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Sample records for repeated small doses

  1. Assessing small-volume spinal cord dose for repeat spinal stereotactic body radiotherapy treatments

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    Ma, Lijun; Kirby, Neil; Korol, Renee; Larson, David A.; Sahgal, Arjun

    2012-12-01

    Spinal cord biologically effective dose (BED) limits are critical to safe spine stereotactic body radiotherapy (SBRT) delivery. In particular, when repeating SBRT to the same site, the problem of adding non-uniform BED distributions within small volumes of spinal cord has yet to be solved. We report a probability-based generalized BED (gBED) model to guide repeat spine SBRT treatment planning. The gBED was formulated by considering the sequential damaging probabilities of repeat spine SBRT treatments. Parameters from the standard linear-quadratic model, such as α/β = 2 Gy for the spinal cord, were applied. We tested the model based on SBRT specific spinal cord tolerance using a simulated and ten clinical repeat SBRT cases. The gBED provides a consistent solution for superimposing non-uniform dose distributions from different fractionation schemes, analogous to the BED for uniform dose distributions. Based on ten clinical cases, the gBED was observed to eliminate discrepancies in the cumulative BED of approximately 5% to 20% within small volumes (e.g. 0.1-2.0 cc) of spinal cord, as compared to a conventional calculation method. When assessing spinal cord tolerance for repeat spinal SBRT treatments, caution should be exercised when applying conventional BED calculations for small volumes of spinal cord irradiated, and the gBED potentially provides more conservative and consistently derived dose surrogates to guide safe treatment planning and treatment outcome modeling.

  2. Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

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    Wust Peter

    2010-05-01

    Full Text Available Abstract Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion, and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy for different α/β values (2, 3, 10, 20, 100 based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p 90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy. This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD. Repeated small volume irradiation may be applied safely within the limits of this study.

  3. Dose estimation for repeated phosphorus-32 ingestion in human subjects

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    Chao, J.H.; Tseng, C.L.; Hsieh, W.A.; Hung, D.Z.; Chang, W.P. E-mail: wpc94@mailsrv.ym.edu.tw

    2001-01-15

    Dose estimation was conducted for internal phosphorus-32 exposure in one young male subject from repeated oral mis-ingestion for >1 year. Since disclosure for previous continuous contamination, a series of urine samples were collected from this individual weekly for a period of >2 months. P-32 radioactivity in urine samples were measured by the acid precipitation method. Estimation for retrospective total effective dose equivalent received by this subject was conducted for cumulative internal dose estimation. A minimum of 9.4 mSv was estimated for an assumed single ingestion. As this was a rare case in radiation protection and internal radiation dosimetry, its implications were of considerable significance.

  4. Repeated dose pharmacokinetics of pancopride in human volunteers.

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    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Pharmacology of ayahuasca administered in two repeated doses.

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    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

    2012-02-01

    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

  6. The excess of small inverted repeats in prokaryotes.

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    Ladoukakis, Emmanuel D; Eyre-Walker, Adam

    2008-09-01

    Recent analyses have shown that there is a large excess of perfect inverted repeats in many prokaryotic genomes but not in eukaryotic ones. This difference could be due to a genuine difference between prokaryotes and eukaryotes or to differences in the methods and types of data analyzed--full genome versus protein coding sequences. We used simulations to show that the method used previously tends to underestimate the expected number of inverted repeats. However, this bias is not large and cannot explain the excess of inverted repeats observed in real data. In contrast, our method is unbiased. When both methods are applied to bacterial protein coding sequences they both detect an excess of inverted repeats, which is much lower than previously reported in whole prokaryotic genomes. This suggests that the reported large excess of inverted repeats is due to repeats found in intergenic regions. These repeats could be due to transcription factor binding sites, or other types of repetitive DNA, on opposite strands of the DNA sequence. In contrast, the smaller, but significant, excess of inverted repeats that we report in protein coding sequences may be due to sequence-directed mutagenesis (SDM). SDM is a process where one copy of a small, imperfect, inverted repeat corrects the other copy via strand misalignment, resulting in a perfect repeat and a series of mutations. We show by simulation that even very low levels of SDM, relative to the rate of point mutation, can generate a substantial excess of inverted repeats.

  7. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

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    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  8. Repeated dose of ketamine effect to the rat hippocampus tissue

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    Mehtap Okyay Karaca

    2015-01-01

    Full Text Available Aim: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. Materials and Methods: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5 th day while the ones in Group III on 21 st day. Cornu ammonis (CA and gyrus dentatus (GD regions in hippocampus tissue of rats were studied using optic fractionation method. Findings: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. Conclusion: Repeated ketamine doses caused neurotoxicity in rat hippocampus.

  9. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats.

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    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  10. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

    NARCIS (Netherlands)

    Tluczkiewicz, I.; Batke, M.; Kroese, D.; Buist, H.; Aldenberg, T.; Pauné, E.; Grimm, H.; Kühne, R.; Schüürmann, G.; Mangelsdorf, I.; Escher, S.E.

    2013-01-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evalua

  11. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

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    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  12. Detecting small seamounts in AltiKa repeat cycle data

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    Marks, K. M.; Smith, W. H. F.

    2016-12-01

    We present a technique of stacking repeat cycles of satellite altimeter sea surface height profiles that lowers the noise and improves the resolution of small seamounts. Our approach differs from other studies because it uses the median (not the mean) of the stacks, which suppresses outliers. Seamounts as small as 720 m tall are easily detected in stacked 40 Hz AltiKa data profiles, and a 500 m tall seamount is perceptible. Noise variance decreases with an increase in the number of cycles stacked, and RMS noise dips below 2 cm when 11 or more cycles are stacked. Coherence analyses between geoid height and bathymetry show that full wavelengths down to about 10 km can be resolved. Comparisons of study areas with and without seamounts find that signal from small seamounts lies in the 10-28 km waveband. A simple Gaussian band-pass filter based on the seamount waveband passes signals that can be used in seamount detection studies. Such studies may find seamounts <2 km tall that are predicted to be abundant on the ocean floor.

  13. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

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    aan het Rot, Marije; Collins, Katherine A.; Murrough, James W.; Perez, Andrew M.; Reich, David L.; Charney, Dennis S.; Mathew, Sanjay J.

    2010-01-01

    Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days)

  14. A GPU implementation of a track-repeating algorithm for proton radiotherapy dose calculations

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    Yepes, Pablo P; Taddei, Phillip J

    2010-01-01

    An essential component in proton radiotherapy is the algorithm to calculate the radiation dose to be delivered to the patient. The most common dose algorithms are fast but they are approximate analytical approaches. However their level of accuracy is not always satisfactory, especially for heterogeneous anatomic areas, like the thorax. Monte Carlo techniques provide superior accuracy, however, they often require large computation resources, which render them impractical for routine clinical use. Track-repeating algorithms, for example the Fast Dose Calculator, have shown promise for achieving the accuracy of Monte Carlo simulations for proton radiotherapy dose calculations in a fraction of the computation time. We report on the implementation of the Fast Dose Calculator for proton radiotherapy on a card equipped with graphics processor units (GPU) rather than a central processing unit architecture. This implementation reproduces the full Monte Carlo and CPU-based track-repeating dose calculations within 2%, w...

  15. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.

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    Johnston, C C; Stremler, R; Horton, L; Friedman, A

    1999-03-01

    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  16. CTG trinucleotide repeat "big jumps": large expansions, small mice.

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    Mário Gomes-Pereira

    2007-04-01

    Full Text Available Trinucleotide repeat expansions are the genetic cause of numerous human diseases, including fragile X mental retardation, Huntington disease, and myotonic dystrophy type 1. Disease severity and age of onset are critically linked to expansion size. Previous mouse models of repeat instability have not recreated large intergenerational expansions ("big jumps", observed when the repeat is transmitted from one generation to the next, and have never attained the very large tract lengths possible in humans. Here, we describe dramatic intergenerational CTG*CAG repeat expansions of several hundred repeats in a transgenic mouse model of myotonic dystrophy type 1, resulting in increasingly severe phenotypic and molecular abnormalities. Homozygous mice carrying over 700 trinucleotide repeats on both alleles display severely reduced body size and splicing abnormalities, notably in the central nervous system. Our findings demonstrate that large intergenerational trinucleotide repeat expansions can be recreated in mice, and endorse the use of transgenic mouse models to refine our understanding of triplet repeat expansion and the resulting pathogenesis.

  17. Radiation-induced mutation at tandem repeat DNA Loci in the mouse germline: spectra and doubling doses.

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    Dubrova, Yuri E

    2005-02-01

    The spectra and dose response for mutations at expanded simple tandem repeat (ESTR) loci in the germline of male mice acutely exposed to low-LET X or gamma rays at pre-meiotic stages of spermatogenesis were compared in five strains of laboratory mice. Most mutation events involved the gain or loss of a relatively small number of repeat units, and the distributions of length changes were indistinguishable between the exposed and control males. Overall, a significant bias toward gains of repeats was detected, with approximately 60% of mutants showing gains. The values for ESTR mutation induction did not differ substantially between strains. The highest values of doubling dose were obtained for two genetically related strains, BALB/c and C.B17 (mean value 0.98 Gy). The estimates of doubling dose for three other strains (CBA/H, C57BL/6 x CBA/H F1 and 129SVJ x C57BL/6) were lower, with a mean value of 0.44 Gy. The dose response for ESTR mutation across all five strains was very close to that for the specific loci (Russell 7-locus test). The mechanisms of ESTR mutation induction and applications of this system for monitoring radiation-induced mutation in the mouse germline are discussed.

  18. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

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    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  19. Effect of repeated doses of mercuric chloride on the kinetics of iron in rats

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    Grosicki, A.; Kossakowski, S. [National Veterinary Research Institute, Pulawy (Poland)

    1994-12-31

    The effect of repeated doses of 0.5 and 1.0 mg HgCl{sub 2}/kg b.w. given intragastrically for 30 days on the absorption and distribution of intragastrically trace dose of {sup 59}FeCl{sub 3} was studied in male Wistar rats. Both doses of mercury distributed the absorption of Fe-59 from the gastrointestinal track. Furthermore, the results revealed a dose-dependent influence of mercury on the content of Fe-59 in the organs and the AUC values. (author). 14 refs, 2 figs, 1 tab.

  20. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.

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    Farré, Magí; Tomillero, Angels; Pérez-Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camí, Jordi; de la Torre, Rafael

    2015-10-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

  1. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations.

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    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  2. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.

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    McFadden, Lisa G; Bartels, Michael J; Rick, David L; Price, Paul S; Fontaine, Donald D; Saghir, Shakil A

    2012-07-01

    Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (αmodel was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.

  3. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... strains of young healthy adult animals should be employed. The females should be nulliparous and...

  4. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.

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    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-02-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  5. Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges.

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    Roland R Regoes

    2005-08-01

    Full Text Available BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against "real life" exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions.

  6. Influence of the adaptive iterative dose reduction 3D algorithm on the detectability of low-contrast lesions and radiation dose repeatability in abdominal computed tomography: a phantom study.

    Science.gov (United States)

    Yoon, Jeong Hee; Lee, Jeong Min; Hur, Bo Yun; Baek, Jeehyun; Shim, Hackjoon; Han, Joon Koo; Choi, Byung Ihn

    2015-08-01

    The purpose of the study is to evaluate the influence of the adaptive iterative dose reduction (AIDR 3D) algorithm on the detectability of low-contrast focal liver lesions (FLLs) and the radiation dose repeatability of automatic tube current modulation (ATCM) in abdominal CT scans using anthropomorphic phantoms. Three different sizes of anthropomorphic phantoms, each with 4 low-contrast FLLs, were scanned on a 320-channel CT scanner using the ATCM technique and AIDR 3D, at different radiation doses: full-dose, half-dose, and quarter-dose. Scans were repeated three times and reconstructed with filtered back projection (FBP) and AIDR 3D. Radiation dose repeatability was assessed using the intraclass correlation coefficient (ICC). Image noise, quality, and lesion conspicuity were assessed by four reviewers and the number of invisible FLLs was compared among different radiation doses and reconstruction methods. ICCs of radiation dose among the three CT scans were excellent in all phantoms (0.99). Image noise, quality, and lesion conspicuity in the half-dose group were comparable with full-dose FBP after applying AIDR 3D in all phantoms. In small phantoms, the half-dose group reconstructed with AIDR 3D showed similar sensitivity in visualizing low-contrast FLLs compared to full-dose FBP (P = 0.77-0.84). In medium and large phantoms, AIDR 3D reduced the number of missing low-contrast FLLs [3.1% (9/288), 11.5% (33/288), respectively], compared to FBP [10.4% (30/288), 21.9% (63/288), respectively] in the full-dose group. By applying AIDR 3D, half-dose CT scans may be achievable in small-sized patients without hampering diagnostic performance, while it may improve diagnostic performance in medium- and large-sized patients without increasing the radiation dose.

  7. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).

    Science.gov (United States)

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E

    2013-11-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  8. Repeated doses of melatonin protects against focal cerebral ischemia in the rat

    OpenAIRE

    Pei, Z; Pang, SF; Cheung, RTF

    2000-01-01

    We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. ...

  9. Pharmacokinetics of metadoxine for injection after repeated doses in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    L(U) Yuan; KANG Zi-sheng; LIU Yan; LI Tian-yun; XIAO Yong-hong

    2007-01-01

    @@ Alcohol-induced liver disease is one of the main epidemic problems nowadays. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, help restore the functional structure of the liver and relieve neuro-psychological disorders associated with alcohol intoxication.1-3 The purpose of the study was to assay the pharmacokinetics of domestic metadoxine after repeated doses.

  10. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  11. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats].

    Science.gov (United States)

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M

    1995-01-01

    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study.

  12. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

    Science.gov (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2017-09-01

    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Spliceosomal small nuclear ribonucleoprotein particles repeatedly cycle through Cajal bodies.

    Science.gov (United States)

    Stanek, David; Pridalová-Hnilicová, Jarmila; Novotný, Ivan; Huranová, Martina; Blazíková, Michaela; Wen, Xin; Sapra, Aparna K; Neugebauer, Karla M

    2008-06-01

    The Cajal body (CB) is a nuclear structure closely associated with import and biogenesis of small nuclear ribonucleoprotein particles (snRNPs). Here, we tested whether CBs also contain mature snRNPs and whether CB integrity depends on the ongoing snRNP splicing cycle. Sm proteins tagged with photoactivatable and color-maturing variants of fluorescent proteins were used to monitor snRNP behavior in living cells over time; mature snRNPs accumulated in CBs, traveled from one CB to another, and they were not preferentially replaced by newly imported snRNPs. To test whether CB integrity depends on the snRNP splicing cycle, two human orthologues of yeast proteins involved in distinct steps in spliceosome disassembly after splicing, hPrp22 and hNtr1, were depleted by small interfering RNA treatment. Surprisingly, depletion of either protein led to the accumulation of U4/U6 snRNPs in CBs, suggesting that reassembly of the U4/U6.U5 tri-snRNP was delayed. Accordingly, a relative decrease in U5 snRNPs compared with U4/U6 snRNPs was observed in CBs, as well as in nuclear extracts of treated cells. Together, the data show that particular phases of the spliceosome cycle are compartmentalized in living cells, with reassembly of the tri-snRNP occurring in CBs.

  14. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    Science.gov (United States)

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  15. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-02-01

    Full Text Available Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug

  16. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide.

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  17. Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

    Science.gov (United States)

    Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

    2012-04-01

    The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

  18. Tolerability and pharmacokinetics of ebrotidine in healthy subjects given single and repeated oral doses.

    Science.gov (United States)

    Farré, M; Roset, P N; Badenas, J M; Ugena, B; Márquez, M; Albet, C; Herrero, E; Ortiz, J A

    1997-04-01

    The tolerability and safety of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) and its basic pharmacokinetic parameters were determined after its oral administration to healthy volunteers. Sixteen subjects were selected to participate in two different studies: an increasing single dose study to determine the maximal tolerated dose (from 25 to 1600 mg), and a multiple dose study (stepped doses from 400 to 1600 mg daily for 12 days). The results of the studies showed that ebrotidine has a good tolerability. Vital signs and laboratory tests were not influenced by the study treatment. No clinically relevant adverse effects were reported during the investigation. Ebrotidine reached peak plasma concentrations 2-3 h after oral administration. Its elimination half-life ranged from 9 to 14 h. In conclusion, ebrotidine was well tolerated after administration of oral single doses of up to 1600 mg, and after repeated administration of up to 800 mg/12 h for 12 days.

  19. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Scala, R.A.; Bevan, C.; Beyer, B.K. (Exxon Biomedical Sciences, Inc., East Millstone, NJ (United States))

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  20. Limitations of analytical dose calculations for small field proton radiosurgery

    Science.gov (United States)

    Geng, Changran; Daartz, Juliane; Lam-Tin-Cheung, Kimberley; Bussiere, Marc; Shih, Helen A.; Paganetti, Harald; Schuemann, Jan

    2017-01-01

    The purpose of the work was to evaluate the dosimetric uncertainties of an analytical dose calculation engine and the impact on treatment plans using small fields in intracranial proton stereotactic radiosurgery (PSRS) for a gantry based double scattering system. 50 patients were evaluated including 10 patients for each of 5 diagnostic indications of: arteriovenous malformation (AVM), acoustic neuroma (AN), meningioma (MGM), metastasis (METS), and pituitary adenoma (PIT). Treatment plans followed standard prescription and optimization procedures for PSRS. We performed comparisons between delivered dose distributions, determined by Monte Carlo (MC) simulations, and those calculated with the analytical dose calculation algorithm (ADC) used in our current treatment planning system in terms of dose volume histogram parameters and beam range distributions. Results show that the difference in the dose to 95% of the target (D95) is within 6% when applying measured field size output corrections for AN, MGM, and PIT. However, for AVM and METS, the differences can be as great as 10% and 12%, respectively. Normalizing the MC dose to the ADC dose based on the dose of voxels in a central area of the target reduces the difference of the D95 to within 6% for all sites. The generally applied margin to cover uncertainties in range (3.5% of the prescribed range  +  1 mm) is not sufficient to cover the range uncertainty for ADC in all cases, especially for patients with high tissue heterogeneity. The root mean square of the R90 difference, the difference in the position of distal falloff to 90% of the prescribed dose, is affected by several factors, especially the patient geometry heterogeneity, modulation and field diameter. In conclusion, implementation of Monte Carlo dose calculation techniques into the clinic can reduce the uncertainty of the target dose for proton stereotactic radiosurgery. If MC is not available for treatment planning, using MC dose distributions to

  1. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

    Science.gov (United States)

    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

    2014-01-01

    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  2. Renormalization and small-world model of fractal quantum repeater networks

    Science.gov (United States)

    Wei, Zong-Wen; Wang, Bing-Hong; Han, Xiao-Pu

    2013-01-01

    Quantum networks provide access to exchange of quantum information. The primary task of quantum networks is to distribute entanglement between remote nodes. Although quantum repeater protocol enables long distance entanglement distribution, it has been restricted to one-dimensional linear network. Here we develop a general framework that allows application of quantum repeater protocol to arbitrary quantum repeater networks with fractal structure. Entanglement distribution across such networks is mapped to renormalization. Furthermore, we demonstrate that logarithmical times of recursive such renormalization transformations can trigger fractal to small-world transition, where a scalable quantum small-world network is achieved. Our result provides new insight into quantum repeater theory towards realistic construction of large-scale quantum networks. PMID:23386977

  3. Renormalization and small-world model of fractal quantum repeater networks.

    Science.gov (United States)

    Wei, Zong-Wen; Wang, Bing-Hong; Han, Xiao-Pu

    2013-01-01

    Quantum networks provide access to exchange of quantum information. The primary task of quantum networks is to distribute entanglement between remote nodes. Although quantum repeater protocol enables long distance entanglement distribution, it has been restricted to one-dimensional linear network. Here we develop a general framework that allows application of quantum repeater protocol to arbitrary quantum repeater networks with fractal structure. Entanglement distribution across such networks is mapped to renormalization. Furthermore, we demonstrate that logarithmical times of recursive such renormalization transformations can trigger fractal to small-world transition, where a scalable quantum small-world network is achieved. Our result provides new insight into quantum repeater theory towards realistic construction of large-scale quantum networks.

