between 30 and 40 DAP, and the capability to become hardseeded between 30 and 47 DAP. The time for viability to fall to 50 % (p50) at 60 % relative humidity and 45 °C increased between 36 and 56 DAP, when the seed coats of most individuals had become dark orange, but declined thereafter. Individual seed f. wt at harvest did not correlate with air-dry storage survival period. Analysing survival data for cohorts of seeds reduced the standard deviation of the normal distribution of seed deaths in time, but no sub-population showed complete uniformity of survival period. Conclusions Variation in individual seed behaviours within a developing population is inherent and inevitable. In this outbreeder, there is significant variation in seed longevity which appears dependent on embryo genotype with little effect of maternal genotype or architectural factors. PMID:20228084

Hamstring Stiffness Returns More Rapidly After Static Stretching Than Range of Motion, Stretch Tolerance, and Isometric Peak Torque.

PubMed

Hatano, Genki; Suzuki, Shigeyuki; Matsuo, Shingo; Kataura, Satoshi; Yokoi, Kazuaki; Fukaya, Taizan; Fujiwara, Mitsuhiro; Asai, Yuji; Iwata, Masahiro

2017-12-18

Hamstring injuries are common, and lack of hamstring flexibility may predispose to injury. Static stretching increases range of motion (ROM) but also results in reduced muscle strength after stretching. The effects of stretching on the hamstring muscles and the duration of these effects remain unclear. To determine the effects of static stretching on the hamstrings and the duration of these effects. Randomized crossover study. University laboratory. Twenty-four healthy volunteers. We measured the torque-angle relationship (ROM, passive torque (PT) at the onset of pain, and passive stiffness) and isometric muscle force using an isokinetic dynamometer. After a 60-minute rest, the ROM of the dynamometer was set at maximum tolerable intensity; this position was maintained for 300 seconds while static passive torque (SPT) was measured continuously. We remeasured the torque-angle relationship and isometric muscle force after rest periods of 10, 20, and 30 minutes. Change in SPT during stretching; changes in ROM, PT at the onset of pain, passive stiffness, and isometric muscle force before stretching compared with 10, 20, and 30 minutes after stretching. SPT decreased significantly during stretching. Passive stiffness decreased significantly 10 and 20 minutes after stretching, but there was no significant pre- vs. post-stretching difference after 30 minutes. PT at the onset of pain and ROM increased significantly after stretching at all rest intervals, while isometric muscle force decreased significantly after all rest intervals. The effect of static stretching on passive stiffness of the hamstrings was not maintained as long as the changes in ROM, stretch tolerance, and isometric muscle force. Therefore, frequent stretching is necessary to improve the viscoelasticity of the muscle-tendon unit. Muscle force was decreased for 30 minutes after stretching; this should be considered prior to activities requiring maximal muscle strength.

Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects

PubMed Central

Upreti, Vijay V; Wang, Jessie; Barrett, Yu Chen; Byon, Wonkyung; Boyd, Rebecca A; Pursley, Janice; LaCreta, Frank P; Frost, Charles E

2013-01-01

Aim Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability. Method Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65–85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored. Results Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8–51%] and 20% (90% CI: 11–42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18–41%) and 23% (90% CI: 9–35%) lower apixaban Cmax and AUC(0,∞), respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study. Conclusion The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure. PMID:23488672

SNPs in stress-responsive rice genes: validation, genotyping, functional relevance and population structure

PubMed Central

2012-01-01

Background Single nucleotide polymorphism (SNP) validation and large-scale genotyping are required to maximize the use of DNA sequence variation and determine the functional relevance of candidate genes for complex stress tolerance traits through genetic association in rice. We used the bead array platform-based Illumina GoldenGate assay to validate and genotype SNPs in a select set of stress-responsive genes to understand their functional relevance and study the population structure in rice. Results Of the 384 putative SNPs assayed, we successfully validated and genotyped 362 (94.3%). Of these 325 (84.6%) showed polymorphism among the 91 rice genotypes examined. Physical distribution, degree of allele sharing, admixtures and introgression, and amino acid replacement of SNPs in 263 abiotic and 62 biotic stress-responsive genes provided clues for identification and targeted mapping of trait-associated genomic regions. We assessed the functional and adaptive significance of validated SNPs in a set of contrasting drought tolerant upland and sensitive lowland rice genotypes by correlating their allelic variation with amino acid sequence alterations in catalytic domains and three-dimensional secondary protein structure encoded by stress-responsive genes. We found a strong genetic association among SNPs in the nine stress-responsive genes with upland and lowland ecological adaptation. Higher nucleotide diversity was observed in indica accessions compared with other rice sub-populations based on different population genetic parameters. The inferred ancestry of 16% among rice genotypes was derived from admixed populations with the maximum between upland aus and wild Oryza species. Conclusions SNPs validated in biotic and abiotic stress-responsive rice genes can be used in association analyses to identify candidate genes and develop functional markers for stress tolerance in rice. PMID:22921105

At the edge of the thermal window: effects of elevated temperature on the resting metabolism, hypoxia tolerance and upper critical thermal limit of a widespread African cichlid

PubMed Central

McDonnell, Laura H.; Chapman, Lauren J.

2015-01-01

Tropical inland fishes are predicted to be especially vulnerable to thermal stress because they experience small temperature fluctuations that may select for narrow thermal windows. In this study, we measured resting metabolic rate (RMR), critical oxygen tension (Pcrit) and critical thermal maximum (CTMax) of the widespread African cichlid (Pseudocrenilabrus multicolor victoriae) in response to short-term acclimation to temperatures within and above their natural thermal range. Pseudocrenilabrus multicolor collected in Lake Kayanja, Uganda, a population living near the upper thermal range of the species, were acclimated to 23, 26, 29 and 32°C for 3 days directly after capture, and RMR and Pcrit were then quantified. In a second group of P. multicolor from the same population, CTMax and the thermal onset of agitation were determined for fish acclimated to 26, 29 and 32°C for 7 days. Both RMR and Pcrit were significantly higher in fish acclimated to 32°C, indicating decreased tolerance to hypoxia and increased metabolic requirements at temperatures only slightly (∼1°C) above their natural thermal range. The CTMax increased with acclimation temperature, indicating some degree of thermal compensation induced by short-term exposure to higher temperatures. However, agitation temperature (likely to represent an avoidance response to increased temperature during CTMax trials) showed no increase with acclimation temperature. Overall, the results of this study demonstrate that P. multicolor is able to maintain its RMR and Pcrit across the range of temperatures characteristic of its natural habitat, but incurs a higher cost of resting metabolism and reduced hypoxia tolerance at temperatures slightly above its present range. PMID:27293734

Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.

PubMed

Tabernero, Josep; Chawla, Sant P; Kindler, Hedy; Reckamp, Karen; Chiorean, E Gabriela; Azad, Nilofer S; Lockhart, A Craig; Hsu, Cheng-Pang; Baker, Nigel F; Galimi, Francesco; Beltran, Pedro; Baselga, José

2015-03-01

Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.

Tolerance and resistance characteristics of microalgae Scenedesmus sp. LX1 to methylisothiazolinone.

PubMed

Wang, Xiao-Xiong; Zhang, Tian-Yuan; Dao, Guo-Hua; Hu, Hong-Ying

2018-05-25

Methylisothiazolinone (MIT) has been widely used to control bacterial growth in reverse osmosis (RO) systems. However, MIT's toxicity on microalgae should be determined because residual MIT is concentrated into RO concentrate (ROC) and might have a severe impact on microalgae-based ROC treatment. This study investigated the tolerance of Scenedesmus sp. LX1 to MIT and revealed the mechanism of algal growth inhibition and toxicity resistance. Scenedesmus sp. LX1 was inhibited by MIT with a half-maximal effective concentration at 72 h (72 h-EC 50 ) of 1.00 mg/L, but the strain recovered from the inhibition when its growth was not completely inhibited. It was observed that this inhibition's effect on subsequent growth was weak, and the removal of MIT was the primary reason for the recovery. Properly increasing the initial algal density significantly shortened the adaptation time for accelerated recovery in a MIT-containing culture. Photosynthesis damage by MIT was one of the primary reasons for growth inhibition, but microalgal cell respiration and adenosine triphosphate (ATP) synthesis were not completely inhibited, and the algae were still alive even when growth was completely inhibited, which was notably different from observations made with bacteria and fungi. The algae synthesized more chlorophyll, antioxidant enzymes of superoxide dismutase (SOD) and catalase (CAT), and small molecules, such as reduced glutathione (GSH), to resist MIT poisoning. The microalgae-based process could treat the MIT-containing ROC, since MIT was added for only several hours a week in municipal wastewater reclamation RO processes, and the MIT average concentration was considerably lower than the maximum concentration that algae could tolerate. Copyright © 2018. Published by Elsevier Ltd.