  4. Investigation of the toxicity of some organophosphorus pesticides in a repeated dose study in rats.

    Science.gov (United States)

    Baconi, Daniela Luiza; Bârcă, Maria; Manda, Gina; Ciobanu, Anne Marie; Bălălău, C

    2013-01-01

    The study aimed to the investigation of the toxicity of organophosphorus pesticides malathion (MLT) and diazinon (DZN) in Wistar rats in a repeated dose study for 35 days. MLT and DZN in corn oil vehicle were oral administered. Body and organs weights, plasma and brain cholinesterase activities, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathological changes in liver and kidney, and some parameters of the immune function, such as leukocyte formula, spleen weight and cellularity, spleen lymphocytes proliferation in response to concanavalin A (Con A) were investigated; the potential oxidative stress (malondialdehyde in plasma and brain, and blood catalase activity) was also evaluated. No clinical toxicity signs attributed to pesticides were noted; no significant changes in the organ weights have been found. Body weight tends slightly to increase, predominantly in DZN treated rats. The results suggest that plasma cholinesterase is more susceptible than brain cholinesterase to the inhibitory effect of DZN and MLT. Other serum biochemical parameters showed no significant difference. DZN produced a marked increase of the number of spleen lymphocytes without a significant gain of the relative spleen weight. The both pesticides produced an increase of the number of mononuclear cells÷weight spleen. The splenic lymphocyte proliferation has not been influenced by MLT or DZN treatment. Histopathological observations identified some changes (vasodilatation, microvacuoles, and granular dystrophy) in the liver, with MLT, inducing macrovacuolar steatosis. The study indicates that repeated exposure, at subclinical doses, to organophosphorus MLT and DZN causes some biochemical, histopathological and immune alterations in rats.

  5. The role of exposure history on HIV acquisition: insights from repeated low-dose challenge studies.

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

    Full Text Available To assess the efficacy of HIV vaccine candidates or preventive treatment, many research groups have started to challenge monkeys repeatedly with low doses of the virus. Such challenge data provide a unique opportunity to assess the importance of exposure history for the acquisition of the infection. I developed stochastic models to analyze previously published challenge data. In the mathematical models, I allowed for variation of the animals' susceptibility to infection across challenge repeats, or across animals. In none of the studies I analyzed, I found evidence for an immunizing effect of non-infecting challenges, and in most studies, there is no evidence for variation in the susceptibilities to the challenges across animals. A notable exception was a challenge experiment by Letvin et al. Sci Translat Med (2011 conducted with the strain SIVsmE660. The challenge data of this experiment showed significant susceptibility variation from animal-to-animal, which is consistent with previously established genetic differences between the involved animals. For the studies which did not show significant immunizing effects and susceptibility differences, I conducted a power analysis and could thus exclude a very strong immunization effect for some of the studies. These findings validate the assumption that non-infecting challenges do not immunize an animal - an assumption that is central in the argument that repeated low-dose challenge experiments increase the statistical power of preclinical HIV vaccine trials. They are also relevant for our understanding of the role of exposure history for HIV acquisition and forecasting the epidemiological spread of HIV.

  6. Dose profile analysis of small fields in intensity modulated radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Medel B, E. [IMSS, Centro Medico Nacional Manuel Avila Camacho, Calle 2 Nte. 2004, Barrio de San Francisco, 72090 Puebla, Pue. (Mexico); Tejeda M, G.; Romero S, K., E-mail: romsakaren@gmail.com [Benemerita Universidad Autonoma de Puebla, Facultad de Ciencias Fisico Matematicas, Av. San Claudio y 18 Sur, Ciudad Universitaria, 72570 Puebla, Pue.(Mexico)

    2015-10-15

    Full text: Small field dosimetry is getting a very important worldwide task nowadays. The use of fields of few centimeters is more common with the introduction of sophisticated techniques of radiation therapy, as Intensity Modulated Radiotherapy (IMRT). In our country the implementation of such techniques is just getting started and whit it the need of baseline data acquisition. The dosimetry under small field conditions represents a challenge for the physicists community. In this work, a dose profile analysis was done, using various types of dosimeters for further comparisons. This analysis includes the study of quality parameters as flatness, symmetry, penumbra, and other in-axis measurements. (Author)

  7. Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Jae-Seuk Park

    2010-12-01

    Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

  8. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals.

    Science.gov (United States)

    Adkins, B; O'Connor, R W; Dement, J M

    1987-06-01

    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  9. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-10-01

    Full Text Available Rhabdomyosarcoma (RMS, a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV, are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS and alveolar rhabdomyosarcoma (ARMS cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  10. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine.

    Science.gov (United States)

    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha

    2012-12-01

    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  11. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

    Science.gov (United States)

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L

    2016-01-01

    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

  12. Small doses of melatonin increase intestinal motility in rats.

    Science.gov (United States)

    Drago, Filippo; Macauda, Silvia; Salehi, Soudabeh

    2002-09-01

    Since melatonin receptors are present in the intestines, the possibility that this hormone may affect intestinal motility has been studied in the rat. Sprague-Dawley male rats were given a carmine cochineal powder meal and were injected intraperitoneally with 1, 10, 100, or 1000 microg/kg melatonin. Sixty minutes after treatment, intestinal transit was found to be faster in animals treated with small doses of melatonin (1 or 10 microg/kg) than in saline-injected controls. This effect, however, appear to be clearly reversed with 100 or 1000 microg/kg melatonin. In fact, these doses of the hormone reduced intestinal transit in rats. The nonselective melatonin receptor antagonist, luzindole (administered intraperitoneally in a dose of 0.25 mg/kg, 15 min prior to melatonin injection) totally prevented the accelerating effect of melatonin (10 microg/kg) on intestinal transit. Luzindole per se failed to affect gut motility. Injection of the reversible acetylcholinesterase inhibitor and cholinergic agent, neostigmine, accelerated intestinal transit but failed to influence melatonin effect on this parameter. In contrast, intraperitoneal injection of the muscarinic receptor antagonist atropine delayed intestinal transit per se but did not reduce the stimulating effect of melatonin on this parameter. Intestinal myoelectrical recording revealed that intestinal myoelectrical activity was increased by intraperitoneal injection of melatonin (10 microg/kg). Administration of luzindole totally prevented melatonin-induced increase of intestinal myoelectrical activity. These results indicate that melatonin may affect intestinal motility in rats when administered in small doses. This effect might be mediated by melatonin receptors in the intestines, although the involvement of central receptors for the hormone is also possible.

  13. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    Science.gov (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  14. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    Science.gov (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  15. Safety of Repeated-Dose Intratympanic Injections with AM-101 in Acute Inner Ear Tinnitus.

    Science.gov (United States)

    Staecker, Hinrich; Morelock, Michael; Kramer, Timothy; Chrbolka, Pavel; Ahn, Joong Ho; Meyer, Thomas

    2017-09-01

    Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

  16. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

    Science.gov (United States)

    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  17. Anticonvulsant effects of acute treatment with cyane-carvone at repeated oral doses in epilepsy models.

    Science.gov (United States)

    Marques, Thiago Henrique Costa; Marques, Maria Leonildes Boavista Gomes Castelo Branco; Medeiros, Jand-Venes Rolim; Lima, Tamires Cardoso; de Sousa, Damião Pergentino; de Freitas, Rivelilson Mendes

    2014-09-01

    Epilepsy affects about 40 million people worldwide. Many drugs block seizures, but have little effect in preventing or curing this disease. So the search for new drugs for epilepsy treatment using animal models prior to testing in humans is important. Increasingly pharmaceutical industries invest in the Re​search & Drug Development area to seek safe and effective new therapeutic alternatives to the currently available epilepsy treatment. In this perspective, natural compounds have been investigated in epilepsy models, particularly the monoterpenes obtained from medicinal plants. In our study we investigated the effects of cyane-carvone (CC), a synthetic substance prepared from natural a monoterpene, carvone, against pilocarpine- (PILO), pentylenetetrazole- (PTZ) and picrotoxine (PTX)-induced seizures in mice after acute treatment with repeated oral doses (CC 25, 50 and 75 mg/kg) for 14 days. CC in all doses tested showed increase in latency to first seizure, decrease in percentages of seizuring animals as well as reduction percentages of dead animals (pepilepsy models. In addition, our data suggest that CC could act in an allosteric site of GABAA, which would be different from the site in which BDZ acts, since flumazenil was not able to reverse any of CC effects on the modulation of seizure parameters related with epilepsy models investigated. New studies should be conducted to investigate CC effects in other neurotransmitter systems. Nevertheless, our study reinforces the hypothesis that CC could be used, after further research, as a new pharmaceutical formulation and a promising alternative for epilepsy treatment, since it showed anticonvulsant effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Repeatability of dose painting by numbers treatment planning in prostate cancer radiotherapy based on multiparametric magnetic resonance imaging

    Science.gov (United States)

    van Schie, Marcel A.; Steenbergen, Peter; Viet Dinh, Cuong; Ghobadi, Ghazaleh; van Houdt, Petra J.; Pos, Floris J.; Heijmink, Stijn W. T. J. P.; van der Poel, Henk G.; Renisch, Steffen; Vik, Torbjørn; van der Heide, Uulke A.

    2017-07-01

    Dose painting by numbers (DPBN) refers to a voxel-wise prescription of radiation dose modelled from functional image characteristics, in contrast to dose painting by contours which requires delineations to define the target for dose escalation. The direct relation between functional imaging characteristics and DPBN implies that random variations in images may propagate into the dose distribution. The stability of MR-only prostate cancer treatment planning based on DPBN with respect to these variations is as yet unknown. We conducted a test-retest study to investigate the stability of DPBN for prostate cancer in a semi-automated MR-only treatment planning workflow. Twelve patients received a multiparametric MRI on two separate days prior to prostatectomy. The tumor probability (TP) within the prostate was derived from image features with a logistic regression model. Dose mapping functions were applied to acquire a DPBN prescription map that served to generate an intensity modulated radiation therapy (IMRT) treatment plan. Dose calculations were done on a pseudo-CT derived from the MRI. The TP and DPBN map and the IMRT dose distribution were compared between both MRI sessions, using the intraclass correlation coefficient (ICC) to quantify repeatability of the planning pipeline. The quality of each treatment plan was measured with a quality factor (QF). Median ICC values for the TP and DPBN map and the IMRT dose distribution were 0.82, 0.82 and 0.88, respectively, for linear dose mapping and 0.82, 0.84 and 0.94 for square root dose mapping. A median QF of 3.4% was found among all treatment plans. We demonstrated the stability of DPBN radiotherapy treatment planning in prostate cancer, with excellent overall repeatability and acceptable treatment plan quality. Using validated tumor probability modelling and simple dose mapping techniques it was shown that despite day-to-day variations in imaging data still consistent treatment plans were obtained.

  19. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review.

    Directory of Open Access Journals (Sweden)

    Charles H King

    2011-09-01

    Full Text Available Controversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.We performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms 'schistosomiasis', 'dosing' and 'praziquantel' and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays were, for S. mansoni, 69-91% cure after two doses vs. 42-79% after one dose and, for S. haematobium, 46-99% cure after two doses vs. 37-93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count were also different for the two species-for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.Although schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni-$211 (S. haematobium per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are

  20. A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.

    Science.gov (United States)

    Bañez-Coronel, Mónica; Porta, Silvia; Kagerbauer, Birgit; Mateu-Huertas, Elisabet; Pantano, Lorena; Ferrer, Isidre; Guzmán, Manuel; Estivill, Xavier; Martí, Eulàlia

    2012-01-01

    Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.

  1. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    DEFF Research Database (Denmark)

    Hyldstrup, Lars; Flesch, G; Hauffe, S A

    1993-01-01

    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...

  2. Repeat Gamma-Knife Radiosurgery for Refractory or Recurrent Trigeminal Neuralgia with Consideration About the Optimal Second Dose.

    Science.gov (United States)

    Park, Seong-Cheol; Kwon, Do Hoon; Lee, Do Hee; Lee, Jung Kyo

    2016-02-01

    To investigate adequate radiation doses for repeat Gamma Knife radiosurgery (GKS) for trigeminal neuralgia in our series and meta-analysis. Fourteen patients treated by ipsilateral repeat GKS for trigeminal neuralgia were included. Median age of patients was 65 years (range, 28-78), the median target dose, 140-180). Patients were followed a median of 10.8 months (range, 1-151) after the second gamma-knife surgery. Brainstem dose analysis and vote-counting meta-analysis of 19 studies were performed. After the second gamma-knife radiosurgeries, pain was relieved effectively in 12 patients (86%; Barrow Neurological Institute Pain Intensity Score I-III). Post-gamma-knife radiosurgery trigeminal nerve deficits were mild in 5 patients. No serious anesthesia dolorosa was occurred. The second GKS radiation dose ≤ 60 Gy was significantly associated with worse pain control outcome (P = 0.018 in our series, permutation analysis of variance, and P = 0.009 in the meta-analysis, 2-tailed Fisher's exact test). Cumulative dose ≤ 140-150 Gy was significantly associated with poor pain control outcome (P = 0.033 in our series and P = 0.013 in the meta-analysis, 2-tailed Fisher's exact test). A cumulative brainstem edge dose >12 Gy tended to be associated with trigeminal nerve deficit (P = 0.077). Our study suggests that the second GKS dose is a potentially important factor. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Interaction of small repeating earthquakes in a rate and state fault model

    Science.gov (United States)

    Lapusta, N.; Chen, T.

    2010-12-01

    Small repeating earthquake sequences can be located very close, for example, the San Andreas Fault Observatory at Depth (SAFOD) target cluster repeaters "San Francisco" and "Los Angeles" are separated by only about 50 m. These two repeating sequences also show closeness in occurrence time, indicating substantial interaction. Modeling of the interaction of repeating sequences and comparing the modeling results with observations would help us understand the physics of fault slip. Here we conduct numerical simulations of two asperities in a rate and state fault model (Chen and Lapusta, JGR, 2009), with asperities being rate weakening and the rest of the fault being rate-strengthening. One of our goals is to create a model for the observed interaction between "San Francisco" and "Los Angeles" clusters. The study of Chen and Lapusta (JGR, 2009) and Chen et al (accepted by EPSL, 2010) showed that this approach can reproduce behavior of isolated repeating earthquake sequences, in particular, the scaling of their moment versus recurrence time and the response to accelerated postseismic creep. In this work, we investigate the effect of distance between asperities and asperity size on the interaction, in terms of occurrence time, seismic moment and rupture pattern. The fault is governed by the aging version of rate-and-state friction. To account for relatively high stress drops inferred seismically for Parkfield SAFOD target earthquakes (Dreger et al, 2007), we also conduct simulations that include enhanced dynamic weakening during seismic events. As expected based on prior studies (e.g., Kato, JGR, 2004; Kaneko et al., Nature Geoscience, 2010), the two asperities act like one asperity if they are close enough, and they behave like isolated asperities when they are sufficiently separated. Motivated by the SAFOD target repeaters that rupture separately but show evidence of interaction, we concentrate on the intermediate distance between asperities. In that regime, the

  4. Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

    Science.gov (United States)

    Rzuczek, Suzanne G; Colgan, Lesley A; Nakai, Yoshio; Cameron, Michael D; Furling, Denis; Yasuda, Ryohei; Disney, Matthew D

    2017-02-01

    Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)(exp)) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)(exp). In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)(exp) and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)(exp) in its natural context.

  5. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT

    National Research Council Canada - National Science Library

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-01-01

    .... We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial...

  6. Cloning of Novel Repeat-associated Small RNAs Derived from Hairpin Precursors in Oryza sativa

    Institute of Scientific and Technical Information of China (English)

    Chengguo YAO; Botao ZHAO; Wei LI; Yang LI; Wenming QIN; Bing HUANG; Youxin JIN

    2007-01-01

    Plant small non-coding RNAs including microRNAs (miRNAs), small interfering RNAs (siRNAs) and trans-acting siRNAs, play important roles in modulating gene expression in cells. Here we isolated 21 novel endogenous small RNA molecules, ranging from 18 to 24 nucleotides, in Oryza sativa that can be mapped to 111 hairpin precursors. Further analysis indicated that most of these hairpin sequences originated from putative miniature inverted-repeat transposable elements, a major type of DNA transposon.Considering that miRNA is characteristic of hairpin-like precursor and plant endogenous siRNAs are often located at transposon regions, we hypothesized that our cloned small RNAs might represent the intermediate product in the evolutionary process between siRNAs and miRNAs. Northern blot analysis indicated that five of them were much more abundantly expressed in flower compared to other tissues, implying their potential function in inflorescence. In conclusion, our results enrich rice small RNA data and provide a meaningful perspective for small RNA annotation in plants.

  7. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran

    2016-01-01

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  8. Understanding interaction of small repeating earthquakes through models of rate-and-state faults

    Science.gov (United States)

    Chen, T.; Lui, K.; Lapusta, N.

    2012-12-01

    Due to their short recurrence times and known locations, small repeating earthquakes are widely used to study earthquake physics. Some of the repeating sequences are located close to each other and appear to interact. For example, the "San Francisco" (SF) and "Los Angeles" (LA) repeating sequences, which are targets of the San Andreas Fault Observatory at Depth (SAFOD), have a lateral separation of less than 70 m. The LA events tend to occur within 24 hours after the SF events, suggesting a triggering effect. Our goal is to study interaction of repeating earthquakes in the framework of rate-and-state fault models, in which repeating earthquakes occur on velocity-weakening patches embedded into a larger velocity-strengthening fault area. Such models can reproduce behavior of isolated repeating earthquake sequences, in particular, the scaling of their moment versus recurrence time and the response to accelerated postseismic creep (Chen and Lapusta, 2009; Chen et al., 2010). Our studies of the interaction of seismic events on two patches show that a variety of interesting behaviors. As expected based on intuition prior studies (e.g., Kato, JGR, 2004; Kaneko et al., Nature Geoscience, 2010), the two patches behave independently when they are far apart and rupture together if they are next to each other. In the intermediate range of distances, we observe triggering effects, with ruptures on the two patches clustering in time, but also other patterns, including supercycles that alternate between events that rupture a single asperity and events that rupture both asperities at the same time. When triggering occurs, smaller events tend to trigger larger events, since the nucleation of smaller events tends to be more frequent. To overcome such a pattern, and have larger events trigger smaller events as observed for the SF-LA interaction, the patch for the smaller event needs to be of the order of the nucleation size, so that the smaller event has difficulty nucleating by

  9. Accuracy and repeatability of an optical motion analysis system for measuring small deformations of biological tissues.