Contrasting physiological responses of two co-occurring eucalypts to seasonal drought at restored bauxite mine sites.

PubMed

Szota, Christopher; Farrell, Claire; Koch, John M; Lambers, Hans; Veneklaas, Erik J

2011-10-01

This study describes the physiological response of two co-occurring tree species (Eucalyptus marginata and Corymbia calophylla) to seasonal drought at low- and high-quality restored bauxite mine sites in south-western Australia. Seasonal changes in photosynthesis (A), stomatal conductance (g(s)), leaf water potential (ψ), leaf osmotic potential (ψ), leaf relative water content (RWC) and pressure-volume analysis were captured over an 18-month field study to (i) determine the nature and severity of physiological stress in relation to site quality and (ii) identify any physiological differences between the two species. Root system restriction at the low-quality site reduced maximum rates of gas exchange (g(s) and A) and increased water stress (midday ψ and daily RWC) in both species during drought. Both species showed high stomatal sensitivity during drought; however, E. marginata demonstrated a higher dehydration tolerance where ψ and RWC fell to -3.2 MPa and 73% compared with -2.4 MPa and 80% for C. calophylla. Corymbia calophylla showed lower g(s) and higher ψ and RWC during drought, indicating higher drought tolerance. Pressure-volume curves showed that cell-wall elasticity of E. marginata leaves increased in response to drought, while C. calophylla leaves showed lower osmotic potential at zero turgor in summer than in winter, indicating osmotic adjustment. Both species are clearly able to tolerate seasonal drought at hostile sites; however, by C. calophylla closing stomata earlier in the drought cycle, maintaining a higher water status during drought and having the additional mechanism of osmotic adjustment, it may have a greater capacity to survive extended periods of drought.

A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

PubMed

Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

2017-07-01

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

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.

40 CFR 180.2010 - Threshold of regulation determinations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 24 2014-07-01 2014-07-01 false Threshold of regulation determinations. 180.2010 Section 180.2010 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From...

40 CFR 180.2010 - Threshold of regulation determinations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 25 2013-07-01 2013-07-01 false Threshold of regulation determinations. 180.2010 Section 180.2010 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS TOLERANCES AND EXEMPTIONS FOR PESTICIDE CHEMICAL RESIDUES IN FOOD Pesticide Chemicals Not Requiring a Tolerance or an Exemption From...

Elevated CO2 response of photosynthesis depends on ozone concentration in aspen

Treesearch

A. Noormets; O. Kull; A. Sôber; M.E. Kubiske; D.F. Karnosky

2010-01-01

The effect of elevated CO2 and O3 on apparent quantum yield (f), maximum photosynthesis (Pmax), carboxylation efficiency (Vcmax) and electron transport capacity (Jmax) at different canopy locations was studied in two aspen (Populus tremuloides) clones of contrasting O3 tolerance. Local light climate at every leaf was characterized as fraction of above-canopy...

27 CFR 27.42a - Still wines containing carbon dioxide.

Code of Federal Regulations, 2011 CFR

2011-04-01

.... Still wines may contain not more than 0.392 gram of carbon dioxide per 100 milliliters of wine; except that a tolerance to this maximum limitation, not to exceed 0.009 gram of carbon dioxide per 100 milliliters of wine, will be allowed where the amount of carbon dioxide in excess of 0.392 gram per 100...

27 CFR 24.245 - Use of carbon dioxide in still wine.

Code of Federal Regulations, 2014 CFR

2014-04-01

... than 0.392 grams of carbon dioxide per 100 milliliters of wine. However, a tolerance of not more than 0.009 grams per 100 milliliters to the maximum limitation of carbon dioxide in still wine will be allowed where the amount of carbon dioxide in excess of 0.392 grams per 100 milliliters is due to...

27 CFR 27.42a - Still wines containing carbon dioxide.

Code of Federal Regulations, 2014 CFR

2014-04-01

.... Still wines may contain not more than 0.392 gram of carbon dioxide per 100 milliliters of wine; except that a tolerance to this maximum limitation, not to exceed 0.009 gram of carbon dioxide per 100 milliliters of wine, will be allowed where the amount of carbon dioxide in excess of 0.392 gram per 100...

27 CFR 27.42a - Still wines containing carbon dioxide.

Code of Federal Regulations, 2013 CFR

2013-04-01

.... Still wines may contain not more than 0.392 gram of carbon dioxide per 100 milliliters of wine; except that a tolerance to this maximum limitation, not to exceed 0.009 gram of carbon dioxide per 100 milliliters of wine, will be allowed where the amount of carbon dioxide in excess of 0.392 gram per 100...

27 CFR 27.42a - Still wines containing carbon dioxide.

Code of Federal Regulations, 2012 CFR

2012-04-01

.... Still wines may contain not more than 0.392 gram of carbon dioxide per 100 milliliters of wine; except that a tolerance to this maximum limitation, not to exceed 0.009 gram of carbon dioxide per 100 milliliters of wine, will be allowed where the amount of carbon dioxide in excess of 0.392 gram per 100...

27 CFR 27.42a - Still wines containing carbon dioxide.

Code of Federal Regulations, 2010 CFR

2010-04-01

.... Still wines may contain not more than 0.392 gram of carbon dioxide per 100 milliliters of wine; except that a tolerance to this maximum limitation, not to exceed 0.009 gram of carbon dioxide per 100 milliliters of wine, will be allowed where the amount of carbon dioxide in excess of 0.392 gram per 100...

27 CFR 24.245 - Use of carbon dioxide in still wine.

Code of Federal Regulations, 2012 CFR

2012-04-01

... than 0.392 grams of carbon dioxide per 100 milliliters of wine. However, a tolerance of not more than 0.009 grams per 100 milliliters to the maximum limitation of carbon dioxide in still wine will be allowed where the amount of carbon dioxide in excess of 0.392 grams per 100 milliliters is due to...

A straightforward method to determine flavouring substances in food by GC-MS.

PubMed

Lopez, Patricia; van Sisseren, Maarten; De Marco, Stefania; Jekel, Ad; de Nijs, Monique; Mol, Hans G J

2015-05-01

A straightforward GC-MS method was developed to determine the occurrence of fourteen flavouring compounds in food. It was successfully validated for four generic types of food (liquids, semi-solids, dry solids and fatty solids) in terms of limit of quantification, linearity, selectivity, matrix effects, recovery (53-120%) and repeatability (3-22%). The method was applied to a survey of 61 Dutch food products. The survey was designed to cover all the food commodities for which the EU Regulation 1334/2008 set maximum permitted levels. All samples were compliant with EU legislation. However, the levels of coumarin (0.6-63 mg/kg) may result in an exposure that, in case of children, would exceed the tolerable daily intake (TDI) of 0.1mg/kg bw/day. In addition to coumarin, estragole, methyl-eugenol, (R)-(+)-pulegone and thujone were EU-regulated substances detected in thirty-one of the products. The non-EU regulated alkenylbenzenes, trans-anethole and myristicin, were commonly present in beverages and in herbs-containing products. Copyright © 2014 Elsevier Ltd. All rights reserved.

Validated multiclass targeted determination of antibiotics in fish with high performance liquid chromatography-benchtop quadrupole orbitrap hybrid mass spectrometry.

PubMed

Chiesa, Luca; Panseri, Sara; Pasquale, Elisa; Malandra, Renato; Pavlovic, Radmila; Arioli, Francesco

2018-08-30

High performance liquid chromatography, coupled with a benchtop Q-Exactive Orbitrap high-resolution mass spectrometer, was successfully applied for the determination of 24 target antibiotics (selected beta-lactams, tetracyclines, fluoroquinolones, sulfonamids, phenicols, macrolides, cephalosporins, lincosamides, diaminopyrimidine) in fish matrices. The Q-Exactive parameters were carefully studied to accomplish the best compromise between a suitable scan speed and selectivity, considering the restrictions associated with generic sample preparation methodology. Retention time, an exact mass with tolerance of 2 ppm and data-dependent MS 2 spectra were the main identifiers. The method was validated through specificity, linearity, recovery, intra- and inter-day repeatability, decision limit (CCα) and detection capability (CCβ), according to 2002/657/EC. The values of CCα and CCβ ranged from 29.2 to 36.8 and 32.5 to 48.9, respectively, while overall recovery ranged from 91.1 to 105.6%. Fifty fish samples were analysed, showing the sporadic incidence of enrofloxacin, chlortetracycline, oxytetracycline, amoxicillin and trimethoprim, albeit below the maximum residual levels. Copyright © 2018 Elsevier Ltd. All rights reserved.

Micromolding of polymer waveguides

NASA Astrophysics Data System (ADS)

Hanemann, Thomas; Ulrich, Hermann; Ruprecht, Robert; Hausselt, Juergen H.

1999-10-01

In microsystem technology the fabrication of either passive or active micro optical components made from polymers becomes more and more evident with respect to the intense expanding application possibilities e.g. in telecommunication. Actually, the LIGA process developed at the FZK, Germany allows the direct fabrication of microcomponents with lateral dimensions in the micrometer range, structural details in the submicrometer range, high aspect ratios of up to several hundreds and a final average surface roughness of less than 50 nm in small up to large scales. The molding of polymer components for microoptical applications, especially in the singlemode range, is determined by the achievable maximum accuracy of the molding technique itself and of the acceptable tolerances for low damping and coupling losses. Following the LIGA and related technique e.g. mechanical microengineering we want to present in this work the fabrication of polymer singlemode waveguides using a combination of micromolding and light- curing steps.

Levetiracetam for Treatment of Neonatal Seizures

PubMed Central

Abend, Nicholas S.; Gutierrez-Colina, Ana M.; Monk, Heather M.; Dlugos, Dennis J.; Clancy, Robert R.

2011-01-01

Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications. PMID:21233461

How to obtain a shortest mode converter based on periodic waveguide with limited index contrast?

NASA Astrophysics Data System (ADS)

Zhang, Lingxuan; Zhang, Wenfu; Wang, Guoxi; Hu, Yaowei; Ge, Zhiqiang; Wang, Leiran; Sun, Qibing; Wang, Weiqiang; Gong, Yongkang; Zhao, Wei

2017-05-01

Mode converter is one of most significant elements in photonic integrated circuits. It relies on increasing index contrast to shorten its length. However, index contrast is limited for technology. In addition, an overlarge index contrast leads to some disadvantages, such as large scattering loss, reflection loss, and small tolerance for manufacturing. Thus, an approximate scheme to design a mode converter is manipulating the transverse distribution of index to achieve the minimum length when the index contrast is given. We have analytically deduced the theoretical maximum coupled efficiency in periodic waveguide, which determines the minimum coupling length of mode converter. What is more, we have demonstrated how to construct a distribution function of indices in a cross section of waveguide to achieve the minimum length and a case is also given to illustrate the process. Proofs, based on both mathematic derivation and numerical simulation, have been exhibited in the paper.

Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer

PubMed Central

Shaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S.W.; Felip, Enriqueta; Chow, Laura Q.M.; Camidge, D. Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.

2014-01-01

BACKGROUND Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.) PMID:24670165

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom.

PubMed

Lye, Jessica; Kenny, John; Lehmann, Joerg; Dunn, Leon; Kron, Tomas; Alves, Andrew; Cole, Andrew; Williams, Ivan

2014-10-01

The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%-8%. The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.

Patterns of Tree Species Diversity in Relation to Climatic Factors on the Sierra Madre Occidental, Mexico

PubMed Central

Silva-Flores, Ramón; Pérez-Verdín, Gustavo; Wehenkel, Christian

2014-01-01

Biological diversity can be defined as variability among living organisms from all sources, including terrestrial organisms, marine and other aquatic ecosystems, and the ecological complexes which they are part of. This includes diversity within species, between species, and of ecosystems. Numerous diversity indices combine richness and evenness in a single expression, and several climate-based explanations have been proposed to explain broad-scale diversity patterns. However, climate-based water-energy dynamics appears to be an essential factor that determines patterns of diversity. The Mexican Sierra Madre Occidental occupies an area of about 29 million hectares and is located between the Neotropical and Holarctic ecozones. It shelters a high diversity of flora, including 24 different species of Pinus (ca. 22% on the whole), 54 species of Quercus (ca. 9–14%), 7 species of Arbutus (ca. 50%) and many other trees species. The objectives of this study were to model how tree species diversity is related to climatic and geographic factors and stand density and to test the Metabolic Theory, Productivity-Diversity Hypothesis, Physiological Tolerance Hypothesis, Mid-Domain Effect, and the Water-Energy Dynamic Theory on the Sierra Madre Occidental, Durango. The results supported the Productivity-Diversity Hypothesis, Physiological Tolerance Hypothesis and Water-Energy Dynamic Theory, but not the Mid-Domain Effect or Metabolic Theory. The annual aridity index was the variable most closely related to the diversity indices analyzed. Contemporary climate was found to have moderate to strong effects on the minimum, median and maximum tree species diversity. Because water-energy dynamics provided a satisfactory explanation for the patterns of minimum, median and maximum diversity, an understanding of this factor is critical to future biodiversity research. Quantile regression of the data showed that the three diversity parameters of tree species are generally higher in cold, humid temperate climates than in dry, hot climates. PMID:25127455

Patterns of tree species diversity in relation to climatic factors on the Sierra Madre Occidental, Mexico.

PubMed

Silva-Flores, Ramón; Pérez-Verdín, Gustavo; Wehenkel, Christian

2014-01-01

Biological diversity can be defined as variability among living organisms from all sources, including terrestrial organisms, marine and other aquatic ecosystems, and the ecological complexes which they are part of. This includes diversity within species, between species, and of ecosystems. Numerous diversity indices combine richness and evenness in a single expression, and several climate-based explanations have been proposed to explain broad-scale diversity patterns. However, climate-based water-energy dynamics appears to be an essential factor that determines patterns of diversity. The Mexican Sierra Madre Occidental occupies an area of about 29 million hectares and is located between the Neotropical and Holarctic ecozones. It shelters a high diversity of flora, including 24 different species of Pinus (ca. 22% on the whole), 54 species of Quercus (ca. 9-14%), 7 species of Arbutus (ca. 50%) and many other trees species. The objectives of this study were to model how tree species diversity is related to climatic and geographic factors and stand density and to test the Metabolic Theory, Productivity-Diversity Hypothesis, Physiological Tolerance Hypothesis, Mid-Domain Effect, and the Water-Energy Dynamic Theory on the Sierra Madre Occidental, Durango. The results supported the Productivity-Diversity Hypothesis, Physiological Tolerance Hypothesis and Water-Energy Dynamic Theory, but not the Mid-Domain Effect or Metabolic Theory. The annual aridity index was the variable most closely related to the diversity indices analyzed. Contemporary climate was found to have moderate to strong effects on the minimum, median and maximum tree species diversity. Because water-energy dynamics provided a satisfactory explanation for the patterns of minimum, median and maximum diversity, an understanding of this factor is critical to future biodiversity research. Quantile regression of the data showed that the three diversity parameters of tree species are generally higher in cold, humid temperate climates than in dry, hot climates.

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

PubMed

Fidias, Panos; Pennell, Nathan A; Boral, Anthony L; Shapiro, Geoffrey I; Skarin, Arthur T; Eder, Joseph P; Kwoh, T Jesse; Geary, Richard S; Johnson, Bruce E; Lynch, Thomas J; Supko, Jeffrey G

2009-09-01

A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.

Thermal tolerance of meltwater stonefly Lednia tumana nymphs from an alpine stream in Waterton–Glacier International Peace Park, Montana, USA

USGS Publications Warehouse

Billman, Hilary G.; Giersch, J. Joseph; Kappenman, K.M.; Muhlfeld, Clint C.; Webb, Molly A. H.

2013-01-01

Global climate change threatens to affect negatively the structure, function, and diversity of aquatic ecosystems worldwide. In alpine systems, the thermal tolerances of stream invertebrates can be assessed to understand better the potential effects of rising ambient temperatures and continued loss of glaciers and snowpack on alpine stream ecosystems. We measured the critical thermal maximum (CTM) and lethal temperature maximum (LTM) of the meltwater stonefly (Lednia tumana), a species limited to glacial and snowmelt-driven alpine streams in the Waterton–Glacier International Peace Park area and a candidate for listing under the US Endangered Species Act. We collected L. tumana nymphs from Lunch Creek in Glacier National Park, Montana (USA) and transported them to a laboratory at the University of Montana Flathead Lake Biological Station, Polson, Montana. We placed nymphs in a controlled water bath at 1 of 2 acclimation temperatures, 8.5 and 15°C. We increased water temperature at a constant rate of 0.3°C/min. We calculated the average CTM and LTM (± SD) for each acclimation temperature and compared them with Student’s t-tests. Predicted chronic temperature maxima were determined using the ⅓ rule. Mean LTMs were 32.3 ± 0.28°C and 31.05 ± 0.78°C in the 8.5 and 15°C acclimation treatments, respectively. CTM and LTM metrics were lower in the 15 than in the 8.5°C acclimation treatment, but these differences were not statistically significant (p > 0.05). The predicted chronic temperature maxima were 20.6 and 20.2°C for the 8.5 and 15°C acclimation treatments, respectively. More research is needed on the effects of chronic exposures to rising stream temperatures, but our results can be used to assess the potential effects of warming water temperatures on L. tumana and other aquatic macroinvertebrates in alpine ecosystems.