    Science.gov (United States)

    Liu, Helen; Holt, Cathy; Evans, Sam

    2007-01-01

    Optical motion analysis techniques have been widely used in biomechanics for measuring large-scale motions such as gait, but have not yet been significantly explored for measuring smaller movements such as the tooth displacements under load. In principle, very accurate measurements could be possible and this could provide a valuable tool in many engineering applications. The aim of this study was to evaluate accuracy and repeatability of the Qualisys ProReflex-MCU120 system when measuring small displacements, as a step towards measuring tooth displacements to characterise the properties of the periodontal ligament. Accuracy and repeatability of the system was evaluated using a wedge comparator with a resolution of 0.25 microm to provide measured marker displacements in three orthogonal directions. The marker was moved in ten steps in each direction, for each of seven step sizes (0.5, 1, 2, 3, 5, 10, and 20 microm), repeated five times. Spherical and diamond markers were tested. The system accuracy (i.e. percentage of maximum absolute error in range/measurement range), in the 20-200 microm ranges, was +/-1.17%, +/-1.67% and +/-1.31% for the diamond marker in x, y and z directions, while the system accuracy for the spherical marker was +/-1.81%, +/-2.37% and +/-1.39%. The system repeatability (i.e. maximum standard deviation in the measurement range) measured under the different days, light intensity and temperatures for five times, carried out step up and then step down measurements for the same step size, was +/-1.7, +/-2.3 and +/-1.9 microm for the diamond marker, and +/-2.6, +/-3.9 and +/-1.9 microm for the spherical marker in x, y and z directions, respectively. These results demonstrate that the system suffices accuracy for measuring tooth displacements and could potentially be useful in many other applications.

  10. Repeated treatment with (-)-sulpiride plus a low dose of SCH 23390 displays wider neuroleptic activity without inducing dopaminergic supersensitivity.

    Science.gov (United States)

    Dall'Olio, R; Gandolfi, O; Roncada, P; Vaccheri, A; Montanaro, N

    1990-01-01

    Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.

  11. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.

    Science.gov (United States)

    Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S; Disney, Matthew D

    2016-06-01

    RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

  12. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  13. Small inverted repeats drive mitochondrial genome evolution in Lake Baikal sponges.

    Science.gov (United States)

    Lavrov, Dennis V; Maikova, Olga O; Pett, Walker; Belikov, Sergey I

    2012-08-15

    Demosponges, the largest and most diverse class in the phylum Porifera, possess mitochondrial DNA (mtDNA) markedly different from that in other animals. Although several studies investigated evolution of demosponge mtDNA among major lineages of the group, the changes within these groups remain largely unexplored. Recently we determined mitochondrial genomic sequence of the Lake Baikal sponge Lubomirskia baicalensis and described proliferation of small inverted repeats (hairpins) that occurred in it since the divergence between L. baicalensis and the most closely related cosmopolitan freshwater sponge Ephydatia muelleri. Here we report mitochondrial genomes of three additional species of Lake Baikal sponges: Swartschewskia papyracea, Rezinkovia echinata and Baikalospongia intermedia morpha profundalis (Demospongiae, Haplosclerida, Lubomirskiidae) and from a more distantly related freshwater sponge Corvomeyenia sp. (Demospongiae, Haplosclerida, Metaniidae). We use these additional sequences to explore mtDNA evolution in Baikalian sponges, paying particular attention to the variation in the rates of nucleotide substitutions and the distribution of hairpins, abundant in these genomes. We show that most of the changes in Lubomirskiidae mitochondrial genomes are due to insertion/deletion/duplication of these elements rather than single nucleotide substitutions. Thus inverted repeats can act as an important force in evolution of mitochondrial genome architecture and be a valuable marker for population- and species-level studies in this group. In addition, we infer (((Rezinkovia+Lubomirskia)+Swartschewskia)+Baikalospongia) phylogeny for the family Lubomirskiidae based on the analysis of mitochondrial coding sequences from freshwater sponges.

  14. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

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    Ryu HJ

    2014-12-01

    was dose-dependent irritation at the site of application, there were no abnormal findings related to ZnO NPs in other organs. Increased concentrations of ZnO in the liver, small intestine, large intestine, and feces were thought to result from oral ingestion of ZnO NPs via licking. Penetration of ZnO NPs through the skin seemed to be limited via the dermal route. This study demonstrates that there was no observed adverse effect of ZnO NPs up to 1,000 mg/kg body weight when they are applied dermally. Keywords: zinc oxide, nanoparticles, subchronic toxicity, dermal exposure

  15. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    Science.gov (United States)

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  16. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    Science.gov (United States)

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  17. Airway responses and inflammation in subjects with asthma after four days of repeated high-single-dose allergen challenge

    Directory of Open Access Journals (Sweden)

    Schulze Johannes

    2012-09-01

    Full Text Available Abstract Background Both standard and low-dose allergen provocations are an established tool in asthma research to improve our understanding of the pathophysiological mechanism of allergic asthma. However, clinical symptoms are less likely to be induced. Therefore, we designed a protocol for repetitive high-dose bronchial allergen challenges to generate clinical symptoms and airway inflammation. Methods A total of 27 patients aged 18 to 40 years with positive skin-prick tests and mild asthma underwent repetitive high-dose allergen challenges with household dust mites for four consecutive days. Pulmonary function and exhaled NO were measured at every visit. Induced sputum was analysed before and after the allergen challenges for cell counts, ECP, IL-5, INF-γ, IL-8, and the transcription factor Foxp3. Results We found a significant decrease in pulmonary function, an increased use of salbutamol and the development of a late asthmatic response and bronchial hyperresponsiveness, as well as a significant induction of eNO, eosinophils, and Th-2 cytokines. Repeated provocation was feasible in the majority of patients. Two subjects had severe adverse events requiring prednisolone to cope with nocturnal asthma symptoms. Conclusions Repeated high-dose bronchial allergen challenges resulted in severe asthma symptoms and marked Th-2-mediated allergic airway inflammation. The high-dose challenge model is suitable only in an attenuated form in diseased volunteers for proof-of-concept studies and in clinical settings to reduce the risk of severe asthma exacerbations. Trial registration ClinicalTrials.govNCT00677209

  18. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae in Swiss Mice

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    Germana Freire Rocha Caldas

    2013-01-01

    Full Text Available Hyptis martiusii Benth. (Lamiaceae is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM. Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

  19. Variable Number Tandem Repeat (VNTR) analysis reveals genetic diversity within Mycoplasma mycoides mycoides small colony isolates from Nigeria.

    Science.gov (United States)

    Nwankpa, N D; Manso-silvan, L; Lorenzon, S; Yaya, A; Lombin, L H; Thiaucourt, F

    2010-12-15

    A Variable Number Tandem Repeat (VNTR) analysis was conducted on thirteen (13) M. mycoides mycoides Small Colony isolates from Nigeria using Tandem Repeat (TR) 34 which is a predicted lipoprotein located within the hypothetical protein MAG6170. The analysis revealed diversity within the M. mycoides mycoides Small Colony isolates with five different VNTR types indicated. Some correlation was determined between the VNTR types and their geographical origin. VNTR analysis may represent a useful, rapid first-line test for use in molecular epidemiological analysis of M. mycoides mycoides Small Colony for possible outbreak tracing and disease control.

  20. Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

    Science.gov (United States)

    2012-01-01

    cresyl/-4 H-1: 3: 2-benzodioxa- phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy. Arch. Toxicol. 42, 207–216. French, S. J... organophosphates or other environmental insults, have a greater FIG. 4. Mice that received repeated exposure to low levels of VX (0.2 LD50 and 0.4 LD50...to neuro- behavioral deficits and neuropathology. Although exposure to organophosphates such as pesticides has been shown to affect the expression of

  1. Detection of small RNAs in Bordetella pertussis and identification of a novel repeated genetic element

    Directory of Open Access Journals (Sweden)

    Wulbrecht Bérénice

    2011-04-01

    Full Text Available Abstract Background Small bacterial RNAs (sRNAs have been shown to participate in the regulation of gene expression and have been identified in numerous prokaryotic species. Some of them are involved in the regulation of virulence in pathogenic bacteria. So far, little is known about sRNAs in Bordetella, and only very few sRNAs have been identified in the genome of Bordetella pertussis, the causative agent of whooping cough. Results An in silico approach was used to predict sRNAs genes in intergenic regions of the B. pertussis genome. The genome sequences of B. pertussis, Bordetella parapertussis, Bordetella bronchiseptica and Bordetella avium were compared using a Blast, and significant hits were analyzed using RNAz. Twenty-three candidate regions were obtained, including regions encoding the already documented 6S RNA, and the GCVT and FMN riboswitches. The existence of sRNAs was verified by Northern blot analyses, and transcripts were detected for 13 out of the 20 additional candidates. These new sRNAs were named Bordetella pertussis RNAs, bpr. The expression of 4 of them differed between the early, exponential and late growth phases, and one of them, bprJ2, was found to be under the control of BvgA/BvgS two-component regulatory system of Bordetella virulence. A phylogenetic study of the bprJ sequence revealed a novel, so far undocumented repeat of ~90 bp, found in numerous copies in the Bordetella genomes and in that of other Betaproteobacteria. This repeat exhibits certain features of mobile elements. Conclusion We shown here that B. pertussis, like other pathogens, expresses sRNAs, and that the expression of one of them is controlled by the BvgA/BvgS system, similarly to most virulence genes, suggesting that it is involved in virulence of B. pertussis.

  2. The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.

    Science.gov (United States)

    Molyneux, Gemma; Gibson, Frances M; Chen, Christabelle M; Marway, Harpal K; McKeag, Sean; Mifsud, Charles V J; Pilling, Andrew M; Whayman, Matthew J; Turton, John A

    2008-04-01

    Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

  3. Memory and mood during the night and in the morning after repeated evening doses of MDMA.

    Science.gov (United States)

    Kuypers, K P C; Wingen, M; Ramaekers, J G

    2008-11-01

    Previously it has been shown that MDMA causes memory impairment during daytime testing. However, MDMA is usually taken in the evening or during the night. In addition, it is known that sleep deprivation also causes memory impairment. The present study aimed to assess whether evening doses of MDMA added to, or interacted with the memory impairment due to sleep deprivation. Fourteen healthy subjects participated in a double-blind, placebo-controlled, two-way cross-over study. Treatments consisted of MDMA 75 and 50 mg divided over the evening or double placebo. Memory tests and subjective measures of mood were conducted at baseline and three times post dosing that is at 6.30 pm, 9.30 pm, 1.30 am and 7 am, respectively -1.5, 1.5, 5.5 and 11 h relative to drug intake (first dose). Memory performance detoriated progessively over time as a function of sleep loss, independent of treatment. MDMA added to this impairment as indicated by a significant main effect of MDMA on verbal and spatial memory performance. Mood ratings and response speed revealed an MDMA by Time interaction. After administration of MDMA response speed improved and feelings of vigor, friendliness, elation, anxiety, confusion, arousal and positive mood increased in magnitude during the night, while all these parameters returned to placebo-like levels on the final morning session. It is concluded that evening doses of MDMA selectively impair memory performance, and that this impairment is additional to the effect of sleep deprivation on memory performance.

  4. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    Science.gov (United States)

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  5. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

    Science.gov (United States)

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

    2013-01-01

    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. A small multifunctional pentatricopeptide repeat protein in the chloroplast of Chlamydomonas reinhardtii.

    Science.gov (United States)

    Jalal, Abdullah; Schwarz, Christian; Schmitz-Linneweber, Christian; Vallon, Olivier; Nickelsen, Jörg; Bohne, Alexandra-Viola

    2015-03-01

    Organellar biogenesis is mainly regulated by nucleus-encoded factors, which act on various steps of gene expression including RNA editing, processing, splicing, stabilization, and translation initiation. Among these regulatory factors, pentatricopeptide repeat (PPR) proteins form the largest family of RNA binding proteins, with hundreds of members in flowering plants. In striking contrast, the genome of the unicellular green alga Chlamydomonas reinhardtii encodes only 14 such proteins. In this study, we analyzed PPR7, the smallest and most highly expressed PPR protein in C. reinhardtii. Green fluorescent protein-based localization and gel-filtration analysis revealed that PPR7 forms a part of a high-molecular-weight ribonucleoprotein complex in the chloroplast stroma. RIP-chip analysis of PPR7-bound RNAs demonstrated that the protein associates with a diverse set of chloroplast transcripts in vivo, i.e. rrnS, psbH, rpoC2, rbcL, atpA, cemA-atpH, tscA, and atpI-psaJ. Furthermore, the investigation of PPR7 RNAi strains revealed that depletion of PPR7 results in a light-sensitive phenotype, accompanied by altered levels of its target RNAs that are compatible with the defects in their maturation or stabilization. PPR7 is thus an unusual type of small multifunctional PPR protein, which interacts, probably in conjunction with other RNA binding proteins, with numerous target RNAs to promote a variety of post-transcriptional events.

  7. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

    Science.gov (United States)

    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

    2015-12-28

    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.

  8. Repeated measures dose-finding design with time-trend detection in the presence of correlated toxicity data.

    Science.gov (United States)

    Yin, Jun; Paoletti, Xavier; Sargent, Daniel J; Mandrekar, Sumithra J

    2017-08-01

    Phase I trials are designed to determine the safety, tolerability, and recommended phase 2 dose of therapeutic agents for subsequent testing. The dose-finding paradigm has thus traditionally focused on identifying the maximum tolerable dose of an agent or combination therapy under the assumption that there is a non-decreasing relationship between dose-toxicity and dose-efficacy. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades experienced in the first cycle. More recently, this was extended to a repeated measures design based on the total toxicity profile to account for longitudinal toxicities over multiple treatment cycles in the absence of within-patient correlation. In this work, we propose to extend the design in the presence of within-patient correlation. Furthermore, we provide a framework to detect a toxicity time trend (toxicity increasing, decreasing, or stable) over multiple treatment cycles. We utilize a linear mixed model in the Bayesian framework, with the addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design was evaluated using simulation studies and real data from a phase I trial. We demonstrated that using available toxicity data from all cycles of treatment improves the accuracy of maximum tolerated dose identification and allows for the detection of a time trend. The performance is consistent regardless of the strength of the within-patient correlation. In addition, the use of a quasi-continuous total toxicity profile score significantly increased the power to detect time trends compared to when binary data only were used. The increased interest in molecularly targeted agents and immunotherapies in oncology necessitates innovative phase I study designs. Our proposed framework provides a tool to tackle

  9. Dose evaluation of three-dimensional small animal phantom with film dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Han, Su Chul [Div. of Medical Radiation Equipment, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Park, Seung Woo [Radilogcial and Medico-Oncological Sciences, University of Sciences and Technology, Daejeon (Korea, Republic of)

    2017-03-15

    The weight of small animal dosimetry has been continuously increased in pre-clinical studies using radiation in small animals. In this study, three-dimensional(3D) small animal phantom was fabricated using 3D printer which has been continuously used and studied in the various fields. The absorbed dose of 3D animal phantom was evaluated by film dosimetry. Previously, the response of film was obtained from the materials used for production of 3D small animal phantom and compared with the bolus used as the tissue equivalent material in the radiotherapy. When irradiated with gamma rays from 0.5 Gy to 6 Gy, it was confirmed that there was a small difference of less than 1% except 0.5 Gy dose. And when small animal phantom was irradiated with 5 Gy, the difference between the irradiated dose and calculated dose from film was within 2%. Based on this study, it would be possible to increase the reliability of dose in pre-clinical studies using irradiation in small animals by evaluating dose of 3D small animal phantom.

  10. Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test.

    Science.gov (United States)

    McKee, Richard H; Steup, David; Schreiner, Ceinwen; Podhasky, Paula; Malley, Linda A; Roberts, Linda

    2014-01-01

    Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

  11. Investigation of repeated dose (90 day oral toxicity, reproductive/developmental toxicity and mutagenic potential of ‘Calebin A’

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed

    2015-01-01

    Full Text Available The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as “No Observed Adverse Effect Level (NOAEL” under the test conditions.

  12. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  13. Dose-Dependent Mutation Rates Determine Optimum Erlotinib Dosing Strategies for EGFR Mutant Non-Small Cell Lung Cancer Patients.

    Directory of Open Access Journals (Sweden)

    Lin L Liu

    Full Text Available The advent of targeted therapy for cancer treatment has brought about a paradigm shift in the clinical management of human malignancies. Agents such as erlotinib used for EGFR-mutant non-small cell lung cancer or imatinib for chronic myeloid leukemia, for instance, lead to rapid tumor responses. Unfortunately, however, resistance often emerges and renders these agents ineffective after a variable amount of time. The FDA-approved dosing schedules for these drugs were not designed to optimally prevent the emergence of resistance. To this end, we have previously utilized evolutionary mathematical modeling of treatment responses to elucidate the dosing schedules best able to prevent or delay the onset of resistance. Here we expand on our approaches by taking into account dose-dependent mutation rates at which resistant cells emerge. The relationship between the serum drug concentration and the rate at which resistance mutations arise can lead to non-intuitive results about the best dose administration strategies to prevent or delay the emergence of resistance.We used mathematical modeling, available clinical trial data, and different considerations of the relationship between mutation rate and drug concentration to predict the effectiveness of different dosing strategies.We designed several distinct measures to interrogate the effects of different treatment dosing strategies and found that a low-dose continuous strategy coupled with high-dose pulses leads to the maximal delay until clinically observable resistance. Furthermore, the response to treatment is robust against different assumptions of the mutation rate as a function of drug concentration.For new and existing targeted drugs, our methodology can be employed to compare the effectiveness of different dose administration schedules and investigate the influence of changing mutation rates on outcomes.

  14. Effects of a novel organophosphorus pesticide (RPR-V) on extra hepatic detoxifying enzymes after repeated oral doses in rats.

    Science.gov (United States)

    Mahboob, Mohammed; Kaleem, Mohammed; Siddiqui, Javed

    2004-10-01

    The effects of a novel organophosphorous pesticide, 2-butenoic acid-3-(diethoxy phosphinothionyl) ethyl ester (RPR-V) on glutathione S-transferases (GST), UDP-glucuronyl transferases (UDPGT) and the level of glutathione (GSH) were evaluated in rats after repeated oral administration at 33 microg kg(-1)day(-1) (low), 66 microg kg(-1)day(-1) (mid) and 99 microg kg(-1)day(-1) (high) for 90 days and at 28 days (withdrawal) post-treatment. GSH level and GST in kidney; GSH level in brain decreased significantly at mid and high doses on 45th and 90th day (P RPR-V has the potential to modulate the extrahepatic detoxifying enzymes and thereby interact with other physiological processes in the exposed organisms.