77 FR 41356 - Monsanto Co.; Availability of Petition for Determination of Nonregulated Status of Soybean...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-13

... Engineered for Herbicide Tolerance AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION: Notice... soybean designated as MON 87708, which has been genetically engineered for tolerance to the herbicide... MON 87708, which has been genetically engineered for tolerance to the herbicide dicamba, stating that...

77 FR 41353 - GENECTIVE SA; Availability of Petition for Determination of Nonregulated Status of Maize...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-13

... Engineered for Herbicide Tolerance AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION: Notice... VCO-[Oslash]1981-5, which has been genetically engineered for tolerance to the herbicide glyphosate...- [Oslash]1981-5, which has been genetically engineered for tolerance to the herbicide glyphosate, stating...

The Safety Zone, 2000.

ERIC Educational Resources Information Center

Fiscus, James W., Ed.; Pollack, Ira, Ed.

2000-01-01

This publication is concerned with how to keep schools safe. The spring 2000 issue "Zero Tolerance: Effective Policy or Display of Administrative Machismo?" (James W. Fiscus) discusses how difficult it is to determine just what zero tolerance means and reminds readers that schools were required to pass zero tolerance rules to remain eligible for…

Isopods Failed to Acclimate Their Thermal Sensitivity of Locomotor Performance during Predictable or Stochastic Cooling

PubMed Central

Schuler, Matthew S.; Cooper, Brandon S.; Storm, Jonathan J.; Sears, Michael W.; Angilletta, Michael J.

2011-01-01

Most organisms experience environments that vary continuously over time, yet researchers generally study phenotypic responses to abrupt and sustained changes in environmental conditions. Gradual environmental changes, whether predictable or stochastic, might affect organisms differently than do abrupt changes. To explore this possibility, we exposed terrestrial isopods (Porcellio scaber) collected from a highly seasonal environment to four thermal treatments: (1) a constant 20°C; (2) a constant 10°C; (3) a steady decline from 20° to 10°C; and (4) a stochastic decline from 20° to 10°C that mimicked natural conditions during autumn. After 45 days, we measured thermal sensitivities of running speed and thermal tolerances (critical thermal maximum and chill-coma recovery time). Contrary to our expectation, thermal treatments did not affect the thermal sensitivity of locomotion; isopods from all treatments ran fastest at 33° to 34°C and achieved more than 80% of their maximal speed over a range of 10° to 11°C. Isopods exposed to a stochastic decline in temperature tolerated cold the best, and isopods exposed to a constant temperature of 20°C tolerated cold the worst. No significant variation in heat tolerance was observed among groups. Therefore, thermal sensitivity and heat tolerance failed to acclimate to any type of thermal change, whereas cold tolerance acclimated more during stochastic change than it did during abrupt change. PMID:21698113

Effects of phenylbutazone on glucose tolerance and on secretion of insulin in healthy geldings.

PubMed

Zicker, S C; Brumbaugh, G W

1989-05-01

The effect of phenylbutazone (4.4 mg/kg of body weight, IV, q 24 h, for 5 days) on glucose tolerance and on secretion of insulin in 6 healthy geldings was determined. Phenylbutazone significantly lowered fasting concentrations of glucose in plasma but did not significantly change the concentration of insulin in serum. There was no significant effect of phenylbutazone on glucose tolerance, on secretion of insulin, or on the area under the insulin/glucose ratio vs time curve in healthy geldings, as determined by paired t test analysis.

Thermal tolerance in tropical versus subtropical Pacific reef corals

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

Coles, S.L.; Jokiel, P.L.; Lewis, C.R.

1976-04-01

Upper lethal temperature tolerances of reef corals in Hawaii and at Enewetak, Marshall Islands, were determined in the field and under controlled laboratory conditions. Enewetak corals survived in situ temperatures of nearly 34/sup 0/C, whereas 32/sup 0/C was lethal to Hawaiian corals for similar short-term exposures. Laboratory determinations indicate that the upper thermal limits of Hawaiian corals are approximately 2/sup 0/C less than congeners from the tropical Pacific. Differences in coral thermal tolerances correspond to differences in the ambient temperature patterns between geographic areas.

RELIABILITY OF THE ONE REPETITION-MAXIMUM POWER CLEAN TEST IN ADOLESCENT ATHLETES

PubMed Central

Faigenbaum, Avery D.; McFarland, James E.; Herman, Robert; Naclerio, Fernando; Ratamess, Nicholas A.; Kang, Jie; Myer, Gregory D.

2013-01-01

Although the power clean test is routinely used to assess strength and power performance in adult athletes, the reliability of this measure in younger populations has not been examined. Therefore, the purpose of this study was to determine the reliability of the one repetition maximum (1 RM) power clean in adolescent athletes. Thirty-six male athletes (age 15.9 ± 1.1 yrs, body mass 79.1 ± 20.3 kg, height 175.1 ±7.4 cm) who had more than 1 year of training experience with weightlifting exercises performed a 1 RM power clean on two nonconsecutive days in the afternoon following standardized procedures. All test procedures were supervised by a senior level weightlifting coach and consisted of a systematic progression in test load until the maximum resistance that could be lifted for one repetition using proper exercise technique was determined. Data were analyzed using an intraclass correlation coefficient (ICC [2,k]), Pearson correlation coefficient (r), repeated measures ANOVA, Bland-Altman plot, and typical error analyses. Analysis of the data revealed that the test measures were highly reliable demonstrating a test-retest ICC of 0.98 (95% CI = 0.96–0.99). Testing also demonstrated a strong relationship between 1 RM measures on trial 1 and trial 2 (r=0.98, p<0.0001) with no significant difference in power clean performance between trials (70.6 ± 19.8 vs. 69.8 ± 19.8 kg). Bland Altman plots confirmed no systematic shift in 1 RM between trial 1 and trial 2. The typical error to be expected between 1 RM power clean trials is 2.9 kg and a change of at least 8.0 kg is indicated to determine a real change in lifting performance between tests in young lifters. No injuries occurred during the study period and the testing protocol was well-tolerated by all subjects. These findings indicate that 1 RM power clean testing has a high degree of reproducibility in trained male adolescent athletes when standardized testing procedures are followed and qualified instruction is present. PMID:22233786

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.

F-111 natural laminar flow glove flight test data analysis and boundary layer stability analysis

NASA Technical Reports Server (NTRS)

Runyan, L. J.; Navran, B. H.; Rozendaal, R. A.

1984-01-01

An analysis of 34 selected flight test data cases from a NASA flight program incorporating a natural laminar flow airfoil into partial wing gloves on the F-111 TACT airplane is given. This analysis determined the measured location of transition from laminar to turbulent flow. The report also contains the results of a boundary layer stability analysis of 25 of the selected cases in which the crossflow (C-F) and Tollmien-Schlichting (T-S) disturbance amplification factors are correlated with the measured transition location. The chord Reynolds numbers for these cases ranges from about 23 million to 29 million, the Mach numbers ranged from 0.80 to 0.85, and the glove leading-edge sweep angles ranged from 9 deg to 25 deg. Results indicate that the maximum extent of laminar flow varies from 56% chord to 9-deg sweep on the upper surface, and from 51% chord at 16-deg sweep to 6% chord at 25-deg sweep on the lower. The results of the boundary layer stability analysis indicate that when both C-F and T-S disturbances are amplified, an interaction takes place which reduces the maximum amplification factor of either type of disturbance that can be tolerated without causing transition.

Further investigation of relationships between membrane fluidity and ethanol tolerance in Saccharomyces cerevisiae.

PubMed

Ishmayana, Safri; Kennedy, Ursula J; Learmonth, Robert P

2017-11-27

Membrane lipid unsaturation index and membrane fluidity have been related to yeast ethanol stress tolerance in published studies, however findings have been inconsistent. In this study, viability reduction on exposure to 18% (v/v) ethanol was compared to membrane fluidity determined by laurdan generalized polarization. Furthermore, in the determination of viability reduction, we examined the effectiveness of two methods, namely total plate count and methylene violet staining. We found a strong negative correlation between ethanol tolerance and membrane fluidity, indicated by negative Pearson correlation coefficients of - 0.79, - 0.65 and - 0.69 for Saccharomyces cerevisiae strains A12, PDM and K7, respectively. We found that lower membrane fluidity leads to higher ethanol tolerance, as indicated by decreased viability reduction and higher laurdan generalized polarization in respiratory phase compared to respiro-fermentative phase cells. Total plate count better differentiated ethanol tolerance of yeast cells in different growth phases, while methylene violet staining was better to differentiate ethanol tolerance of the different yeast strains at a particular culture phase. Hence, both viability assessment methods have their own advantages and limitations, which should be considered when comparing stress tolerance in different situations.