  15. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

    Science.gov (United States)

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  16. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

    Science.gov (United States)

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

    2012-03-01

    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  17. Analysis of chronic radiation exposure at small doses

    Energy Technology Data Exchange (ETDEWEB)

    Krestinina, L.Y. [Urals Research Center for Radiation Medicine, Chelyabinsk (Russian Federation)

    2000-05-01

    The purpose of the study was to analyze the late effects of radiation exposure among residents of settlements located on the territory of the East-Urals Radiation Trace (EURT) in the Southern Urals. In 1957 an explosion occurred at the depot of radioactive waste in the Southern Urals. An area of 23000 km{sup 2} was contaminated, with contamination density of over 0.1 Ci/m{sup 2} for {sup 90}Sr. There were 217 populated ares on that territory with total population about 270000. The residents of 22 villages with contamination density of over 4 Ci/km{sup 2} for {sup 90}Sr were evacuated. The times of evacuation differed from 7 to 670 days since the accident, depending on the level of contamination. In 1988-1993 an individualized registry was created at the Urals Research Center for Radiation Medicine (URCRM) which included information on the residents of 22 evacuated villages and a proportion of unevacuated residents of the EURT area. Currently, the registry contains data on 30000 residents. Of that number 17000 persons were born before, and 12000 after the accident (including about 9000 offspring of exposed residents evacuated from the EURT, and about 3000 persons who were born after the accident and have been living permanently in the EURT area). Over the 35-year period since the accident the residents have received mean effective doses ranging from 23 to 530 mSv. The mean effective doses received by permanent residents range from 5 to 60 mSv. The cohort of people exposed on the EURT territory was identified based on the information contained in the registry. If a person happened to be in the EURT area at the time of the accident, he/she was considered to be eligible for inclusion in the cohort. Over the 35-year period (from 1957 through 1992) 29.5% of 17872 residents died, and 35% of the original cohort were lost to follow-up for different reasons. To enable an analysis a control group was established which included residents of villages located outside, but close

  18. Efficacy of repeated doses of levamisole, morantel, fenbendazole, and ivermectin against gastrointestinal nematodes in ewes.

    Science.gov (United States)

    Hembry, F G; Miller, J E; Sims, D; Rodriguez, S; Stagg, L C

    1986-08-01

    Levamisole, morantel, fenbendazole, or ivermectin was administered at 2-week intervals from May 1 through Sept 14, 1985, to breeding ewes (20 ewes/drug) infected with various gastrointestinal nematodes. All ewes had fewer gastrointestinal nematode eggs per gram of feces (epg) after 2 treatments, compared with pretreatment epg counts. Ewes administered ivermectin continued to have a low mean epg (0 to 3) throughout the study. The mean epg counts of ewes treated with levamisole increased from 3 to 483 during the study. This increase was similar to that of ewes treated with morantel (7 to 485 epg). The mean epg count of fenbendazole-treated ewes increased from 4 to 192 during the study. By the end of the study, the mean epg counts when expressed as a percentage of the pretreatment epg counts were 4% (ivermectin), 249% (fenbendazole), 627% (levamisole), and 630% (morantel). With the exception of the ivermectin-treated ewes, the epg count increased almost linearly in the ewes after the 2nd anthelmintic treatment. These data indicate that the gastrointestinal nematodes (including Haemonchus contortus) may have developed more resistance to levamisole and morantel than to fenbendazole. On the basis of the epg counts, resistance to ivermectin did not develop during the 4.5-month treatment period. The percentage of ewes shedding eggs after 2, 4, and 6 anthelmintic treatments was lowest for ewes treated with ivermectin (20%) and was similar (40%) for ewes treated with 1 of the other 3 anthelmintics. At the conclusion of the study, most of the ewes (90%) were shedding at least a small number of eggs, regardless of the anthelmintic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Repeated Intramuscular-dose Toxicity Test of Water-soluble Carthami Flos (WCF Pharmacopuncture in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Yoo-min Choi

    2015-03-01

    Full Text Available Objectives: Water-soluble carthami flos (WCF is a new mixture of Carthami flos (CF pharmacopuncture. We conducted a 4-week toxicity test of repeated intramuscular injections of WCF in Sprague-Dawley rats. Methods: Forty male and 40 female rats were divided into 4 groups of 10 male and 10 female SD rats: The control group received 0.5 mL/animal/day of normal saline whereas the three experimental groups received WCF at doses of 0.125, 0.25, and 0.5 mL/animal/day, respectively. For 4 weeks, the solutions were injected into the femoral muscle of the rats alternating from side to side. Clinical signs, body weights, and food consumption were observed; opthalmological examinations and urinalyses were performed. On day 29, blood samples were taken for hematological and clinical chemistry analyses. Then, necropsy was conducted in all animals to observe weights and external and histopathological changes in the bodily organs. All data were tested using a statistical analysis system (SAS. Results: No deaths were observed. Temporary irregular respiration was observed in male rats of the experimental group for the first 10 days. Body weights, food consumptions, opthalmological examinations, urinalyses, clinical chemistry analyses, organ weights and necropsy produced no findings with toxicological meaning. In the hematological analysis, delay of prothrombin time (PT was observed in male rats of the 0.25- and the 0.5-mL/animal/day groups. In the histopathological test, a dose-dependent inflammatory cell infiltration into the fascia and panniculitis in perimuscular tissues was observed in all animals of the experimental groups. However, those symptoms were limited to local injection points. No toxicological meanings, except localized changes, were noted. Conclusion: WCF solution has no significant toxicological meaning, but does produce localized symptoms. No observed adverse effect level (NOAEL of WCF in male and female rats is expected for doses over 0.5 mL/animal/day.

  20. A single whole-body low dose X-irradiation does not affect L1, B1 and IAP repeat element DNA methylation longitudinally.

    Directory of Open Access Journals (Sweden)

    Michelle R Newman

    Full Text Available The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1, B1 and Intracisternal-A-Particle (IAP repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17-19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen and a tissue fundamental to the aging process (liver. Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA

  1. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

    Science.gov (United States)

    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  2. Lessons Learned: Dose Selection of Small Molecule-Targeted Oncology Drugs.

    Science.gov (United States)

    Bullock, Julie M; Rahman, Atiqur; Liu, Qi

    2016-06-01

    Evaluation of dose plays a critical role in a successful oncology development program. Typically for oncology agents, the first-in-man phase I dose-escalation trials are conducted to determine a maximum tolerated dose (MTD). This MTD is taken forward into subsequent trials to establish the safety and efficacy of the drug product. Although this approach was appropriate historically for cytotoxics, the application of MTD as the recommend phase II dose has been problematic for the newer small molecule-targeted oncology agents. Promising alternative approaches using dose and exposure exploration, including lessons learned from recent targeted oncology agent development and approvals, are summarized and discussed. Clin Cancer Res; 22(11); 2630-8. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "NEW APPROACHES FOR OPTIMIZING DOSING OF ANTICANCER AGENTS".

  3. Source Properties of Repeating Small Earthquakes in the Aftershock Zones of the 1999 Izmit and Duzce Earthquakes

    Science.gov (United States)

    Ben-Zion, Y.; Peng, Z.

    2006-12-01

    We estimate the source parameters of repeating small earthquakes in the aftershock zones of the 1999 Mw7.4 Izmit and Mw7.1 Duzce earthquakes. The analysis employs 36 sets of highly repeating earthquakes, ranging in size from M 0 to M 3.0, that occurred from August 1999 to February 2000 along the Karadere-Duzce segment of the north Anatolian fault [Peng and Ben-Zion, 2006]. A local PASSCAL network consisting of 10 short-period stations recorded the data. We compute spectra from each seismogram using a multitaper technique. We measure the difference between events by dividing the spectra of the each individual record to the average spectra at that station [Vidale et al., 1994]. Stable spectra ratios are obtained by stacking the ratios calculated from moving windows starting from the P waves to the S-coda waves [Imanishi and Ellsworth, 2006]. Next, we estimate the seismic potencies and corner frequencies for events in each cluster using a simple source model. The continuing work will focus on deriving static stress drops, apparent stresses and radiated energy of these repeating earthquakes. A comparison of the source properties of the repeating small earthquakes with those of large aftershocks and the Duzce main shock would allow us to examine whether there are systematic variations with location and/or size.

  4. Radiation dose is associated with prognosis of small cell lung cancer with superior vena cava syndrome

    Science.gov (United States)

    Wang, Zhen-Bo; Ning, Fang-Ling; Wang, Xiao-Le; Cheng, Yu-Feng; Dong, Xin-Jun; Liu, Chang-Min; Chen, Shao-Shui

    2015-01-01

    Approximately 10% of small cell lung cancer (SCLC) cases develop superior vena cava syndrome (SVCS). Many SCLC patients with SVCS have relatively limited disease, requiring curative rather than palliative treatment. Besides chemotherapy, radiotherapy is important for treating SCLC with SVCS. We retrospectively evaluated the influence of radiotherapy dose on the prognosis of 57 patients with SCLC with SVCS treated with concurrent chemoradiotherapy. The mean biological equivalent radiation dose was 71.5 Gy. We administered etoposide/cisplatin as sequential and concurrent chemotherapy. All patients received at least one cycle of concurrent chemotherapy. All patients had partial or complete response; SVCS-associated symptoms were reduced in 87.7% (50/57) of patients within 3-10 days after treatment. Radiation dose did not affect 2-year local control (74.2% vs. 80.8%). Patients who received high-dose radiation had a lower 2-year overall survival rate than those who received low-dose radiation (11.6 vs. 33%; P = 0.024). The high dose group median survival was 15.0 months (95% confidence interval [CI]: 11.2-19.0) compared with 18.7 months (95% CI: 13.9-23.6) in the low dose group. Grade 3/4 neutropenia occurred in 22/26 high dose patients (84.6%) and 21/31 low dose patients (67.7%). In the high dose group, 30.8% of patients had grade 3/4 esophagitis compared with 19.4% of low dose patients. Only 29.0% of low dose patients received < 4 cycles of chemotherapy in the first 12 weeks after treatment began compared with 46.2% of high dose patients. Concurrent chemoradiotherapy is a tolerable modality for treating stage IIIA/IIIB SCLC with SVCS. Moderate-dose radiotherapy is preferable. PMID:26064339

  5. Validation of fast Monte Carlo dose calculation in small animal radiotherapy with EBT3 radiochromic films

    Science.gov (United States)

    Noblet, C.; Chiavassa, S.; Smekens, F.; Sarrut, D.; Passal, V.; Suhard, J.; Lisbona, A.; Paris, F.; Delpon, G.

    2016-05-01

    In preclinical studies, the absorbed dose calculation accuracy in small animals is fundamental to reliably investigate and understand observed biological effects. This work investigated the use of the split exponential track length estimator (seTLE), a new kerma based Monte Carlo dose calculation method for preclinical radiotherapy using a small animal precision micro irradiator, the X-RAD 225Cx. Monte Carlo modelling of the irradiator with GATE/GEANT4 was extensively evaluated by comparing measurements and simulations for half-value layer, percent depth dose, off-axis profiles and output factors in water and water-equivalent material for seven circular fields, from 20 mm down to 1 mm in diameter. Simulated and measured dose distributions in cylinders of water obtained for a 360° arc were also compared using dose, distance-to-agreement and gamma-index maps. Simulations and measurements agreed within 3% for all static beam configurations, with uncertainties estimated to 1% for the simulation and 3% for the measurements. Distance-to-agreement accuracy was better to 0.14 mm. For the arc irradiations, gamma-index maps of 2D dose distributions showed that the success rate was higher than 98%, except for the 0.1 cm collimator (92%). Using the seTLE method, MC simulations compute 3D dose distributions within minutes for realistic beam configurations with a clinically acceptable accuracy for beam diameter as small as 1 mm.

  6. Small Cell Lung Cancer: The Influence of Dose and Treatment Volume on Outcome.

    Science.gov (United States)

    Lichter; Turrisi

    1995-01-01

    The treatment of small cell lung cancer is clearly enhanced by the addition of radiation therapy. Survival increases modestly while local thoracic failure as first site of progression is reduced from approximately 60% when chemotherapy alone is used to 30% after combined modality therapy. The variables of radiation dose and treatment volume seem to be important in the successful management of this disease. Local chest control appears to increase as doses are escalated from low levels (25 Gy) to moderate levels (45 to 50 Gy(. With about one third of patients experiencing local chest progression, one can speculate that higher radiation doses might be of value. However, at this time there is no proof that increased dose or dose intensity bears out this promise. Indeed, increasing dose intensity of radiotherapy, eg, twice-daily treatment, increases esophagitis, perhaps reduces local failure, but has not improved overall survival. Using larger total doses or altered fraction schemes must still be considered to be under investigation. To increase dose in a safe manner, reduction in the volume covered by radiation portals will likely need to take place. Modern trials suggest that prophylactic treatment of the radiographically or clinically negative contralateral hilum and/or supraclavicular nodal regions may not be necessary for survival or local control. Importantly, reducing treatment volumes may permit increasing doses without exceding normal tissue tolerance. Also, reduced volumes pave the way for further clinical trials that improve radiation dose delivery by better target definition and more conformal therapy.

  7. Percutaneous endoscopic gastrojejunostomy for a patient with an intractable small bowel injury after repeat surgeries: a case report

    OpenAIRE

    Takeyama Hiromitsu; Takayama Satoru; Hara Masayasu

    2011-01-01

    Abstract Introduction The management of intestinal injury can be challenging, because of the intractable nature of the condition. Surgical treatment for patients with severe adhesions sometimes results in further intestinal injury. We report a conservative management strategy using percutaneous endoscopic gastrojejunostomy for an intractable small bowel surgical injury after repeated surgeries. Case presentation A 78-year-old Japanese woman had undergone several abdominal surgeries including ...

  8. Lung and Heart Dose Variability During Radiation Therapy of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Jan, Nuzhat; Guy, Christopher; Reshko, Leonid B; Hugo, Geoffrey D; Weiss, Elisabeth

    2017-07-01

    To investigate the hypothesis that positional and anatomic variations during radiation therapy induce changes in lung and heart volumes and associated radiation doses. In this longitudinal investigation, variations in lung and heart volumes and standard dose parameters of mean lung dose, lung V20Gy, mean heart dose, and heart V40Gy were analyzed on weekly 4-dimensional CT scans of 15 lung cancer patients during conventionally fractionated radiochemotherapy. Tumor, individual lung lobes, and heart were delineated on the mid-ventilation phase of weekly 4-dimensional CT scans. Lung lobes and heart were also contoured on individual breathing phases of pre-, mid-, and end-of-treatment scans. Planning dose was transferred to consecutive scans via rigid registration. Volume and dose variations were assessed relative to the initial planning scan. Interfraction lung volume variability relative to week 0 was twice as large as tidal volume variability (8.0% ± 5.3% vs 4.0% ± 3.3%, P=.003). Interfraction lung volume variation ranged between 0.8% and 17.1% for individual patient means. Lower lung lobes had larger volume variability compared with upper lobes (13.5% ± 8.1% vs 7.0% ± 5.0%, Pheart volume variation was 7.2% (range, 3.4%-12.6%). Average mean heart dose variation was 1.2 Gy (range, 0.1-3.0 Gy) and average heart V40Gy variation 1.4% (range, 0%-4.2%). Anatomic and positional variations during radiation therapy induce changes in radiation doses to lung and heart. Repeated lung and heart dose assessment will provide a better estimate of the actual delivered dose and will improve prediction models for normal tissue toxicity, if assessed in larger cohorts. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Repeatability of testing a small broadband sensor in the Albuquerque Seismological Laboratory Underground Vault

    Science.gov (United States)

    Ringler, Adam; Holland, Austin; Wilson, David

    2017-01-01

    Variability in seismic instrumentation performance plays a fundamental role in our ability to carry out experiments in observational seismology. Many such experiments rely on the assumed performance of various seismic sensors as well as on methods to isolate the sensors from nonseismic noise sources. We look at the repeatability of estimating the self‐noise, midband sensitivity, and the relative orientation by comparing three collocated Nanometrics Trillium Compact sensors. To estimate the repeatability, we conduct a total of 15 trials in which one sensor is repeatedly reinstalled, alongside two undisturbed sensors. We find that we are able to estimate the midband sensitivity with an error of no greater than 0.04% with a 99th percentile confidence, assuming a standard normal distribution. We also find that we are able to estimate mean sensor self‐noise to within ±5.6  dB with a 99th percentile confidence in the 30–100‐s‐period band. Finally, we find our relative orientation errors have a mean difference in orientation of 0.0171° from the reference, but our trials have a standard deviation of 0.78°.

  10. Nonlinear Effects of Nanoparticles: Biological Variability From Hormetic Doses, Small Particle Sizes, and Dynamic Adaptive Interactions

    OpenAIRE

    Bell, Iris R.; Ives, John A.; Wayne B. Jonas

    2013-01-01

    Researchers are increasingly focused on the nanoscale level of organization where biological processes take place in living systems. Nanoparticles (NPs, e.g., 1–100 nm diameter) are small forms of natural or manufactured source material whose properties differ markedly from those of the respective bulk forms of the “same” material. Certain NPs have diagnostic and therapeutic uses; some NPs exhibit low-dose toxicity; other NPs show ability to stimulate low-dose adaptive responses (hormesis). B...

  11. Small repeating earthquakes activity and interplate quasi-static slips in the Hyuga-nada, SW Japan

    Science.gov (United States)

    Yamashita, Y.; Shimizu, H.; Goto, K.