Computer program determines exact two-sided tolerance limits for normal distributions

NASA Technical Reports Server (NTRS)

Friedman, H. A.; Webb, S. R.

1968-01-01

Computer program determines by numerical integration the exact statistical two-sided tolerance limits, when the proportion between the limits is at least a specified number. The program is limited to situations in which the underlying probability distribution for the population sampled is the normal distribution with unknown mean and variance.

77 FR 53144 - Nitric Acid; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-31

... Cosmetic Act (FFDCA), requesting establishment of an exemption from the requirement of a tolerance. This... ingredients. IV. Aggregate Risk Assessment and Determination of Safety Section 408(c)(2)(A)(i) of FFDCA allows... to assess the hazards of and to make a determination on aggregate exposure for nitric acid including...

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.

PubMed

Murthy, Rashmi; Borges, Virginia F; Conlin, Alison; Chaves, Jorge; Chamberlain, Marc; Gray, Todd; Vo, Alex; Hamilton, Erika

2018-05-24

Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases. In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m 2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192. Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab. Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794). Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ultralow-quiescent-current and wide-load-range low-dropout linear regulator with self-biasing technique for micropower battery management

NASA Astrophysics Data System (ADS)

Ozaki, Toshihiro; Hirose, Tetsuya; Asano, Hiroki; Kuroki, Nobutaka; Numa, Masahiro

2017-04-01

In this paper, we present a 151 nA quiescent and 6.8 mA maximum-output-current low-dropout (LDO) linear regulator for micropower battery management. The LDO regulator employs self-biasing and multiple-stacked cascode techniques to achieve efficient, accurate, and high-voltage-input-tolerant operation. Measurement results demonstrated that the proposed LDO regulator operates with an ultralow quiescent current of 151 nA. The maximum output currents with a 4.16 V output were 1.0 and 6.8 mA when the input voltages were 4.25 and 5.0 V, respectively.

Improving the maximum transmission distance of continuous-variable quantum key distribution using a noiseless amplifier

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

Blandino, Rémi; Etesse, Jean; Grangier, Philippe

2014-12-04

We show that the maximum transmission distance of continuous-variable quantum key distribution in presence of a Gaussian noisy lossy channel can be arbitrarily increased using a heralded noiseless linear amplifier. We explicitly consider a protocol using amplitude and phase modulated coherent states with reverse reconciliation. Assuming that the secret key rate drops to zero for a line transmittance T{sub lim}, we find that a noiseless amplifier with amplitude gain g can improve this value to T{sub lim}/g{sup 2}, corresponding to an increase in distance proportional to log g. We also show that the tolerance against noise is increased.

Do fattening process and biological parameters affect the accumulation of metals in Atlantic bluefin tuna?

PubMed

Milatou, Niki; Dassenakis, Manos; Megalofonou, Persefoni

2015-01-01

The objective of this study was to determine the current levels of heavy metals and trace elements in Atlantic bluefin tuna muscle tissues and how they are influenced by the fattening process and various life history parameters to ascertain whether the concentrations in muscle tissue exceed the maximum levels defined by the European Commission Decision and to evaluate the health risk posed by fish consumption. A total of 20 bluefin tuna reared in sea cages, ranging from 160 to 295 cm in length and from 80 to 540 kg in weight, were sampled from a bluefin tuna farm in the Ionian Sea. The condition factor K of each specimen was calculated and their age was estimated. Heavy metal and trace element (Hg, Zn, Fe and Cu) contents were determined in muscle tissue using cold vapour atomic absorption spectrometry and flame and graphite furnace atomic absorption spectrometry. The total Hg concentrations ranged from 0.28 to 1.28 mg kg(-1) w/w, Zn from 5.81 to 76.37 mg kg(-1) w/w, Fe from 12.14 to 39.58 mg kg(-1) w/w, and Cu from 0.36 to 0.94 mg kg(-1) w/w. Only 5% of the muscle samples of tuna contained Hg above the maximum level laid down by the European Commission Decision. Moreover, 15% of the muscle samples contained Zn above the maximum level, while Fe and Cu concentrations were within the acceptable tolerable guideline values. The reared bluefin tuna had lower concentrations of Hg than the wild ones from the Mediterranean Sea. Hg and Fe concentrations showed a positive relationship with size and age of bluefin tuna, whereas negative relationships were found for the concentrations of Zn and Cu. The estimated dietary intake values of the analysed metals were mostly below the derived guidelines.

pH Tolerance in Freshwater Bacterioplankton: Trait Variation of the Community as Measured by Leucine Incorporation

PubMed Central

Kritzberg, Emma

2015-01-01

pH is an important factor determining bacterial community composition in soil and water. We have directly determined the community tolerance (trait variation) to pH in communities from 22 lakes and streams ranging in pH from 4 to 9 using a growth-based method not relying on distinguishing between individual populations. The pH in the water samples was altered to up to 16 pH values, covering in situ pH ± 2.5 U, and the tolerance was assessed by measuring bacterial growth (Leu incorporation) instantaneously after pH adjustment. The resulting unimodal response curves, reflecting community tolerance to pH, were well modeled with a double logistic equation (mean R2 = 0.97). The optimal pH for growth (pHopt) among the bacterial communities was closely correlated with in situ pH, with a slope (0.89 ± 0.099) close to unity. The pH interval, in which growth was ≥90% of that at pHopt, was 1.1 to 3 pH units wide (mean 2.0 pH units). Tolerance response curves of communities originating from circum-neutral pH were symmetrical, whereas in high-pH (8.9) and especially in low-pH (<5.5) waters, asymmetric tolerance curves were found. In low-pH waters, decreasing pH was more detrimental for bacterial growth than increasing pH, with a tendency for the opposite for high-pH waters. A pH tolerance index, using the ratio of growth at only two pH values (pH 4 and 8), was closely related to pHopt (R2 = 0.83), allowing for easy determination of pH tolerance during rapid changes in pH. PMID:26276108

Evaluation of Saccharomyces cerevisiae GAS1 with respect to its involvement in tolerance to low pH and salt stress.

PubMed

Matsushika, Akinori; Suzuki, Toshihiro; Goshima, Tetsuya; Hoshino, Tamotsu

2017-08-01

We previously showed that overexpression of IoGAS1, which was isolated from the multiple stress-tolerant yeast Issatchenkia orientalis, endows Saccharomyces cerevisiae cells with the ability to grow and ferment under acidic and high-salt conditions. The deduced amino acid sequence of the IoGAS1 gene product exhibits 60% identity with the S. cerevisiae Gas1 protein, a glycosylphosphatidylinositol-anchored protein essential for maintaining cell wall integrity. However, the functional roles of ScGAS1 in stress tolerance and pH regulation remain unclear. In the present study, we characterized ScGAS1 regarding its roles in tolerance to low pH and high salt concentrations. Transcriptional analysis indicated that, as for the IoGAS1 gene, ScGAS1 expression was pH dependent, with maximum expression at pH 3.0; the presence of salt increased endogenous expression of both GAS1 genes at almost all pH levels. These results suggested that ScGAS1, like IoGAS1, is involved in a novel acid- and salt-stress adaptation mechanism in S. cerevisiae. Overexpression of ScGAS1 in S. cerevisiae improved growth and ethanol production from glucose under acid stress without added salt, although the stress tolerance of the ScGAS1-overexpressing strain was inferior to that of the IoGAS1-overexpressing strain. However, overexpression of ScGAS1 did not result in increased tolerance of S. cerevisiae to combined acid and salt stress, even though ScGAS1 appears to be a salt-responsive gene. Thus, ScGAS1 is directly implicated in tolerance to low pH but does not confer salinity tolerance, supporting the view that ScGAS1 and IoGAS1 have overlapping yet distinct roles in stress tolerance in yeast. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Removal of cadmium by Lactobacillus kefir as a protective tool against toxicity.

PubMed

Gerbino, Esteban; Carasi, Paula; Tymczyszyn, E Elizabeth; Gómez-Zavaglia, Andrea

2014-08-01

The aim of this work was to evaluate the capacity of Lactobacillus kefir strains to remove cadmium cations and protect eukaryotic cells from cadmium toxicity. Lb. kefir CIDCA 8348 and JCM 5818 were grown in a 1/2 dilution of MRS broth supplemented with Cd(NO3)2 ranging 0 to 1 mM. Growth kinetics were followed during 76 h at 30 °C by registering optical density at 600 nm every 4-10 h. The accumulated concentration of cadmium was determined on cultures in the stationary phase by atomic absorption. The viability of a human hepatoma cell line (HepG2) upon exposure to (a) free cadmium and (b) cadmium previously incubated with Lb. kefir strains was evaluated by determining the mitochondrial dehydrogenase activity. Lb. kefir strains were able to grow and tolerate concentrations of cadmium cations up to 1 mM. The addition of cadmium to the culture medium increased the lag time in all the concentrations used. However, a decrease of the total biomass (maximum Absorbance) was observed only at concentrations above 0.0012 and 0.0011 mM for strains CIDCA 8348 and JCM 5818, respectively. Shorter and rounder lactobacilli were observed in both strains upon microscopic observations. Moreover, dark precipitates compatible with intracellular precipitation of cadmium were observed in the cytoplasm of both strains. The ability of Lb. kefir to protect eukaryotic cells cultures from cadmium toxicity was analysed using HepG2 cells lines. Concentrations of cadmium greater than 3×10(-3) mM strongly decreased the viability of HepG2 cells. However, when the eukaryotic cells were exposed to cadmium pre-incubated 1 h with Lb. kefir the toxicity of cadmium was considerably lower, Lb. kefir JCM 5818 being more efficient. The high tolerance and binding capacity of Lb. kefir strains to cadmium concentrations largely exceeding the tolerated weekly intake (TWI) of cadmium for food (2.5 μg per kg of body weight) and water (3 μg/l) addressed to human consumption, is an important added value when thinking in health-related applications.

Tolerant chalcogenide cathodes of membraneless micro fuel cells.

PubMed

Gago, Aldo Saul; Gochi-Ponce, Yadira; Feng, Yong-Jun; Esquivel, Juan Pablo; Sabaté, Neus; Santander, Joaquin; Alonso-Vante, Nicolas

2012-08-01

The most critical issues to overcome in micro direct methanol fuel cells (μDMFCs) are the lack of tolerance of the platinum cathode and fuel crossover through the polymer membrane. Thus, two novel tolerant cathodes of a membraneless microlaminar-flow fuel cell (μLFFC), Pt(x)S(y) and CoSe(2), were developed. The multichannel structure of the system was microfabricated in SU-8 polymer. A commercial platinum cathode served for comparison. When using 5 M CH(3)OH as the fuel, maximum power densities of 6.5, 4, and 0.23 mW cm(-2) were achieved for the μLFFC with Pt, Pt(x)S(y), and CoSe(2) cathodes, respectively. The Pt(x)S(y) cathode outperformed Pt in the same fuel cell when using CH(3)OH at concentrations above 10 M. In a situation where fuel crossover is 100 %, that is, mixing the fuel with the reactant, the maximum power density of the micro fuel cell with Pt decreased by 80 %. However, for Pt(x)S(y) this decrease corresponded to 35 % and for CoSe(2) there was no change in performance. This result is the consequence of the high tolerance of the chalcogenide-based cathodes. When using 10 M HCOOH and a palladium-based anode, the μLFFC with a CoSe(2) cathode achieved a maxiumum power density of 1.04 mW cm(-2). This micro fuel cell does not contain either Nafion membrane or platinum. We report, for the first time, the evaluation of Pt(x)S(y)- and CoSe(2)-based cathodes in membraneless micro fuel cells. The results suggest the development of a novel system that is not size restricted and its operation is mainly based on the selectivity of its electrodes. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of warming rate, acclimation temperature and ontogeny on the critical thermal maximum of temperate marine fish larvae

PubMed Central

Candebat, Caroline; Ruhbaum, Yannick; Álvarez-Fernández, Santiago; Claireaux, Guy; Zambonino-Infante, José-Luis; Peck, Myron A.

2017-01-01

Most of the thermal tolerance studies on fish have been performed on juveniles and adults, whereas limited information is available for larvae, a stage which may have a particularly narrow range in tolerable temperatures. Moreover, previous studies on thermal limits for marine and freshwater fish larvae (53 studies reviewed here) applied a wide range of methodologies (e.g. the static or dynamic method, different exposure times), making it challenging to compare across taxa. We measured the Critical Thermal Maximum (CTmax) of Atlantic herring (Clupea harengus) and European seabass (Dicentrarchus labrax) larvae using the dynamic method (ramping assay) and assessed the effect of warming rate (0.5 to 9°C h-1) and acclimation temperature. The larvae of herring had a lower CTmax (lowest and highest values among 222 individual larvae, 13.1–27.0°C) than seabass (lowest and highest values among 90 individual larvae, 24.2–34.3°C). At faster rates of warming, larval CTmax significantly increased in herring, whereas no effect was observed in seabass. Higher acclimation temperatures led to higher CTmax in herring larvae (2.7 ± 0.9°C increase) with increases more pronounced at lower warming rates. Pre-trials testing the effects of warming rate are recommended. Our results for these two temperate marine fishes suggest using a warming rate of 3–6°C h-1: CTmax is highest in trials of relatively short duration, as has been suggested for larger fish. Additionally, time-dependent thermal tolerance was observed in herring larvae, where a difference of up to 8°C was observed in the upper thermal limit between a 0.5- or 24-h exposure to temperatures >18°C. The present study constitutes a first step towards a standard protocol for measuring thermal tolerance in larval fish. PMID:28749960

Characterization of Cu(II) and Cd(II) resistance mechanisms in Sphingobium sp. PHE-SPH and Ochrobactrum sp. PHE-OCH and their potential application in the bioremediation of heavy metal-phenanthrene co-contaminated sites.

PubMed

Chen, Chen; Lei, Wenrui; Lu, Min; Zhang, Jianan; Zhang, Zhou; Luo, Chunling; Chen, Yahua; Hong, Qing; Shen, Zhenguo

2016-04-01

Soil that is co-contaminated with heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) is difficult to bioremediate due to the ability of toxic metals to inhibit PAH degradation by bacteria. We demonstrated the resistance mechanisms to Cu(II) and Cd(II) of two newly isolated strains of Sphingobium sp. PHE-SPH and Ochrobactrum sp. PHE-OCH and further tested their potential application in the bioremediation of HM-phenanthrene (PhA) co-contaminated sites. The PHE-SPH and PHE-OCH strains tolerated 4.63 and 4.34 mM Cu(II) and also showed tolerance to 0.48 and 1.52 mM Cd(II), respectively. Diverse resistance patterns were detected between the two strains. In PHE-OCH cells, the maximum accumulation of Cu(II) occurred in the cell wall, while the maximum accumulation was in the cytoplasm of PHE-SPH cells. This resulted in a sudden suppression of growth in PHE-OCH and a gradual inhibition in PHE-SPH as the concentration of Cu(II) increased. Organic acid production was markedly higher in PHE-OCH than in PHE-SPH, which may also have a role in the resistance mechanisms, and contributes to the higher Cd(II) tolerance of PHE-OCH. The factors involved in the absorption of Cu(II) or Cd(II) in PHE-SPH and PHE-OCH were identified as proteins and carbohydrates by Fourier transform infrared (FT-IR) spectroscopy. Furthermore, both strains showed the ability to efficiently degrade PhA and maintained this high degradation efficiency under HM stress. The high tolerance to HMs and the PhA degradation capacity make Sphingobium sp. PHE-SPH and Ochrobactrum sp. PHE-OCH excellent candidate organisms for the bioremediation of HM-PhA co-contaminated sites.

Limits to the thermal tolerance of corals adapted to a highly fluctuating, naturally extreme temperature environment

PubMed Central

Schoepf, Verena; Stat, Michael; Falter, James L.; McCulloch, Malcolm T.

2015-01-01

Naturally extreme temperature environments can provide important insights into the processes underlying coral thermal tolerance. We determined the bleaching resistance of Acropora aspera and Dipsastraea sp. from both intertidal and subtidal environments of the naturally extreme Kimberley region in northwest Australia. Here tides of up to 10 m can cause aerial exposure of corals and temperatures as high as 37 °C that fluctuate daily by up to 7 °C. Control corals were maintained at ambient nearshore temperatures which varied diurnally by 4-5 °C, while treatment corals were exposed to similar diurnal variations and heat stress corresponding to ~20 degree heating days. All corals hosted Symbiodinium clade C independent of treatment or origin. Detailed physiological measurements showed that these corals were nevertheless highly sensitive to daily average temperatures exceeding their maximum monthly mean of ~31 °C by 1 °C for only a few days. Generally, Acropora was much more susceptible to bleaching than Dipsastraea and experienced up to 75% mortality, whereas all Dipsastraea survived. Furthermore, subtidal corals, which originated from a more thermally stable environment compared to intertidal corals, were more susceptible to bleaching. This demonstrates that while highly fluctuating temperatures enhance coral resilience to thermal stress, they do not provide immunity to extreme heat stress events. PMID:26627576

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

PubMed

Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

2018-02-01

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

Phase I Pharmacokinetic Study of the VEGFR Tyrosine Kinase Inhibitor Vatalanib (PTK787) plus Imatinib and Hydroxyurea for Malignant Glioma

PubMed Central

Reardon, David A.; Egorin, Merrill J.; Desjardins, Annick; Vredenburgh, James J.; Beumer, Jan H.; Lagattuta, Theodore F.; Gururangan, Sridharan; Herndon, James E.; Salvado, August J.; Friedman, Henry S.