    2009-12-01

    The Hyuga-nada region, a high-angle subduction zone belong the Kyushu-Ryukyu arc, is one of the most seismically active area in Japan and earthquakes with magnitude from 6.5 to 7.5 usually occur at dozens of years interval. In this region, the Philippine Sea Plate (PHS) subducts northwestward beneath the Eurasian Plate (EU) at a rate of about 5cm/year [Seno et al. (1993)]. We detected small repeating earthquakes in and around the Hyuga-nada using waveform similarity based on Igarashi et al. (2003). We used about 20,000 earthquakes which occurred in and around the Hyuga-nada and magnitude range is more than 2.0 detected by SEVO, Kyushu University from 1994 to 2008. We identified about 1,000 small repeating earthquakes, and they were compiled 390 groups. Most of small repeating earthquakes occur near the plate boundary between the PHS and the EU. They do not distribute in large moment-release areas of large earthquakes, but they distribute in those areas surrounding them; these characteristics are also found in NE Japan [e.g. Igarashi et al. (2003); Uchida et al. (2003)]. We selected 145 groups of small repeating earthquakes occurring in the plate boundary based on focal mechanism analysis. Almost all of them distribute the southern side from 32.5N, which suggests that an interplate coupling is probably changing near 32.5N. This result is consistent with present study of interplate coupling in and around Hyuga-nada using a geodetic data by GPS observation [e.g., Nishimura et al. (1999)]. We also estimated interplate quasi-static slip rate distribution in the Hyuga-nada using small repeating earthquakes. The result shows that the slip rate of shallow side of plate boundary is relatively larger than deep side of that in the area of 31.3~32N. In the deep side, the Hyuga-nada earthquakes (Mw6.7) occurred in Dec. 1996. It suggests that the interplate coupling of deep side is stronger than that of shallow side. Acknowledgments: In this study, we have used the data of

  12. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    Science.gov (United States)

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  13. Optimization of extracranial stereotactic radiation therapy of small lung lesions using accurate dose calculation algorithms

    Directory of Open Access Journals (Sweden)

    Polednik Martin

    2006-11-01

    Full Text Available Abstract Background The aim of this study was to compare and to validate different dose calculation algorithms for the use in radiation therapy of small lung lesions and to optimize the treatment planning using accurate dose calculation algorithms. Methods A 9-field conformal treatment plan was generated on an inhomogeneous phantom with lung mimics and a soft tissue equivalent insert, mimicking a lung tumor. The dose distribution was calculated with the Pencil Beam and Collapsed Cone algorithms implemented in Masterplan (Nucletron and the Monte Carlo system XVMC and validated using Gafchromic EBT films. Differences in dose distribution were evaluated. The plans were then optimized by adding segments to the outer shell of the target in order to increase the dose near the interface to the lung. Results The Pencil Beam algorithm overestimated the dose by up to 15% compared to the measurements. Collapsed Cone and Monte Carlo predicted the dose more accurately with a maximum difference of -8% and -3% respectively compared to the film. Plan optimization by adding small segments to the peripheral parts of the target, creating a 2-step fluence modulation, allowed to increase target coverage and homogeneity as compared to the uncorrected 9 field plan. Conclusion The use of forward 2-step fluence modulation in radiotherapy of small lung lesions allows the improvement of tumor coverage and dose homogeneity as compared to non-modulated treatment plans and may thus help to increase the local tumor control probability. While the Collapsed Cone algorithm is closer to measurements than the Pencil Beam algorithm, both algorithms are limited at tissue/lung interfaces, leaving Monte-Carlo the most accurate algorithm for dose prediction.

  14. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Science.gov (United States)

    Wang, Bing; Feng, Weiyue; Zhu, Motao; Wang, Yun; Wang, Meng; Gu, Yiqun; Ouyang, Hong; Wang, Huajian; Li, Ming; Zhao, Yuliang; Chai, Zhifang; Wang, Haifang

    2009-01-01

    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe2O3 nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 μg) intranasal exposure of nano- and submicron-sized Fe2O3 particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe2O3 particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe2O3 particle treatment ( p < 0.05). The nano-sized Fe2O3 generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe2O3 particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe2O3 treatment. In contrast, in the submicron-sized Fe2O3 treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe2O3 nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the larger particle did. This is the first study to compare the neurotoxicity of nano- and submicron-sized Fe2O3

  15. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang Bing; Feng Weiyue, E-mail: fengwy@mail.ihep.ac.cn; Zhu Motao; Wang Yun; Wang Meng [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Gu Yiqun [Maternity Hospital of Haidian District (China); Ouyang Hong; Wang Huajian; Li Ming; Zhao Yuliang, E-mail: zhaoyuliang@mail.ihep.ac.cn; Chai Zhifang [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Wang Haifang [Peking University, College of Chemistry and Molecular Engineering (China)

    2009-01-15

    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe{sub 2}O{sub 3} nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 {mu}g) intranasal exposure of nano- and submicron-sized Fe{sub 2}O{sub 3} particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe{sub 2}O{sub 3} particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe{sub 2}O{sub 3} particle treatment (p < 0.05). The nano-sized Fe{sub 2}O{sub 3} generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe{sub 2}O{sub 3} particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe{sub 2}O{sub 3} treatment. In contrast, in the submicron-sized Fe{sub 2}O{sub 3} treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe{sub 2}O{sub 3} nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the

  16. Targeted histology sampling from atypical small acinar proliferation area detected by repeat transrectal prostate biopsy

    Directory of Open Access Journals (Sweden)

    A. V. Karman

    2017-01-01

    Full Text Available Оbjective: to define the approach to the management of patients with the detected ASAP area.Materials and methods. In the time period from 2012 through 2015, 494 patients with previously negative biopsy and remaining suspicion of prostate cancer (PCa were examined. The patients underwent repeat 24-core multifocal prostate biopsy with taking additional tissue samples from suspicious areas detected by multiparametric magnetic resonance imaging and transrectal ultrasound. An isolated ASAP area was found in 127 (25. 7 % of the 494 examined men. All of them were offered to perform repeat target transrectal biopsy of this area. Targeted transrectal ultrasound guided biopsy of the ASAP area was performed in 56 (44.1 % of the 127 patients, 53 of them being included in the final analysis.Results. PCa was diagnosed in 14 (26.4 % of the 53 patients, their mean age being 64.4 ± 6.9 years. The average level of prostate-specific antigen (PSA in PCa patients was 6.8 ± 3.0 ng/ml, in those with benign lesions – 9.3 ± 6.5 ng/ml; the percentage ratio of free/total PSA with PCa was 16.2 ± 7,8 %, with benign lesions – 23.3 ± 7.7 %; PSA density in PCa patients was 0.14 ± 0.07 ng/ml/cm3, in those with benign lesions – 0.15 ± 0.12 ng/ml/cm3. Therefore, with ASAP area being detected in repeat prostate biopsy samples, it is advisable that targeted extended biopsy of this area be performed. 

  17. Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats.

    Science.gov (United States)

    Kobayashi, Katsumi; Sakuratani, Yuki; Abe, Takemaru; Yamazaki, Kazuko; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto

    2011-01-01

    In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment-related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level.

  18. Performing Repeated Quantitative Small-Animal PET with an Arterial Input Function Is Routinely Feasible in Rats.

    Science.gov (United States)

    Huang, Chi-Cheng; Wu, Chun-Hu; Huang, Ya-Yao; Tzen, Kai-Yuan; Chen, Szu-Fu; Tsai, Miao-Ling; Wu, Hsiao-Ming

    2017-04-01

    Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal (18)F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent (18)F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4Results: On 6 mornings, we completed 12 (18)F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 μmol/100 g/min; n = 6) was comparable to that for (14)C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  19. Influence of the jaw tracking technique on the dose calculation accuracy of small field VMAT plans.

    Science.gov (United States)

    Swinnen, Ans C C; Öllers, Michel C; Roijen, Erik; Nijsten, Sebastiaan M; Verhaegen, Frank

    2017-01-01

    The aim of this study was to evaluate experimentally the accuracy of the dose calculation algorithm AcurosXB in small field highly modulated Volumetric Modulated Arc Therapy (VMAT). The 1000SRS detector array inserted in the rotational Octavius 4D phantom (PTW) was used for 3D dose verification of VMAT treatments characterized by small to very small targets. Clinical treatment plans (n = 28) were recalculated on the phantom CT data set in the Eclipse TPS. All measurements were done on a Varian TrueBeamSTx, which can provide the jaw tracking technique (JTT). The effect of disabling the JTT, thereby fixing the jaws at static field size of 3 × 3 cm(2) and applying the MLC to shape the smallest apertures, was investigated for static fields between 0.5 × 0.5-3 × 3 cm(2) and for seven VMAT patients with small brain metastases. The dose calculation accuracy has been evaluated by comparing the measured and calculated dose outputs and dose distributions. The dosimetric agreement has been presented by a local gamma evaluation criterion of 2%/2 mm. Regarding the clinical plans, the mean ± SD of the volumetric gamma evaluation scores considering the dose levels for evaluation of 10%, 50%, 80% and 95% are (96.0 ± 6.9)%, (95.2 ± 6.8)%, (86.7 ± 14.8)% and (56.3 ± 42.3)% respectively. For the smallest field VMAT treatments, discrepancies between calculated and measured doses up to 16% are obtained. The difference between the 1000SRS central chamber measurements compared to the calculated dose outputs for static fields 3 × 3, 2 × 2, 1 × 1 and 0.5 × 0.5 cm(2) collimated with MLC whereby jaws are fixed at 3 × 3 cm(2) and for static fields shaped with the collimator jaws only (MLC retracted), is on average respectively, 0.2%, 0.8%, 6.8%, 5.7% (6 MV) and 0.1%, 1.3%, 11.7%, 21.6% (10 MV). For the seven brain mets patients was found that the smaller the target volumes, the higher the improvement in agreement between measured and calculated doses after disabling the JTT

  20. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats.

    Science.gov (United States)

    Institóris, L; Siroki, O; Undeger, U; Basaran, N; Banerjee, B D; Dési, I

    2001-06-21

    In the present study, an immunotoxicity test system, containing general toxicological (body weight gain, organ weights), haematological (WBC,RBC, Ht, mean cell volume of the RBCs, cell content of the femoral bone marrow), and immune function (PFC assay, DTH reaction) investigations, was used for detection the effects of a 4 weeks repeated low dose combined oral exposure of male Wistar rats with propoxur and the heavy metals arsenic or mercury. Two doses of the compounds were used: a higher one (the lowest dose which resulted in significant change of at least one parameter examined in previous dose-effect experiments), and a lower one (the highest dose which proved to be non-effective). The applied doses were: 8.51 and 0.851 mg kg(-1) of propoxur, 13.3 and 3.33 mg kg(-1) of NaAsO(2), and 3.20 and 0.40 mg kg(-1) of HgCl(2). In the combination treatment, the high dose of propoxur was combined with the low dose of arsenic or mercury, and the high doses of each heavy metals were combined with the low dose of propoxur. The main finding of this study was that some of the combinations significantly altered the relative weight of liver, adrenals and kidneys, related to both the untreated and the high dose internal control. Among the immune functions examined, only the PFC content of the spleen showed a trend of changes in certain combinations versus the corresponding high dose control. According to the present results, combined exposure with propoxur and the heavy metals examined can modify the detection limit of the single compounds and/or may alter their toxic effects.

  1. Small field dose delivery evaluations using cone beam optical computed tomography-based polymer gel dosimetry

    Directory of Open Access Journals (Sweden)

    Timothy Olding

    2011-01-01

    Full Text Available This paper explores the combination of cone beam optical computed tomography with an N-isopropylacrylamide (NIPAM-based polymer gel dosimeter for three-dimensional dose imaging of small field deliveries. Initial investigations indicate that cone beam optical imaging of polymer gels is complicated by scattered stray light perturbation. This can lead to significant dosimetry failures in comparison to dose readout by magnetic resonance imaging (MRI. For example, only 60% of the voxels from an optical CT dose readout of a 1 l dosimeter passed a two-dimensional Low′s gamma test (at a 3%, 3 mm criteria, relative to a treatment plan for a well-characterized pencil beam delivery. When the same dosimeter was probed by MRI, a 93% pass rate was observed. The optical dose measurement was improved after modifications to the dosimeter preparation, matching its performance with the imaging capabilities of the scanner. With the new dosimeter preparation, 99.7% of the optical CT voxels passed a Low′s gamma test at the 3%, 3 mm criteria and 92.7% at a 2%, 2 mm criteria. The fitted interjar dose responses of a small sample set of modified dosimeters prepared (a from the same gel batch and (b from different gel batches prepared on the same day were found to be in agreement to within 3.6% and 3.8%, respectively, over the full dose range. Without drawing any statistical conclusions, this experiment gives a preliminary indication that intrabatch or interbatch NIPAM dosimeters prepared on the same day should be suitable for dose sensitivity calibration.

  2. Long term/low dose formalin exposure to small-scale recirculation aquaculture systems

    DEFF Research Database (Denmark)

    Pedersen, Lars-Flemming; Pedersen, Per Bovbjerg; Nielsen, Jeppe L.

    2010-01-01

    Repetitive long term formalin application at low dose was investigated to determine the effect on formaldehyde removal rate, biofilter nitrification and the microbial composition in small-scale recirculation aquaculture biofilters. Six pilot-scale recirculation aquaculture systems holding rainbow...... Nitrobacter sp. was not detected. The relative abundances of AOB and NOB in the untreated system were generally higher compared to the system exposed to formalin. Low dose formalin in recirculated aquaculture systems proved to be a possible treatment strategy, as the effect on nitrification was minimal. Since...

  3. Effect of dosimeter type for commissioning small photon beams on calculated dose distribution in stereotactic radiosurgery

    Energy Technology Data Exchange (ETDEWEB)

    García-Garduño, O. A., E-mail: oagarciag@innn.edu.mx, E-mail: amanda.garcia.g@gmail.com [Laboratorio de Física Médica, Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, México and Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada, Unidad Legaria, Instituto Politécnico Nacional, Legaria 694, México City 11500, México (Mexico); Rodríguez-Ponce, M. [Departamento de Biofísica, Instituto Nacional de Cancerología, Mexico City 14080, México (Mexico); Gamboa-deBuen, I. [Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510 (Mexico); Rodríguez-Villafuerte, M. [Instituto de Física, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510 (Mexico); Galván de la Cruz, O. O. [Laboratorio de Física Médica, Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, México (Mexico); and others

    2014-09-15

    Purpose: To assess the impact of the detector used to commission small photon beams on the calculated dose distribution in stereotactic radiosurgery (SRS). Methods: In this study, six types of detectors were used to characterize small photon beams: three diodes [a silicon stereotactic field diode SFD, a silicon diode SRS, and a silicon diode E], an ionization chamber CC01, and two types of radiochromic film models EBT and EBT2. These detectors were used to characterize circular collimated beams that were generated by a Novalis linear accelerator. This study was conducted in two parts. First, the following dosimetric data, which are of particular interest in SRS, were compared for the different detectors: the total scatter factor (TSF), the tissue phantom ratios (TPRs), and the off-axis ratios (OARs). Second, the commissioned data sets were incorporated into the treatment planning system (TPS) to compare the calculated dose distributions and the dose volume histograms (DVHs) that were obtained using the different detectors. Results: The TSFs data measured by all of the detectors were in good agreement with each other within the respective statistical uncertainties: two exceptions, where the data were systematically below those obtained for the other detectors, were the CC01 results for all of the circular collimators and the EBT2 film results for circular collimators with diameters below 10.0 mm. The OAR results obtained for all of the detectors were in excellent agreement for all of the circular collimators. This observation was supported by the gamma-index test. The largest difference in the TPR data was found for the 4.0 mm circular collimator, followed by the 10.0 and 20.0 mm circular collimators. The results for the calculated dose distributions showed that all of the detectors passed the gamma-index test at 100% for the 3 mm/3% criteria. The aforementioned observation was true regardless of the size of the calculation grid for all of the circular collimators

  4. Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats.

    Science.gov (United States)

    Tamura, Toru; Yokoi, Ryohei; Okuhara, Yuji; Harada, Chiho; Terashima, Yukari; Hayashi, Morimichi; Nagasawa, Tatsuya; Onozato, Tomoya; Kobayashi, Kazuo; Kuroda, Junji; Kusama, Hiroshi

    2009-01-01

    In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20 mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.

  5. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

    Science.gov (United States)

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M

    2009-01-01

    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  6. Variations in rupture process with recurrence interval in a repeated small earthquake

    Science.gov (United States)

    Vidale, J.E.; Ellsworth, W.L.; Cole, A.; Marone, C.

    1994-01-01

    In theory and in laboratory experiments, friction on sliding surfaces such as rock, glass and metal increases with time since the previous episode of slip. This time dependence is a central pillar of the friction laws widely used to model earthquake phenomena. On natural faults, other properties, such as rupture velocity, porosity and fluid pressure, may also vary with the recurrence interval. Eighteen repetitions of the same small earthquake, separated by intervals ranging from a few days to several years, allow us to test these laboratory predictions in situ. The events with the longest time since the previous earthquake tend to have about 15% larger seismic moment than those with the shortest intervals, although this trend is weak. In addition, the rupture durations of the events with the longest recurrence intervals are more than a factor of two shorter than for the events with the shortest intervals. Both decreased duration and increased friction are consistent with progressive fault healing during the time of stationary contact.In theory and in laboratory experiments, friction on sliding surfaces such as rock, glass and metal increases with time since the previous episode of slip. This time dependence is a central pillar of the friction laws widely used to model earthquake phenomena. On natural faults, other properties, such as rupture velocity, porosity and fluid pressure, may also vary with the recurrence interval. Eighteen repetitions of the same small earthquake, separated by intervals ranging from a few days to several years, allow us to test these laboratory predictions in situ. The events with the longest time since the previous earthquake tend to have about 15% larger seismic moment than those with the shortest intervals, although this trend is weak. In addition, the rupture durations of the events with the longest recurrence intervals are more than a factor of two shorter than for the events with the shortest intervals. Both decreased duration and

  7. Volume dose ratios relevant for alanine dosimetry in small, 6 MV photon beams

    DEFF Research Database (Denmark)

    Cronholm, Rickard O.; Andersen, Claus Erik; Behrens, Claus F.

    2012-01-01

    averaged doses to water (D¯W) and alanine (D¯det) was found to be approximately 1.025 for most situations studied, and a constant ratio is likely to be representative for many applications in radiation therapy. However, D¯W/D¯det was found to be as low as 0.9908 ± 0.0037 in situations where one might...... therapy). To this end, we here present the results of a Monte Carlo simulation study with DOSRZnrc that investigated the influence of field and detector size for small 6 MV photon beams. The study focusses on doses averaged over the volume of the detector rather than point doses.The ratio of volume...

  8. Therapeutic efficacy of small doses of colchicine combined with glucocorticoid for acute gouty arthritis

    Directory of Open Access Journals (Sweden)

    Ying LIU

    2015-10-01

    Full Text Available Objective To observe the clinical effect of small dose of colchicine combined with glucocorticoid for acute gouty arthritis. Methods Ninety-two patients with acute gouty arthritis were equally and randomly divided into small doses of colchicine combined with dexamethasone treatment group (treatment group and conventional large dose colchicine treatment group (control group between January 2009 and December 2013. The articular lesion scoring and clinical efficacy evaluation were performed at 3, 6, 12, 24, 48, and 72h after treatment. Erythrocyte sedimentation rate (ESR, white blood cells, hepatorenal function and glomerular filtration rate (GFR were determined before and 72h after treatment respectively. The gastrointestinal adverse events and recurrence rate were observed within one month after treatment. Results The articular lesion scores were significantly decreased at 6, 12, 48, and 72h after treatment in treatment group compared with control group (P0.05. Serum uric acid, glutamic-pyruvic transaminase in serum (SGPT, and GFR did not show any change before and 72h after the treatment, and there was also no significant difference between groups (P>0.05. The incidence of gastrointestinal adverse events were obviously higher in control group (76.1% compared with that of the treatment group (P<0.05, and the differences was statistically significant. There was no statistical difference in recurrence rate between the control group and treatment group after a follow-up of one month. Conclusions Compared with conventional large dose colchicine, small dose of colchicine combined with dexamethasone can more rapidly and effectively control acute gouty arthritis, with good tolerability and safety, thus being worthy of popularization clinically. DOI: 10.11855/j.issn.0577-7402.2015.08.10

  9. TH-C-19A-04: Commissioning and Validation of EBT3 Gafchromic Films for Measurements of Dose Profiles and Integrals of Dose in Small Fields

    Energy Technology Data Exchange (ETDEWEB)

    Dufreneix, S; Bordy, J; Delaunay, F; Daures, J; Gouriou, J; Le, Roy M; Ostrowsky, A; Rapp, B; Sommier, L [CEA, LIST, Laboratoire National Henri Becquerel, Gif-sur-Yvette (France)

    2014-06-15

    Purpose: The use of a primary dosimeter larger than the radiation field gives access to the integral of dose over a specified surface normal to the beam. If a relative dose profile of the beam is well known, it is then possible to calculate the distribution of the absorbed dose at any point on the considered surface. This study aims at validating the use of EBT3 gafchromic films for the measurement of 2D dose distribution and integrals of dose in small fields for such use. Methods: New EBT3 films have been fully characterized: the response versus energy, dose-rate and dose has been investigated. Profiles measured in circular field with a diameter of 20 mm have been compared to the ones measured with a diamond detector developed at CEA/LIST/LCD. The ratio of dose area products measured with EBT3 on a 6 mm and 30 mm diameter surface has been compared to the ratio measured with primary dosimeters (calorimeters) and calculated with Monte Carlo simulations. Results: There was no significant difference between the dose-calibration curves in a 6 MV and a 60Co beam. Deviation was within uncertainty bars when the dose rate inside a pulse was divided by a factor of 80 in the 6 MV photon beam. Profiles in small fields are in good agreement with the diamond profiles. Dose area product ratios obtained with EBT3, calorimeters and simulations are within 1%. Conclusion: EBT3 films are good candidates for the measurement of relative dose distribution in small fields as long as the average of several films is considered. They can be used in association with primary measurements to determinate dosimetric references in small fields and to transfer them to the end user.

  10. Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin

    Institute of Scientific and Technical Information of China (English)

    Urara Nishida; Mototsugu Kato; Mutsumi Nishida; Go Kamada; Takeshi Yoshida; Shouko Ono; Yuichi Shimizu; Masahiro Asaka

    2011-01-01

    AIM: To investigate the relationship between low-dose aspirin-induced small bowel mucosal damage and blood flow, and the effect of rebamipide.METHODS: Ten healthy volunteers were enrolled in this study. The subjects were divided into two groups:a placebo group given low-dose aspirin plus placebo and a rebamipide group given low-dose aspirin plus rebamipide for a period of 14 d. Capsule endoscopy and contrast-enhanced ultrasonography were performed before and after administration of drugs. Areas under the curves and peak value of time-intensity curve were calculated.RESULTS: Absolute differences in areas under the curves were -1102.5 (95% CI: -1980.3 to -224.7, P = 0.0194) in the placebo group and -152.7 (95% CI:-1604.2 to 641.6, P = 0.8172) in the rebamipide group.Peak values of time intensity curves were -148.0 (95%CI: -269.4 to -26.2, P = 0.0225) in the placebo group and 28.3 (95% CI: -269.0 to 325.6, P = 0.8343) in the rebamipide group. Capsule endoscopy showed mucosal breaks only in the placebo group.CONCLUSION: Short-term administration of low-dose aspirin is associated with small bowel injuries and blood flow.

  11. Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin

    Science.gov (United States)

    Nishida, Urara; Kato, Mototsugu; Nishida, Mutsumi; Kamada, Go; Yoshida, Takeshi; Ono, Shouko; Shimizu, Yuichi; Asaka, Masahiro

    2011-01-01

    AIM: To investigate the relationship between low-dose aspirin-induced small bowel mucosal damage and blood flow, and the effect of rebamipide. METHODS: Ten healthy volunteers were enrolled in this study. The subjects were divided into two groups: a placebo group given low-dose aspirin plus placebo and a rebamipide group given low-dose aspirin plus rebamipide for a period of 14 d. Capsule endoscopy and contrast-enhanced ultrasonography were performed before and after administration of drugs. Areas under the curves and peak value of time-intensity curve were calculated. RESULTS: Absolute differences in areas under the curves were -1102.5 (95% CI: -1980.3 to -224.7, P = 0.0194) in the placebo group and -152.7 (95% CI: -1604.2 to 641.6, P = 0.8172) in the rebamipide group. Peak values of time intensity curves were -148.0 (95% CI: -269.4 to -26.2, P = 0.0225) in the placebo group and 28.3 (95% CI: -269.0 to 325.6, P = 0.8343) in the rebamipide group. Capsule endoscopy showed mucosal breaks only in the placebo group. CONCLUSION: Short-term administration of low-dose aspirin is associated with small bowel injuries and blood flow. PMID:21245996

  12. Individualized dose prescription for hypofractionation in advanced non-small-cell lung cancer radiotherapy: an in silico trial.

    NARCIS (Netherlands)

    Hoffmann, A.L.; Troost, E.G.C.; Huizenga, H.; Kaanders, J.H.A.M.; Bussink, J.

    2012-01-01

    PURPOSE: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various h

  13. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    Science.gov (United States)

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

  14. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line?

    Science.gov (United States)

    Hong, Julian C; Salama, Joseph K

    2016-02-01

    Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR-activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors.

  15. Percutaneous endoscopic gastrojejunostomy for a patient with an intractable small bowel injury after repeat surgeries: a case report.

    Science.gov (United States)

    Hara, Masayasu; Takayama, Satoru; Takeyama, Hiromitsu

    2011-02-10

    The management of intestinal injury can be challenging, because of the intractable nature of the condition. Surgical treatment for patients with severe adhesions sometimes results in further intestinal injury. We report a conservative management strategy using percutaneous endoscopic gastrojejunostomy for an intractable small bowel surgical injury after repeated surgeries. A 78-year-old Japanese woman had undergone several abdominal surgeries including urinary cystectomy for bladder cancer. After this operation, she developed peritonitis as a result of a small bowel perforation thought to be due to an injury sustained during the operation, with signs consistent with systemic inflammatory response syndrome: body temperature 38.5°C, heart rate 92 beats/minute, respiratory rate 23 breaths/minute, white blood cell count 11.7 × 109/L (normal range 4-11 × 109/μL). Two further surgical interventions failed to control the leak, and our patient's clinical condition and nutritional status continued to deteriorate. We then performed percutaneous endoscopic gastrojejunostomy, and continuous suction was applied as an alternative to a third surgical intervention. With this endoscopic intervention, the intestinal leak gradually closed and oral feeding became possible. We suggest that the technique of percutaneous endoscopic gastrojejunostomy combined with a somatostatin analog is a feasible alternative to surgical treatment for small bowel leakage, and is less invasive than a nasojejunal tube.

  16. Percutaneous endoscopic gastrojejunostomy for a patient with an intractable small bowel injury after repeat surgeries: a case report

    Directory of Open Access Journals (Sweden)

    Takeyama Hiromitsu

    2011-02-01

    Full Text Available Abstract Introduction The management of intestinal injury can be challenging, because of the intractable nature of the condition. Surgical treatment for patients with severe adhesions sometimes results in further intestinal injury. We report a conservative management strategy using percutaneous endoscopic gastrojejunostomy for an intractable small bowel surgical injury after repeated surgeries. Case presentation A 78-year-old Japanese woman had undergone several abdominal surgeries including urinary cystectomy for bladder cancer. After this operation, she developed peritonitis as a result of a small bowel perforation thought to be due to an injury sustained during the operation, with signs consistent with systemic inflammatory response syndrome: body temperature 38.5°C, heart rate 92 beats/minute, respiratory rate 23 breaths/minute, white blood cell count 11.7 × 109/L (normal range 4-11 × 109/μL. Two further surgical interventions failed to control the leak, and our patient's clinical condition and nutritional status continued to deteriorate. We then performed percutaneous endoscopic gastrojejunostomy, and continuous suction was applied as an alternative to a third surgical intervention. With this endoscopic intervention, the intestinal leak gradually closed and oral feeding became possible. Conclusion We suggest that the technique of percutaneous endoscopic gastrojejunostomy combined with a somatostatin analog is a feasible alternative to surgical treatment for small bowel leakage, and is less invasive than a nasojejunal tube.

  17. Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

    Science.gov (United States)

    Angelbello, Alicia J; González, Àlex L; Rzuczek, Suzanne G; Disney, Matthew D

    2016-12-01

    RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG)(exp)). Several small molecules have been found to disrupt the MBNL1-r(CUG)(exp) complex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells.

  18. Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan.

    Science.gov (United States)

    Scott, Paul G; McEwan, Paul A; Dodd, Carole M; Bergmann, Ernst M; Bishop, Paul N; Bella, Jordi

    2004-11-02

    Decorin is a ubiquitous extracellular matrix proteoglycan with a variety of important biological functions that are mediated by its interactions with extracellular matrix proteins, cytokines, and cell surface receptors. Decorin is the prototype of the family of small leucine-rich repeat proteoglycans and proteins (SLRPs), characterized by a protein core composed of leucine-rich repeats (LRRs), flanked by two cysteine-rich regions. We report here the crystal structure of the dimeric protein core of decorin, the best characterized member of the SLRP family. Each monomer adopts the curved solenoid fold characteristic of LRR domains, with a parallel beta-sheet on the inside interwoven with loops containing short segments of beta-strands, 3(10) helices, and polyproline II helices on the outside. Two main features are unique to this structure. First, decorin dimerizes through the concave surfaces of the LRR domains, which have been implicated previously in protein-ligand interactions. The amount of surface buried in this dimer rivals the buried surfaces of some of the highest-affinity macromolecular complexes reported to date. Second, the C-terminal region adopts an unusual capping motif that involves a laterally extended LRR and a disulfide bond. This motif seems to be unique to SLRPs and has not been observed in any other LRR protein structure to date. Possible implications of these features for decorin ligand binding and SLRP function are discussed.

  19. Isolation and Characterization of Simple Sequence Repeats (SSR) Markers from the Moss Genus Orthotrichum Using a Small Throughput Pyrosequencing Machine

    Science.gov (United States)

    Sawicki, Jakub; Kwaśniewski, Mirosław; Szczecińska, Monika; Chwiałkowska, Karolina; Milewicz, Monika; Plášek, Vítězslav

    2012-01-01

    Here, we report the results of next-generation sequencing on the GS Junior system to identify a large number of microsatellites from the epiphytic moss Orthotrichum speciosum. Using a combination of a total (non-enrichment) genomic library and small-scale 454 pyrosequencing, we determined 5382 contigs whose length ranged from 103 to 5445 bp. In this dataset we identified 92 SSR (simple sequence repeats) motifs in 89 contigs. Forty-six of these had flanking regions suitable for primer design. We tested PCR amplification, reproducibility, and the level of polymorphism of 46 primer pairs for Orthotrichum speciosum using 40 individuals from two populations. As a result, the designed primers revealed 35 polymorphic loci with more than two alleles detected. This method is cost- and time-effective in comparison with traditional approaches involving cloning and sequencing. PMID:22837714

  20. Repeated sprints, high-intensity interval training, small-sided games: theory and application to field sports.

    Science.gov (United States)

    Hoffmann, James J; Reed, Jacob P; Leiting, Keith; Chiang, Chieh-Ying; Stone, Michael H

    2014-03-01

    Due to the broad spectrum of physical characteristics necessary for success in field sports, numerous training modalities have been used develop physical preparedness. Sports like rugby, basketball, lacrosse, and others require athletes to be not only strong and powerful but also aerobically fit and able to recover from high-intensity intermittent exercise. This provides coaches and sport scientists with a complex range of variables to consider when developing training programs. This can often lead to confusion and the misuse of training modalities, particularly in the development of aerobic and anaerobic conditioning. This review outlines the benefits and general adaptations to 3 commonly used and effective conditioning methods: high-intensity interval training, repeated-sprint training, and small-sided games. The goals and outcomes of these training methods are discussed, and practical implementations strategies for coaches and sport scientists are provided.

  1. Effect of Small-Sided Games and Repeated Shuffle Sprint Training on Physical Performance in Elite Handball Players.

    Science.gov (United States)

    Dello Iacono, Antonio; Ardigò, Luca P; Meckel, Yoav; Padulo, Johnny

    2016-03-01

    This study was designed to compare the effects of small-sided games (SSGs) and repeated shuffle sprint (RSS) training on repeated sprint ability (RSA) and countermovement jump (CMJ) tests performances of elite handball players. Eighteen highly trained players (24.8 ± 4.4 years) were assigned to either SSG or RSS group training protocols twice a week for 8 weeks. The SSG training consisted of 5 small-sided handball games with 3-a-side teams excluding goalkeepers. The RSS consisted of 2 sets of 14-17 of 20-m shuttle sprints and 9-m jump shots interspersed by 20-second recoveries. Before and after training, the following performance variables were assessed: speed on 10-m and 20-m sprint time, agility and RSA time, CMJ height, standing throw, and jump shot speed. Significant pre-to-post treatment improvements were found in all the assessed variables following both training protocols (multivariate analysis of variance, p ≤ 0.05). There was a significantly greater improvement on 10-m sprint, CMJ, and jump shooting, after the RSS in comparison with SSG training (+4.4% vs. +2.4%, +8.6% vs. +5.6%, and +5.5% vs. +2.7%, respectively). Conversely, agility and standing throwing showed lower improvements after RSS in comparison with SSG (+1.0% vs. +7.8% and +1.6% vs. +9.0%, respectively). These results indicate that these training methods are effective for fitness development among elite adult handball players during the last period of the competitive season. Specifically, SSG seems to be more effective in improving agility and standing throw, whereas RSS seems preferable in improving 10-m sprint, CMJ, and jump shot.

  2. Repeated BCG treatment of mouse bladder selectively stimulates small GTPases and HLA antigens and inhibits single-spanning uroplakins

    Directory of Open Access Journals (Sweden)

    O'Donnell Michael A

    2007-11-01

    Full Text Available Abstract Background Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following repeated intravesical BCG therapy. Methods Mice were transurethrally instilled with BCG or pyrogen-free on days 1, 7, 14, and 21. Seven days after the last instillation, urothelia along with the submucosa was removed and amplified ds-DNA was prepared from control- and BCG-treated bladder mucosa and used to generate suppression subtractive hybridization (SSH. Plasmids from control- and BCG-specific differentially expressed clones and confirmed by Virtual Northern were then purified and the inserts were sequenced and annotated. Finally, chromatin immune precipitation combined with real-time polymerase chain reaction assay (ChIP/Q-PCR was used to validate SSH-selected transcripts. Results Repeated intravesical BCG treatment induced an up regulation of genes associated with antigen presentation (B2M, HLA-A, HLA-DQA1, HLA-DQB2, HLA-E, HLA-G, IGHG, and IGH and representatives of two IFNγ-induced small GTPase families: the GBPs (GBP1, GBP2, and GBP5 and the p47GTPases (IIGTP1, IIGTP2, and TGTP. Genes expressed in saline-treated bladders but down-regulated by BCG included: the single-spanning uroplakins (UPK3a and UPK2, SPRR2G, GSTM5, and RSP 19. Conclusion Here we introduced a hypothesis-generator approach to determine key genes involved in the urothelium/sumbmucosa responses to BCG therapy. Urinary bladder responds to repeated BCG treatment by up-regulating not only antigen presentation-related genes, but also GBP and p47 small GTPases, both potentially

  3. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Science.gov (United States)

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

    2000-10-01

    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  4. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

    Science.gov (United States)

    Ishii, Shun-ichiro; Ube, Masayuki; Okada, Miyoko; Adachi, Tamiko; Sugimoto, Jiro; Inoue, Yoshimi; Uno, Yoshifumi; Mutai, Mamoru

    2009-01-01

    To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

  5. Stereotactic ablative radiotherapy for small lung tumors with a moderate dose. Favorable results and low toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Duncker-Rohr, V.; Nestle, U. [Universitaetsklinikum Freiburg (Germany); Momm, F. [Ortenau Klinikum Offenburg (Germany)] [and others

    2013-01-15

    Background: Stereotactic ablative body radiotherapy (SBRT, SABR) is being increasingly applied because of its high local efficacy, e.g., for small lung tumors. However, the optimum dosage is still under discussion. Here, we report data on 45 lung lesions [non-small cell lung cancer (NSCLC) or metastases] in 39 patients treated between 2009 and 2010 by SABR. Patients and methods: SABR was performed with total doses of 35 Gy (5 fractions) or 37.5 Gy (3 fractions) prescribed to the 60% isodose line encompassing the planning target volume. Three-monthly follow-up CT scans were supplemented by FDG-PET/CT if clinically indicated. Results: The median follow-up was 17 months. Local progression-free survival rates were 90.5% (all patients), 95.0% (NSCLC), and 81.8% (metastases) at 1 year. At 2 years, the respective local progression-free survival rates were 80.5%, 95.0%, and 59.7%. Overall survival rates were 71.1% (all patients), 65.4% (NSCLC), and 83.3% (metastases) at 1 year. Overall survival rates at 2 years were 52.7%, 45.9%, and 66.7%, respectively. Acute side effects were mild. Conclusion: With the moderate dose schedule used, well-tolerated SABR led to favorable local tumor control as in other published series. Standardization in reporting the dose prescription for SABR is needed to allow comparison of different series in order to determine optimum dosage. (orig.)

  6. Novel Approach to Repeated Arterial Blood Sampling in Small Animal PET : Application in a Test-Retest Study with the Adenosine A1 Receptor Ligand [C-11]MPDX

    NARCIS (Netherlands)

    Sijbesma, Jürgen W A; Zhou, Xiaoyun; Vállez García, David; Houwertjes, Martin C; Doorduin, Janine; Kwizera, Chantal; Maas, Bram; Meerlo, Peter; Dierckx, Rudi A; Slart, Riemer H J A; Elsinga, Philip H; van Waarde, Aren

    2016-01-01

    Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial

  7. Radiotherapy combined with small doses of CDDP and THP for head and neck squamous cell carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Miyaguchi, Mamoru; Sakai, Shunichi; Takashima, Hitoshi; Hosokawa, Atsuyuki [Kagawa Medical School, Miki (Japan)

    1995-02-01

    From February 1992 through June 1993, 19 cases of head and neck squamous cell carcinomas were treated with radiotherapy combined with administration of small doses of CDDP and THP. Radiation was administered in a dose of 2 Gy given five times a week combined with CDDP in a dose of 10 mg on day 1 and 3, and THP in a dose of 10 mg on day 5 of each treatment week. Survival was 63 percent at one year and 58 percent at two years. Incidence of the acute complications severer than grade 2 were myelosuppression 12/19 (63%), stomatitis 11/19 (58%), appetite loss 9/19 (47%), and nausea 4/19 (21%). Myelosuppression with grade 3 occurred in 5 patients and could be treated with granulocyte colony stimulating factor. Stomatitis with grade 3 occurred in two patients and they needed a nasogastric feeding tube. The result of this combination therapy with radiation, CDDP and THP was good. However, a new treatment regimen should be necessary to avoid severe stomatitis. (author).

  8. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage.