2009-01-01

Background We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. Methods All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. Results Thirty-seven recurrent patients, including 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. Conclusion Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea are well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and PDGFR, respectively, are safe among recurrent malignant glioma patients and may enhance anti-angiogenesis activity. PMID:19248046

Graphene-derived Fe/Co-N-C catalyst in direct methanol fuel cells: Effects of the methanol concentration and ionomer content on cell performance

NASA Astrophysics Data System (ADS)

Park, Jong Cheol; Choi, Chang Hyuck

2017-08-01

Non-precious metal catalysts (typically Fe(Co)-N-C catalysts) have been widely investigated for use as cost-effective cathode materials in low temperature fuel cells. Despite the high oxygen reduction activity and methanol-tolerance of graphene-based Fe(Co)-N-C catalysts in an acidic medium, their use in direct methanol fuel cells (DMFCs) has not yet been successfully implemented, and only a few studies have investigated this topic. Herein, we synthesized a nano-sized graphene-derived Fe/Co-N-C catalyst by physical ball-milling and a subsequent chemical modification of the graphene oxide. Twelve membrane-electrode-assemblies are fabricated with various cathode compositions to determine the effects of the methanol concentration, ionomer (i.e. Nafion) content, and catalyst loading on the DMFC performance. The results show that a graphene-based catalyst is capable of tolerating a highly-concentrated methanol feed up to 10.0 M. The optimized electrode composition has an ionomer content and catalyst loading of 66.7 wt% and 5.0 mg cm-2, respectively. The highest maximum power density is ca. 32 mW cm-2 with a relatively low PtRu content (2 mgPtRu cm-2). This study overcomes the drawbacks of conventional graphene-based electrodes using a nano-sized graphene-based catalyst and further shows the feasibility of their potential applications in DMFC systems.

Limits to the thermal tolerance of corals adapted to a highly fluctuating, naturally extreme temperature environment.

PubMed

Schoepf, Verena; Stat, Michael; Falter, James L; McCulloch, Malcolm T

2015-12-02

Naturally extreme temperature environments can provide important insights into the processes underlying coral thermal tolerance. We determined the bleaching resistance of Acropora aspera and Dipsastraea sp. from both intertidal and subtidal environments of the naturally extreme Kimberley region in northwest Australia. Here tides of up to 10 m can cause aerial exposure of corals and temperatures as high as 37 °C that fluctuate daily by up to 7 °C. Control corals were maintained at ambient nearshore temperatures which varied diurnally by 4-5 °C, while treatment corals were exposed to similar diurnal variations and heat stress corresponding to ~20 degree heating days. All corals hosted Symbiodinium clade C independent of treatment or origin. Detailed physiological measurements showed that these corals were nevertheless highly sensitive to daily average temperatures exceeding their maximum monthly mean of ~31 °C by 1 °C for only a few days. Generally, Acropora was much more susceptible to bleaching than Dipsastraea and experienced up to 75% mortality, whereas all Dipsastraea survived. Furthermore, subtidal corals, which originated from a more thermally stable environment compared to intertidal corals, were more susceptible to bleaching. This demonstrates that while highly fluctuating temperatures enhance coral resilience to thermal stress, they do not provide immunity to extreme heat stress events.

Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer

PubMed Central

Macarulla, T; Cervantes, A; Tabernero, J; Roselló, S; Van Cutsem, E; Tejpar, S; Prenen, H; Martinelli, E; Troiani, T; Laffranchi, B; Jego, V; von Richter, O; Ciardiello, F

2015-01-01

Background: The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib. Methods: Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI. Results: Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated. Conclusions: Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified. PMID:25989270

Antimicrobial resistant coliform bacteria in the Gomti river water and determination of their tolerance level.

PubMed

Akhter, Asma; Imran, Mohd; Akhter, Firoz

2014-01-01

The distribution of resistance to ampicillin, chloramphenicol, sulfonamides, tetracycline, and streptomycin among coliform in the Gomti river water samples was investigated. The coliform populations were isolated on Mac Conky and eosin methylene blue (EMB) agar plates supplemented with antibiotics. The incidence of resistance among the coliform population varied considerably in different drug and water sampling sites. Coliform bacteria showed lower drug resistant viable count in sampling site-III (receiving treated wastewater) as compared to more polluted site-I and site-II. Viable count of coliform population obtained on both medium was recorded higher against erythromycin from sampling site-III. Lower viable count of coliforms was recorded against tetracycline in site-II and III. Similar resistance pattern was obtained in the frequency of E. coli and Enterobacter species from all the three sampling sites. Percentage of antibiotic resistant E. coli was observed higher than Enterobacter spp among the total coliforms against all antibiotics tested without Erythromycin and penicillin in site-I and II respectively. Isolates of E. coli and Enterobacter spp. showed their tolerance level (MIC) in the range of 2-100 against the antibiotics tested. Maximum number of isolates of both genus exhibited their MICs at lower concentration range 2-5µg/ml against ciprofloxacin, tetracyclin and amoxycillin. EMB - Eosin methylene blue, IMViC tests - Indole, Methyl Red, Voges Proskauer and Citrate Utilization Tests, MIC - Minimum inhibitory concentration.

Antimicrobial resistant coliform bacteria in the Gomti river water and determination of their tolerance level

PubMed Central

Akhter, Asma; Imran, Mohd; Akhter, Firoz

2014-01-01

The distribution of resistance to ampicillin, chloramphenicol, sulfonamides, tetracycline, and streptomycin among coliform in the Gomti river water samples was investigated. The coliform populations were isolated on Mac Conky and eosin methylene blue (EMB) agar plates supplemented with antibiotics. The incidence of resistance among the coliform population varied considerably in different drug and water sampling sites. Coliform bacteria showed lower drug resistant viable count in sampling site-III (receiving treated wastewater) as compared to more polluted site-I and site-II. Viable count of coliform population obtained on both medium was recorded higher against erythromycin from sampling site-III. Lower viable count of coliforms was recorded against tetracycline in site-II and III. Similar resistance pattern was obtained in the frequency of E. coli and Enterobacter species from all the three sampling sites. Percentage of antibiotic resistant E. coli was observed higher than Enterobacter spp among the total coliforms against all antibiotics tested without Erythromycin and penicillin in site-I and II respectively. Isolates of E. coli and Enterobacter spp. showed their tolerance level (MIC) in the range of 2-100 against the antibiotics tested. Maximum number of isolates of both genus exhibited their MICs at lower concentration range 2-5µg/ml against ciprofloxacin, tetracyclin and amoxycillin. Abbreviations EMB - Eosin methylene blue, IMViC tests - Indole, Methyl Red, Voges Proskauer and Citrate Utilization Tests, MIC - Minimum inhibitory concentration. PMID:24966515

Tracing Personalized Health Curves during Infections

PubMed Central

Schneider, David S.

2011-01-01

It is difficult to describe host–microbe interactions in a manner that deals well with both pathogens and mutualists. Perhaps a way can be found using an ecological definition of tolerance, where tolerance is defined as the dose response curve of health versus parasite load. To plot tolerance, individual infections are summarized by reporting the maximum parasite load and the minimum health for a population of infected individuals and the slope of the resulting curve defines the tolerance of the population. We can borrow this method of plotting health versus microbe load in a population and make it apply to individuals; instead of plotting just one point that summarizes an infection in an individual, we can plot the values at many time points over the course of an infection for one individual. This produces curves that trace the course of an infection through phase space rather than over a more typical timeline. These curves highlight relationships like recovery and point out bifurcations that are difficult to visualize with standard plotting techniques. Only nine archetypical curves are needed to describe most pathogenic and mutualistic host–microbe interactions. The technique holds promise as both a qualitative and quantitative approach to dissect host–microbe interactions of all kinds. PMID:21957398

Prediction of pain in orthodontic patients based on preoperative pain assessment

PubMed Central

Zheng, Baoyu; Ren, Manman; Lin, Feiou; Yao, Linjie

2016-01-01

Aim To investigate whether pretreatment assessment of experimental pain can predict the level of pain after archwire placement. Methods One hundred and twenty-one general university students seeking orthodontic treatment were enrolled in this study. A cold pressor test was performed to estimate the pain tolerance of subjects before treatment. Self-reported pain intensity was calculated using a 10 cm visual analog scale during the 7 days after treatment. The relationship between pain tolerance and orthodontic pain was analyzed using Spearman’s correlation analysis. Results The maximum mean level of pain intensity occurred at 24 hours after bonding (53.31±16.13) and fell to normal levels at day 7. Spearman’s correlation analysis found a moderate positive association between preoperative pain tolerance and self-reported pain after archwire placement (P<0.01). There was no significant difference in pain intensity between male and female patients at any time point (P>0.05). Conclusion A simple and noninvasive preoperative sensory test (the cold pressor test) was useful in predicting the risk of developing unbearable pain in patients after archwire placement. Self-reported pain after archwire placement decreased as individual pain tolerance increased. PMID:27042019

Energy attenuation performance of impact protection worn by motorcyclists in real-world crashes.