    Directory of Open Access Journals (Sweden)

    Toshio Watanabe

    Full Text Available Low-dose aspirin (LDA frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity from baseline to 8 weeks.The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13. After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046. While the difference was not significant (p = 0.13, the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25 tended to be higher than that in the placebo group (7.7%, 1 of 13. Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02, whereas placebo did not. The triple dose of rebamipide was well tolerated.High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.UMIN Clinical Trials Registry UMIN000003463.

  9. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage.

    Science.gov (United States)

    Watanabe, Toshio; Takeuchi, Toshihisa; Handa, Osamu; Sakata, Yasuhisa; Tanigawa, Tetsuya; Shiba, Masatsugu; Naito, Yuji; Higuchi, Kazuhide; Fujimoto, Kazuma; Yoshikawa, Toshikazu; Arakawa, Tetsuo

    2015-01-01

    Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy. We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks. The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated. High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy. UMIN Clinical Trials Registry UMIN000003463.

  10. The highest-copy repeats are methylated in the small genome of the early divergent vascular plant Selaginella moellendorffii

    Directory of Open Access Journals (Sweden)

    Quan Hui

    2008-06-01

    Full Text Available Abstract Background The lycophyte Selaginella moellendorffii is a vascular plant that diverged from the fern/seed plant lineage at least 400 million years ago. Although genomic information for S. moellendorffii is starting to be produced, little is known about basic aspects of its molecular biology. In order to provide the first glimpse to the epigenetic landscape of this early divergent vascular plant, we used the methylation filtration technique. Methylation filtration genomic libraries select unmethylated DNA clones due to the presence of the methylation-dependent restriction endonuclease McrBC in the bacterial host. Results We conducted a characterization of the DNA methylation patterns of the S. moellendorffii genome by sequencing a set of S. moellendorffii shotgun genomic clones, along with a set of methylation filtered clones. Chloroplast DNA, which is typically unmethylated, was enriched in the filtered library relative to the shotgun library, showing that there is DNA methylation in the extremely small S. moellendorffii genome. The filtered library also showed enrichment in expressed and gene-like sequences, while the highest-copy repeats were largely under-represented in this library. These results show that genes and repeats are differentially methylated in the S. moellendorffii genome, as occurs in other plants studied. Conclusion Our results shed light on the genome methylation pattern in a member of a relatively unexplored plant lineage. The DNA methylation data reported here will help understanding the involvement of this epigenetic mark in fundamental biological processes, as well as the evolutionary aspects of epigenetics in land plants.

  11. Construction of a repeat-free dual color fluorescent in situ hybridization probe for ROS1 gene in non-small cell lung cancer diagnosis

    Institute of Scientific and Technical Information of China (English)

    程弘夏

    2014-01-01

    Objective To establish a repeat-free ROS1 gene fluorescence in situ hybridization(FISH)probe,and to compare its efficacy with those of commercial FISH probes in non-small cell lung cancer.Methods The probe was constructed by combining human Cot-1 DNA genome into double-stranded sequence,and then digested by duples specific nuclease to establish a repeat-free sequene.The final repeat-free ROS1 FISH probe was labeled by red and green fluoresceins.Results Compared

  12. Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI.

    Science.gov (United States)

    Buus, Simon; Lizondo, Maria; Hokland, Steffen; Rylander, Susanne; Pedersen, Erik M; Tanderup, Kari; Bentzen, Lise

    2017-09-18

    To quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration. Twenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTVprostate+3mm. The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy. Needle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTVprostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively. Substantial needle migration in high-dose-rate brachytherapy occurs frequently in 1-3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  13. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    Science.gov (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  14. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

    Science.gov (United States)

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS

    2009-01-01

    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  15. Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children.

    Directory of Open Access Journals (Sweden)

    Adoke Yeka

    Full Text Available The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT, artesunate-amodiaquine (ASAQ and artemether-lumefantrine (AL are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1-26. For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5% was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]. PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2-18, ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.Current Controlled Trials NCT00699920.

  16. Repeated exposure of male mice to low doses of lipopolysaccharide: dose and time dependent development of behavioral sensitization and tolerance in an automated light-dark anxiety test.

    Science.gov (United States)

    Banasikowski, Tomek J; Cloutier, Caylen J; Ossenkopp, Klaus-Peter; Kavaliers, Martin

    2015-06-01

    Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 μg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light-dark apparatus (total time in the light chamber, number of light-dark transitions, nose pokes into the light chamber). LPS at 1.0 μg/kg, while having no significant effects on anxiety-like behaviors in the light-dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 μg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 μg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS-induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner.

  17. Distribution and antitumor activity of adriamycin given in a high-dose and a repeated low-dose schedule to mice.

    Science.gov (United States)

    Pacciarini, M A; Barbieri, B; Colombo, T; Broggini, M; Garattini, S; Donelli, M G

    1978-05-01

    Experimental studies on the distribution of adriamycin (AM) under different treatment conditions and possible correlations between tissue and plasma levels and chemotherapeutic activity are discussed. C57BL/6J mice bearing im Lewis lung carcinoma and (C3H x O2O)F1 mice bearing mammary carcinoma were injected iv with AM at a single dose of 15 mg/kg or with the same total amount of drug administered in spaced doses of 3.75 mg/kg for 4 consecutive days. In the two experimental systems studied, the drug reached approximately the same value in the tumor and spleen with both types of treatment, but with the 3.75-mg/kg x 4 schedule much lower AM concentrations were observed in the heart than with the single high-dose treatment. The therapeutic activity of the two treatments also differed: the antitumor and antimetastatic effect was the same in the two tumor systems, but with the 3.75-mg/kg x 4 schedule, increased survival and somewhat lower toxicity were observed. Daunorubicin, tested in the mammary carcinoma system with the two schedules of treatment, behaves very similarly to AM in terms of both distribution and chemotherapeutic effect.

  18. Mutations induced in Tradescantia by small doses of X-rays and neutrons - Analysis of dose-response curves.

    Science.gov (United States)

    Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.

    1972-01-01

    Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.

  19. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    Science.gov (United States)

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

  20. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning

    Energy Technology Data Exchange (ETDEWEB)

    Kerkhof, E M; Put, R W van der; Raaymakers, B W; Heide, U A van der; Vulpen, M van; Lagendijk, J J W [Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht (Netherlands)], E-mail: E.Kerkhof@umcutrecht.nl

    2008-10-21

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  1. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning

    Science.gov (United States)

    Kerkhof, E. M.; van der Put, R. W.; Raaymakers, B. W.; van der Heide, U. A.; van Vulpen, M.; Lagendijk, J. J. W.

    2008-10-01

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  2. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning.

    Science.gov (United States)

    Kerkhof, E M; van der Put, R W; Raaymakers, B W; van der Heide, U A; van Vulpen, M; Lagendijk, J J W

    2008-10-21

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  3. Individualized Dose Prescription for Hypofractionation in Advanced Non-Small-Cell Lung Cancer Radiotherapy: An in silico Trial

    Energy Technology Data Exchange (ETDEWEB)

    Hoffmann, Aswin L.; Troost, Esther G.C.; Huizenga, Henk; Kaanders, Johannes H.A.M. [Radboud University Nijmegen Medical Centre, Department of Radiation Oncology, Nijmegen (Netherlands); Bussink, Johan, E-mail: j.bussink@rther.umcn.nl [Radboud University Nijmegen Medical Centre, Department of Radiation Oncology, Nijmegen (Netherlands)

    2012-08-01

    Purpose: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various hypofractionation schemes delivered with intensity-modulated radiation therapy. Methods and Materials: For 38 Stage III NSCLC patients, the dose level of an existing curative treatment plan with standard fractionation (66 Gy) was rescaled based on dose constraints for the lung, spinal cord, esophagus, brachial plexus, and heart. The effect on tumor total dose (TTD) and biologic tumor effective dose in 2-Gy fractions (TED) corrected for overall treatment time (OTT) was compared for isotoxic and maximally tolerable schemes given in 15, 20, and 33 fractions. Rescaling was accomplished by altering the dose per fraction and/or the number of fractions while keeping the relative dose distribution of the original treatment plan. Results: For 30 of the 38 patients, dose escalation by individualized hypofractionation yielded therapeutic gain. For the maximally tolerable dose scheme in 33 fractions (MTD{sub 33}), individualized dose escalation resulted in a 2.5-21% gain in TTD. In the isotoxic schemes, the number of fractions could be reduced with a marginal increase in TED. For the maximally tolerable dose schemes, the TED could be escalated up to 36.6%, and for all patients beyond the level of the isotoxic and the MTD{sub 33} schemes (range, 3.3-36.6%). Reduction of the OTT contributed to the therapeutic gain of the shortened schemes. For the maximally tolerable schemes, the maximum esophageal dose was the dominant dose-limiting constraint in most patients. Conclusions: This modeling study showed that individualized dose prescription for hypofractionation in NSCLC radiotherapy, based on scaling of existing treatment plans up to normal tissue dose constraints, enables dose

  4. Dose calculation algorithm accuracy for small fields in non-homogeneous media: The lung SBRT case.

    Science.gov (United States)

    Fogliata, Antonella; Cozzi, Luca

    2016-11-24

    This review addresses the theme of dose calculation accuracy in the case of the stereotactic treatment of lung lesions. Based on the classical categories of type "a", "b" and "c" algorithms (according to their degree of complexity in the management of charged particle transport), a summary of findings from literature is reported. Two main critical areas have been identified: the use of small fields and the presence of low density medium. Concerning the latter point, the algorithm accuracy is intrinsic of the algorithm core, and, notwithstanding the materials discretization and their chemical composition knowledge, type "c" are, at the most, able to reproduce the actual physical dose distribution in heterogeneous media. For what concerns the small field management, the final accuracy could be strongly related to the beam configuration appropriateness in the TPS (as well for MC this relates to the proper linac head description). As a very crude summary, type "a" should be considered as unsuitable for this kind of treatment calculations (with differences of the order of 20-30%), while type "b" and "c" could keep their accuracy approximatively within 10 and 5%, respectively. Copyright © 2016. Published by Elsevier Ltd.

  5. PCP METHODOLOGY FOR DETERMINING DOSE RATES FOR SMALL GRAM QUANTITIES IN SHIPPING PACKAGINGS

    Energy Technology Data Exchange (ETDEWEB)

    Nathan, S.

    2011-08-23

    The Small Gram Quantity (SGQ) concept is based on the understanding that small amounts of hazardous materials, in this case radioactive materials, are significantly less hazardous than large amounts of the same materials. This study describes a methodology designed to estimate an SGQ for several neutron and gamma emitting isotopes that can be shipped in a package compliant with 10 CFR Part 71 external radiation level limits regulations. These regulations require packaging for the shipment of radioactive materials perform, under both normal and accident conditions, the essential functions of material containment, subcriticality, and maintain external radiation levels within regulatory limits. 10 CFR 71.33(b)(1)(2)&(3) state radioactive and fissile materials must be identified and their maximum quantity, chemical and physical forms be included in an application. Furthermore, the U.S. Federal Regulations require application contain an evaluation demonstrating the package (i.e., the packaging and its contents) satisfies the external radiation standards for all packages (10 CFR 71.31(2), 71.35(a), & 71.47). By placing the contents in a He leak-tight containment vessel, and limiting the mass to ensure subcriticality, the first two essential functions are readily met. Some isotopes emit sufficiently strong photon radiation that small amounts of material can yield a large external dose rate. Quantifying of the dose rate for a proposed content is a challenging issue for the SGQ approach. It is essential to quantify external radiation levels from several common gamma and neutron sources that can be safely placed in a specific packaging, to ensure compliance with federal regulations. The Packaging Certification Program (PCP) Methodology for Determining Dose Rate for Small Gram Quantities in Shipping Packagings described in this report provides bounding mass limits for a set of proposed SGQ isotopes. Methodology calculations were performed to estimate external radiation levels

  6. Repeated flood disturbance enhances rotifer dominance and diversity in a zooplankton community of a small dammed mountain pond

    Directory of Open Access Journals (Sweden)

    Carmen Gabaldón

    2016-12-01

    Full Text Available The zooplankton community in a relatively small and mountain pond was studied during the spring growing season. To investigate which factors operate in the community structure, we explored several physical conditions, such as high inflows, and the biotic dynamics of the main zooplankton groups (i.e., rotifers, cladocerans and copepods.  Two extreme flood events occurred during the investigated period and caused dramatic changes in physical conditions and reduction of the planktonic community abundances. The short period between both high-flow events was enough for the recovery of microplankton, but not for the metazoan zooplankton. Our results are in agreement with the common situation in which high flood events commonly favour rotifers over crustaceans, likely due to rotifer species have great colonization ability and grow faster. However, we found that the dominance of rotifers over crustaceans in our system is evidenced by an extremely, unusual high ratio between their abundances.  We observed that, at the time of the great floods, crustacean abundances as well as rotifer populations notably decreased until near zero values. Although rotifer abundance began declining before high floods, the decrease was particularly notable when the great flood happened.  Our results evidenced that i dilution rate and temperature were the main drivers which are operating in the structure of the zooplankton community; and ii no negative biotic interactions were detected between large and small cladocerans and rotifers. Additionally, we found surprisingly that a repeated disturbance caused by high flood events does increase the species diversity of rotifers. Finally, our study also detected some cues which may indicate that diapausing egg bank is also playing an important role in the zooplankton community, favouring the dominance of rotifers; however, this phenomenon deserves further studies. 

  7. ARTIFICIAL SPAWNING OF EUROPEAN CATFISH (Silurus glanis L. USING SMALL DOSES OF CARP PITUITARY GLANDS

    Directory of Open Access Journals (Sweden)

    Ivan Stević

    1998-12-01

    Full Text Available In 1997 and 1998 in the “Ribnjak 1905”•d. d. Našice hatchery artificial spawing of European catfish (Silurus glanis L. was researched under productive conditions using small doses of carp pituitary (CP. Befiwe dosing the carp pituitary glands female catfish were marked, weighed out, grouped according-to their maturity and devided in 5 categories based on grade of their maturity (MC. We used our own criteria. In the controlled group (n=21 female catfish received a single CP shot dosed at 4.5 mg. kg -1 of the body weight (b. w., while in the experimental group (n=62 female fish were treated with single low dosed CP on three levels. It was found out that the minimal CP dosage for the artificial spawning on the 3rd MG is 2.04+-0.15, on the 4th MG 1.59+-0.16 and on the 5th MG 1.25+-0.10 mg. kg-1 of the b. m. Simultaneously, the efficiency of spawning compared to the controlled group was not reduced because it ranged between 92-100% (p<0.0.5, while relative fertility on the 3rd, 4th and 5th maturity grade totalled 9.9+-2.1, 10.4+-1.6 and 11.5+-1.3%, (p<0.05 adequately. The established minimal CP dosages for spawning of European catfish are two to three times lower than relevant data from the reference literature. It is assumed that they will have positive influence on final harmonic maturing process of the oocytes oocita, and by that on better quality of ovulated eggs.

  8. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    NARCIS (Netherlands)

    Radhakishun, F.S.; Ree, J.M. van

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not

  9. Compared efficacy of repeated annual and semi-annual doses of ivermectin and diethylcarbamazine for prevention of Wuchereria bancrofti filariasis in French Polynesia. Final evaluation.

    Science.gov (United States)

    Cartel, J L; Spiegel, A; Nguyen Ngnoc, L; Cardines, R; Plichart, R; Martin, P M; Roux, J F; Moulia-Pelat, J P

    1992-06-01

    In October 1989, 58 apparently healthy Polynesian Wuchereria bancrofti carriers, in whom microfilarial (mf) density was greater than or equal to 100 mf/ml, were randomly allocated to treatment groups receiving single doses of either ivermectin at 100 mcg/kg or diethylcarbamazine (DEC) at 3 and 6 mg/kg. Six months later, half of the carriers initially treated with ivermectin 100 mcg/kg or DEC 3 mg/kg were given a second similar dose while the rest were given a placebo. Six months later again, all of the carriers received a last treatment dose similar to the initial one. The results observed during the 12-month period which followed this last treatment have confirmed that (i) in terms of immediate clearance or complete negativation of microfilaremia, the efficacy of ivermectin is higher than that of DEC (at dosage of 3 or 6 mg/kg), (ii) DEC is more effective than ivermectin in sustaining the reduction of microfilaremia over a longer period of time and (iii) the efficacy of repeated single doses of either DEC 3 mg/kg or ivermectin 100 mcg/kg is much higher when given semi-annually than annually.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    Science.gov (United States)

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  11. Repeated high-dose (5 × 10(8) TCID50) toxicity study of a third generation smallpox vaccine (IMVAMUNE) in New Zealand white rabbits.

    Science.gov (United States)

    Tree, Julia A; Hall, Graham; Rees, Peter; Vipond, Julia; Funnell, Simon G P; Roberts, Allen D

    2016-07-01

    Concern over the release of variola virus as an agent of bioterrorism remains high and a rapid vaccination regimen is desirable for use in the event of a confirmed release of virus. A single, high-dose (5×10(8) TCID50) of Bavarian Nordic's IMVAMUNE was tested in a Phase-II clinical trial, in humans, as a substitute for the standard (1×10(8) TCID50), using a 2-dose, 28-days apart regimen. Prior to this clinical trial taking place a Good Laboratory Practice, repeated high-dose, toxicology study was performed using IMVAMUNE, in New Zealand white rabbits and the results are reported here. Male and female rabbits were dosed twice, subcutaneously, with 5×10(8) TCID50 of IMVAMUNE (test) or saline (control), 7-days apart. The clinical condition, body-weight, food consumption, haematology, blood chemistry, immunogenicity, organ-weight, and macroscopic and microscopic pathology were investigated. Haematological investigations indicated changes within the white blood cell profile that were attributed to treatment with IMVAMUNE; these comprised slight increases in neutrophil and monocyte numbers, on study days 1-3 and a marginal increase in lymphocyte numbers on day 10. Macroscopic pathology revealed reddening at the sites of administration and thickened skin in IMVAMUNE, treated animals. After the second dose of IMVAMUNE 9/10 rabbits seroconverted, as detected by antibody ELISA on day 10, by day 21, 10/10 rabbits seroconverted. Treatment-related changes were not detected in other parameters. In conclusion, the subcutaneous injection of 2 high-doses of IMVAMUNE, to rabbits, was well tolerated producing only minor changes at the site of administration. Vaccinia-specific antibodies were raised in IMVAMUNE-vaccinated rabbits only.

  12. Repeat spinal anesthesia in cesarean section: A comparison between 10 mg and 12 mg doses of intrathecal hyperbaric (0.05%) bupivacaine repeated after failed spinal anesthesia: A prospective, parallel group study.