PubMed

Albanese, Bianca; Gibson, Tom; Whyte, Tom; Meredith, Lauren; Savino, Giovanni; de Rome, Liz; Baldock, Matthew; Fitzharris, Michael; Brown, Julie

2017-05-29

Laboratory studies have demonstrated that impact protectors (IP) used in motorcycle clothing can reduce fracture severities. While crash studies have reported IP are associated with reduced likelihood of soft tissue injury, there is little evidence of their effectiveness in reducing fracture likelihood. This discrepancy might be related to IP quality. There are mandatory requirements for IP supplied with protective clothing in Europe, but not elsewhere. This study examines the energy attenuation performance of IP used by Australian riders. IP were harvested from clothing worn by crashed riders admitted to hospital. The IP were examined and energy attenuation properties were determined using EN 1621-1 test procedures. Impact injury was identified from medical records and defined as fractures, dislocations, and avulsions that occurred following impact to the rider's shoulders, elbows, hips, and/or knees. Fisher's exact test was used to examine the relationship between meeting the EN 1621-1 energy attenuation requirements and impact injury. The association between the average and maximum transmitted force, and impact injury was examined using generalized estimating equations. Motorcycle riders were recruited as part of an in-depth crash study through three hospitals in New South Wales, Australia, between 2012 and 2014. Riders were interviewed, and engineers conducted site, vehicle, and clothing inspections. Clothing was collected, or identical garments were purchased. Clothing was inspected for 62 riders. Of these, 19 wore clothing incorporating 76 IP. Twenty-six of these were impacted in the crash event. Almost all impacted IP (96%) were CE marked, and most (83%) met Level 1 energy attenuation requirements of EN 1621-1 when tested. Of the 26 impacted IP, four were associated with impact injuries, including midshaft and distal clavicle fractures and a scapula and olecranon fracture. No associations between meeting EN 1621-1 requirements and impact injury were found (p = 0.5). There was no association between average force transmitted and impact injury (95% CI: 0.91-1.24); however, as maximum force transmitted increased, the odds of impact injury increased (95% CI: 1.01-1.2). These results indicate a high probability of impact injury at 50 kN, the limit of maximum transmitted force specified in EN 1621-1. The allowable transmitted force of EN 1621-1 may be too high to effectively reduce the probability of impact injury. This is not surprising, given human tolerance levels that are reported in literature. Reducing the force limit below the reported fracture tolerance limits might be difficult with current technology. However, there is scope to reduce the EN 1621-1 maximum limit of 50 kN transmitted force. A reduction in the maximum force limit would improve rider protection and appears feasible, as 77% of tested IP recorded a maximum force <35 kN. This level of transmitted force is estimated to be associated with <20% probability of impact injury. While the performance of IP available to Australian riders is not regulated, most IP was CE marked. The results indicate a significant association between maximum transmitted force, tested according to EN 1621-1 procedures, and impact injury. Further investigation of the EN 1621-1 requirements may be warranted. This work will interest those targeting protective equipment for motorcyclists as a mechanism for reducing injury to these vulnerable road users.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

PubMed

Creelan, Ben C; Gabrilovich, Dmitry I; Gray, Jhanelle E; Williams, Charles C; Tanvetyanon, Tawee; Haura, Eric B; Weber, Jeffrey S; Gibney, Geoffrey T; Markowitz, Joseph; Proksch, Joel W; Reisman, Scott A; McKee, Mark D; Chin, Melanie P; Meyer, Colin J; Antonia, Scott J

2017-01-01

Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

High tolerance to high-light conditions for the protected species Ariocarpus kotschoubeyanus (Cactaceae)

PubMed Central

Arroyo-Pérez, Erika; González-Salvatierra, Claudia; Matías-Palafox, María L.; Jiménez-Sierra, Cecilia

2017-01-01

Abstract We determined the seasonal ecophysiological performance under perennial plants and under high solar radiation for adult individuals from the ‘living rock’ cactus Ariocarpus kotschoubeyanus, which occurs equally under nurse plants and in open spaces. We evaluated the effective quantum yield of photosystem II (ΦPSII) and the dissipation of thermal energy [non-photochemical quenching (NPQ)] thorough the year. The maximum apparent electron transport rate (ETRmax) and the saturating photosynthetically active photon flux density for PSII (PFDsat) were also determined from rapid light curves. We found that although the ΦPSII was higher in shaded sites under potential nurse plants than in exposed sites, all values were close to the optimal value of 0.83. The high ΦPSII found for A. kotschoubeyanus plants suggests that they use a great proportion of the absorbed light for photosynthesis, under nurse plants as well as in open spaces. We also found higher NPQ values in exposed sites than in shaded ones but only in Autumn, thus reducing the risk of photoinhibition. In addition, the PFDsat was higher in exposed sites than in shaded ones in Spring, Summer and Autumn, but in Winter there were no differences between treatments. We also found high saturating light levels for ETR (PFDsat higher than 1378 μmol m−2 s−1) in all seasons but in winter for shaded and non-shaded plants. Our findings indicate that A. kotschoubeyanus plants use a great proportion of the light that they absorb for photosynthesis. This high tolerance to high-light conditions could explain why A. kotschoubeyanus do not show preferences for protected sites under nurse plants. PMID:28729902

Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer

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

Shinoto, Makoto, E-mail: shinoto@saga-himat.jp; Ion Beam Therapy Center, SAGA HIMAT Foundation, Tosu; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka

Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m{sup 2} under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions undermore » the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m{sup 2}. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m{sup 2}) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.« less

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.

PubMed

Tiphaine, Adam de Beaumais; Hjalgrim, Lisa Lynqsie; Nersting, Jacob; Breitkreutz, Joerg; Nelken, Brigitte; Schrappe, Martin; Stanulla, Martin; Thomas, Caroline; Bertrand, Yves; Leverger, Guy; Baruchel, André; Schmiegelow, Kjeld; Jacqz-Aigrain, Evelyne

2016-02-15

6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination. The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred. Pharmacokinetic, palatability and safety data support the use of Loulla in children. Copyright © 2015 Elsevier B.V. All rights reserved.

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

PubMed

Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

2013-11-19

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

Compensation and resistance to herbivory in seagrasses: induced responses to simulated consumption by fish.

PubMed

Vergés, Adriana; Pérez, Marta; Alcoverro, Teresa; Romero, Javier

2008-04-01

Herbivory can induce changes in plant traits that may involve both tolerance mechanisms that compensate for biomass loss and resistance traits that reduce herbivore preference. Seagrasses are marine vascular plants that possess many attributes that may favour tolerance and compensatory growth, and they are also defended with mechanisms of resistance such as toughness and secondary metabolites. We quantified phenotypic changes induced by herbivore damage on the temperate seagrass Posidonia oceanica in order to identify specific compensatory and resistance mechanisms in this plant, and to assess any potential trade-offs between these two strategies of defence. We simulated three natural levels of fish herbivory by repeatedly clipping seagrass leaves during the summer period of maximum herbivory. Compensatory responses were determined by measuring shoot-specific growth, photosynthetic rate, and the concentration of nitrogen and carbon resources in leaves and rhizomes. Induced resistance was determined by measuring the concentration of phenolic secondary metabolites and by assessing the long-term effects of continued clipping on herbivore feeding preferences using bioassays. Plants showed a significant ability to compensate for low and moderate losses of leaf biomass by increasing aboveground growth of damaged shoots, but this was not supported by an increase in photosynthetic capacity. Low levels of herbivory induced compensatory growth without any measurable effects on stored resources. In contrast, nitrogen reserves in the rhizomes played a crucial role in the plant's ability to compensate and survive herbivore damage under moderate and high levels of herbivory, respectively. We found no evidence of inducibility of long-term resistance traits in response to herbivory. The concentration of phenolics decreased with increasing compensatory growth despite all treatments having similar carbon leaf content, suggesting reallocation of these compounds towards primary functions such as cell-wall construction.