    Science.gov (United States)

    Bhar, Debasish; RoyBasunia, Sandip; Das, Anjan; Chhaule, Subinay; Mondal, Sudipta Kumar; Bisai, Subrata; Chattopadhyay, Surajit; Mandal, Subrata Kumar

    2016-01-01

    Spinal anesthesia for cesarean section is not a 100% successful technique. At times, despite straightforward insertion and drug administration, intrathecal anesthesia for cesarean section fails to obtain any sensory or motor block. Very few studies and literature are available regarding repeat administration of spinal anesthesia and its drug dosage, especially after first spinal failure in cesarean section lower segment cesarean section (LSCS) due to fear of the excessive spread of drug. The aim of our study is to compare the outcome between two different doses of 0.5% hyperbaric bupivacaine repeated intrathecally after failed spinal. After taking informed consent and Ethical Committee approval this prospective, randomized single-blinded study was conducted in 100 parturients of American Society of Anesthesiologists I-II who were posted for elective LSCS and had Bromage score 0 and no sensory block even at L4 dermatome after 10 min of first spinal anesthesia; were included in the study. Group A (n = 50) patients received 2.4 ml and Group B (n = 50) patients received 2 ml of 0.5% hyperbaric bupivacaine respectively for administering repeat spinal anesthesia. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation, respiratory rate and electrocardiogram were monitored both intra- and post-operatively and complications were recorded. Incidence of high spinal, bradycardia, hypotension, respiratory complications, and nausea vomiting are significantly higher in Group A compared to Group B (P cesarean section with 10 mg of 0.5% hyperbaric bupivacaine provided after first spinal anesthesia, the level of sensory block is below L4 and motor power in Bromage scale is 0.

  13. Detector dose response in megavoltage small photon beams. I. Theoretical concepts

    Energy Technology Data Exchange (ETDEWEB)

    Bouchard, Hugo, E-mail: hugo.bouchard@npl.co.uk; Duane, Simon [Acoustics and Ionising Radiation Team, National Physical Laboratory, Hampton Road, Teddington TW11 0LW (United Kingdom); Seuntjens, Jan [Medical Physics Unit, McGill University, Montréal, Québec H3G 1A4 (Canada); Kamio, Yuji [Centre hospitalier de l’Université de Montréal (CHUM), 1560 Sherbrooke est, Montréal, Québec H2L 4M1 (Canada); Palmans, Hugo [Acoustics and Ionising Radiation Team, National Physical Laboratory, Hampton Road, Teddington TW11 0LW (United Kingdom); Medical Physics, EBG MedAustron GmbH, A-2700 Wiener Neustadt (Austria)

    2015-10-15

    Purpose: To explain the reasons for significant quality correction factors in megavoltage small photon fields and clarify the underlying concepts relevant to dosimetry under such conditions. Methods: The validity of cavity theory and the requirement of charged particle equilibrium (CPE) are addressed from a theoretical point of view in the context of nonstandard beams. Perturbation effects are described into four main subeffects, explaining their nature and pointing out their relative importance in small photon fields. Results: It is demonstrated that the failure to meet classical cavity theory requirements, such as CPE, is not the reason for significant quality correction factors. On the contrary, it is shown that the lack of CPE alone cannot explain these corrections and that what matters most, apart from volume averaging effects, is the relationship between the lack of CPE in the small field itself and the density of the detector cavity. The density perturbation effect is explained based on Fano’s theorem, describing the compensating effect of two main contributions to cavity absorbed dose. Using the same approach, perturbation effects arising from the difference in atomic properties of the cavity medium and the presence of extracameral components are explained. Volume averaging effects are also discussed in detail. Conclusions: Quality correction factors of small megavoltage photon fields are mainly due to differences in electron density between water and the detector medium and to volume averaging over the detector cavity. Other effects, such as the presence of extracameral components and differences in atomic properties of the detection medium with respect to water, can also play an accentuated role in small photon fields compared to standard beams.

  14. Influence of Food on the Bioavailability of an Enteric-Coated Tablet Formulation of Omeprazole 20 mg Under Repeated Dose Conditions

    Directory of Open Access Journals (Sweden)

    ABR Thomson

    1997-01-01

    Full Text Available The objective of this study was to investigate the influence of food on the bioavailability of omeprazole (20 mg given as an enteric-coated tablet under repeated dose conditions. This open randomized crossover study consisted of three seven-day treatment periods, each separated by a drug-free period. During each treatment period an enteric-coated tablet of omeprazole was taken once daily either under fasting conditions, or immediately before or after a standardized breakfast. On the last day of each treatment period, blood samples for the determination of plasma omeprazole concentrations were collected at baseline and at predetermined intervals over the 24 h period following drug administration. Fifty-seven male and female subjects, aged 18 to 52 years, completed the study according to the protocol. No statistically significant differences were found when comparing either the before breakfast or after breakfast treatment regimens with the fasting regimen for the estimated mean area under the plasma concentration-time curve (AUC. The maximum plasma concentration was not found to differ significantly among any of the treatment regimens. However, the lower limit of the CI for the comparison of fasting/before breakfast was not contained within the limits of bioequivalence. The time to reach maximum plasma concentration was significantly different when fasting and after breakfast regimens were compared. Thus, under repeated dose conditions, food has no influence on the bioavailability (expressed as AUC of omeprazole given as the enteric-coated tablet formulation.

  15. Low-Radiation-Dose Modified Small Bowel CT for Evaluation of Recurrent Crohn's Disease

    Directory of Open Access Journals (Sweden)

    A. Z. Kielar

    2012-01-01

    Full Text Available Crohn's disease affects any part of the GI tract, commonly the terminal ileum. To decrease radiation exposure we developed a low-radiation-dose unenhanced CT (modified small Bowel CT, MBCT to evaluate the small bowel using hyperdense oral contrast. Technique. MBCT was investigated in patients with pathologically proven Crohn's disease presenting with new symptoms from recurrent inflammation or stricture. After ethics board approval, 98 consecutive patients were retrospectively evaluated. Kappa values from two independent reviewers were calculated for presence of obstruction, active inflammation versus chronic stricture, and ancillary findings. Forty-two patients underwent surgery or colonoscopy within 3 months. Results. Kappa was 0.84 for presence of abnormality versus a normal exam and 0.89 for differentiating active inflammation from chronic stricture. Level of agreement for presence of skip areas, abscess formation, and fistula was 0.62, 0.75, and 0.78, respectively. In the subset with “gold standard” follow-up, there was 83% agreement. Conclusions. MBCT is a low-radiation technique with good to very good interobserver agreement for determining presence of obstruction and degree of disease activity in patients with Crohn's disease. Further investigation is required to refine parameters of disease activity compared to CT enterography and small bowel follow through.

  16. Measurement and properties of the dose-area product ratio in external small-beam radiotherapy

    Science.gov (United States)

    Niemelä, Jarkko; Partanen, Mari; Ojala, Jarkko; Sipilä, Petri; Björkqvist, Mikko; Kapanen, Mika; Keyriläinen, Jani

    2017-06-01

    In small-beam radiation therapy (RT) the measurement of the beam quality parameter, i.e. the tissue-phantom ratio or TPR20,10, using a conventional point detector is a challenge. To obtain reliable results, one has to consider potential sources of error, including volume averaging and adjustment of the point detector into the narrow beam. To overcome these challenges, a different type of beam quality parameter in small beams was studied, namely the dose-area product ratio, or DAPR20,10. With this method, the measurement of a dose-area product (DAP) using a large-area plane-parallel chamber (LAC) eliminates the uncertainties in detector positioning and volume averaging that are present when using a point detector. In this study, the properties of the DAPR20,10 of a cone-collimated 6 MV photon beam were investigated using Monte Carlo (MC) calculations and the obtained values were compared to measurements obtained using two LAC detectors, PTW Type 34073 and PTW Type 34070. In addition, the possibility of determining the DAP using EBT3 film and a Razor diode detector was studied. The determination of the DAPR20,10 value was found to be feasible in external small-beam radiotherapy using cone-collimated beams with diameters from 4-40 mm, based on the results of the two LACs, the MC calculations and the Razor diode. The measurements indicated a constant DAPR20,10 value for fields 20-40 mm in diameter, with a maximum relative change of 0.6%, but an increase of 7.0% for fields from 20-4 mm in diameter for the PTW Type 34070 chamber. Simulations and measurements showed an increase of DAPR20,10 with increasing LAC size or dose integral area for the studied 4-40 mm cone-collimated 6 MV photon beams. This has the consequence that there should be a reference to the size of the used LAC active area or the DAP integration area with the reported DAPR20,10 value.

  17. Measurement and properties of dose-area product ratio in external small-beam radiotherapy.

    Science.gov (United States)

    Niemelä, Jarkko Tapio; Partanen, Mari; Ojala, Jarkko; Sipilae, Petri; Björkqvist, Mikko; Kapanen, Mika; Keyriläinen, Jani

    2017-03-22

    In small-beam radiation therapy (RT) the measurement of beam quality parameter i.e. tissue-phantom ratio or TPR20,10 with conventional point detector is a challenge. To obtain reliable results, one has to consider potential sources of error, including volume averaging and adjustment of the point detector into the narrow beam. To overcome these challenges, a different type of possible beam quality parameter in small beams was studied, namely the dose-area product ratio or DAPR20,10. With this method, the measurement of a dose-area product (DAP) with a large-area plane-parallel chamber (LAC) eliminates the uncertainties in detector positioning and volume averaging present with the use of a point detector. In this study, properties of DAPR20,10 of cone-collimated 6 MV photon beam were investigated with Monte Carlo (MC) calculations and the obtained values were compared to measurements obtained by two LAC detectors PTW Type 34073 and PTW Type 34070. In addition, the possibility of determining the DAP with EBT3 film and Razor diode detector was studied. The determination of DAPR20,10 value was found to be feasible in external small-beam radiotherapy of cone-collimated beams with diameters from 4 to 40 mm with the two LACs, MC calculation and Razor diode. Measurements indicated a constant DAPR20,10 value for fields from 20 to 40 mm in diameter with maximum relative change of 0.6%, but an increase of 7.0% for fields from 20 to 4 mm in diameter for PTW Type 34070 chamber. Simulations and measurements showed an increase of DAPR20,10 with increasing LAC size or dose integral area for studied cone-collimated 6 MV photon beams from 4 to 40 mm in diameter. This has a consequence that with reported DAPR20,10 value there should be a reference to the size of the used LAC active area or the DAP integration area.

  18. Erlotinib dosing-to-rash: A phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer

    NARCIS (Netherlands)

    A. mita (Alain); K. Papadopoulos (K.); M.J.A. de Jonge (Maja); G. Schwartz (G.); J. Verweij (Jaap); A. Ricart (A.); Q.S.C. Chu (Q. S C); A.W. Tolcher (A. W.); L. Wood (Lori); S.W. McCarthy (Stanley); M. Hamilton; K.K. Iwata (Kenneth); B. Wacker; K. de Witte (Karel); E.K. Rowinsky (Eric Keith)

    2011-01-01

    textabstractBackground: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacok

  19. Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions

    Directory of Open Access Journals (Sweden)

    Victoria Ríos

    2014-03-01

    Full Text Available The cyanobacterial toxin Cylindrospermopsin (CYN, a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days. In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR of the antioxidant enzymes glutathione peroxidase (GPx and soluble glutathione-S-transferases (sGST, and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance or 7 days (GPx gene expression, sGST activity. These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects.

  20. Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

    Science.gov (United States)

    Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

    2014-05-01

    In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

  1. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

    Science.gov (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  2. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach.

    Science.gov (United States)

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie

    2014-10-01

    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  3. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  4. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs.

    Science.gov (United States)

    Yimam, Mesfin; Lee, Young Chul; Jia, Qi

    2016-07-01

    The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs.

  5. Impact of small MU/segment and dose rate on delivery accuracy of volumetric-modulated arc therapy (VMAT).

    Science.gov (United States)

    Huang, Long; Zhuang, Tingliang; Mastroianni, Anthony; Djemil, Toufik; Cui, Taoran; Xia, Ping

    2016-05-08

    Volumetric-modulated arc therapy (VMAT) plans may require more control points (or segments) than some of fixed-beam IMRT plans that are created with a limited number of segments. Increasing number of control points in a VMAT plan for a given prescription dose could create a large portion of the total number of segments with small number monitor units (MUs) per segment. The purpose of this study is to investigate the impact of the small number MU/segment on the delivery accuracy of VMAT delivered with various dose rates. Ten patient datasets were planned for hippocampus sparing for whole brain irradiation. For each dataset, two VMAT plans were created with maximum dose rates of 600 MU/min (the maximum field size of 21 × 40 cm2) and 1000 MU/min (the maximum field size of 15 × 15 cm2) for a daily dose of 3 Gy. Without reoptimization, the daily dose of these plans was purposely reduced to 1.5 Gy and 1.0 Gy while keeping the same total dose. Using the two dose rates and three different daily doses, six VMAT plans for each dataset were delivered to a physical phantom to investigate how the changes of dose rate and daily doses impact on delivery accuracy. Using the gamma index, we directly compared the delivered planar dose profiles with the reduced daily doses (1.5 Gy and 1.0 Gy) to the delivered planar dose at 3 Gy daily dose, delivered at dose rate of 600 MU/min and 1000 MU/min, respectively. The average numbers of segments with MU/segment ≤ 1 were 35 ± 8, 87 ± 6 for VMAT-600 1.5 Gy, VMAT-600 1 Gy plans, and 30 ± 7 and 42 ± 6 for VMAT-1000 1.5 Gy and VMAT-1000 1 Gy plans, respectively. When delivered at 600 MU/min dose rate, the average gamma index passing rates (1%/1 mm criteria) of comparing delivered 1.5 Gy VMAT planar dose profiles to 3.0 Gy VMAT delivered planar dose profiles was 98.28% ± 1.66%, and the average gamma index passing rate of comparing delivered 1.0 Gy VMAT planar dose to 3.0 Gy VMAT delivered planar dose was 83.75% ± 4.86%. If using 2%/2mm

  6. Optimal image reconstruction for detection and characterization of small pulmonary nodules during low-dose CT

    Energy Technology Data Exchange (ETDEWEB)

    Hashemi, SayedMasoud; Cobbold, Richard S.C. [University of Toronto, Institute of Biomaterial and Biomedical Engineering, Toronto, ON (Canada); Mehrez, Hatem [Toshiba of Canada Ltd, Markham, ON (Canada); Paul, Narinder S. [University Health Network, Medical Imaging, Toronto General Hospital, Toronto, ON (Canada)

    2014-06-15

    To optimize the slice thickness/overlap parameters for image reconstruction and to study the effect of iterative reconstruction (IR) on detectability and characterization of small non-calcified pulmonary nodules during low-dose thoracic CT. Data was obtained from computer simulations, phantom, and patient CTs. Simulations and phantom CTs were performed with 9 nodules (5, 8, and 10 mm with 100, -630, and -800 HU). Patient data were based on 11 ground glass opacities (GGO) and 9 solid nodules. For each analysis the nodules were reconstructed with filtered back projection and IR algorithms using 10 different combinations of slice thickness/overlap (0.5-5 mm). The attenuation (CT) and the contrast to noise ratio (CNR) were measured. Spearman's coefficient was used to correlate the error in CT measurements and slice thickness. Paired Student's t test was used to measure the significance of the errors. CNR measurements: CNR increases with increasing slice thickness/overlap for large nodules and peaks at 4.0/2.0 mm for smaller ones. Use of IR increases the CNR of GGOs by 60 %. CT measurements: Increasing slice thickness/overlap above 3.0/1.5 mm results in decreased CT measurement accuracy. Optimal detection of small pulmonary nodules requires slice thickness/overlap of 4.0/2.0 mm. Slice thickness/overlap of 2.0/2.0 mm is required for optimal nodule characterization. IR improves conspicuity of small ground glass nodules through a significant increase in nodule CNR. (orig.)

  7. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    Science.gov (United States)

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  8. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    Science.gov (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  9. A small-dose naloxone infusion alleviates nausea and sedation without impacting analgesia via intravenous tramadol

    Institute of Scientific and Technical Information of China (English)

    JIA Dong-lin; NI Cheng; XU Ting; ZHANG Li-ping; GUO Xiang-yang

    2010-01-01

    Background Early studies showed that naloxone infusion decreases the incidence of morphine-related side effects from intravenous patient-controlled analgesia. This study aimed to determine whether naloxone preserved analgesia while minimizing side effects caused by intravenous tramadol administration. Methods Eighty patients undergoing general anesthesia for cervical vertebrae surgery were randomly divided into four groups. All patients received 1 mg/kg tramadol 30 minutes before the end of surgery, followed by a continuous infusion with 0.3 mgkg-1·h-1 tramadol with no naloxone (group I, n=20), 0.05 μg-kg-1·h-1 naloxone (group II, n=20), 0.1 μg·kg-1·h-1 naloxone (group III, n=20) and 0.2 μg·kg-1·h-1 naloxone (group IV, n=20). Visual analog scales (VAS) for pain during rest and cough, nausea five-point scale (NFPS) for nausea and vomiting, and ramsay sedation score (RSS) for sedation were assessed at 2, 6,12, 24 and 48 hours postoperatively. Analgesia and side effects were evaluated by blinded observers. Results Seventy-eight patients were included in this study. The intravenous tramadol administration provided the satisfied analgesia. There was no significant difference in either resting or coughing VAS scores among naloxone groups and control group. Compared with control group, sedation was less in groups II, III, and IV at 6, 12, and 24 hours (P <0.05); nausea was less in groups II, III and IV than group I at 2, 6, 12, 24 and 48 hours postoperatively (P <0.05). The incidence of vomiting in the control group was 35% vs. 10% for the highest dose naloxone group (group IV) (P<0.01). Conclusion A small-dose naloxone infusion could reduce tramadol induced side effects without reversing its analgesic effects.

  10. Experimental study on port-wine stain treated by small dose HpD and variable pulsed 532nm laser

    Science.gov (United States)

    Qin, Meixiang; Zhu, Jing; Yuan, Xiawen

    2005-07-01

    To obtain a new therapy for port-wine stain (PWS) with good effect and few side effects, the Leghorn chicken combs chosen as the animal models and treated by small dose HpD and variable pulsed 532nm laser were evaluated clinically using four different scoring systems commonly used in previous publication. Result: It was shown significant difference among 5 groups (p<0.01), and the treatment groups have better effect than the control groups. There's also difference among the four treatment groups and the higher dose of HpD has better effect. In all groups the higher the fluency of laser was used, the better the effect produce. Conclusion: The results provide evidence that small dose HpD and variable pulsed 532nm laser can increase the efficacy of treatment in PWS. Increasing the fluency of laser and the dose of HpD can improve the efficacy.

  11. Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury.

    Science.gov (United States)

    Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R

    2010-04-01

    Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

  12. SMALL-DOSE CYTOKINES IN COMBINATION WITH 5-FLUOROURACIL IN OLISSEMINATED RENAL CELL CARCINOMA: FINAL RESULTS OF A RANDOMIZED TRIAL

    Directory of Open Access Journals (Sweden)

    L. V. Demidov

    2009-01-01

    Full Text Available Background: High and intermediate IL-2 regimens are difficult to recommend because of great toxicity and efficacy is not sufficient. We suggest that a combination of very low-dose cytokines is effective and safe in metastatic renal cell carcinoma (MRCC patients (pts. A prospective randomized study was started in 2003. The primary end-point was a response rate. Methods: The eligibility criteria included histopathologically confirmed MRCC, ECOG PS 0-2, no autoimmune diseases, no brain metastases, and normal organ function. All pts were randomized in three arms: IL-2 alone, 1.5 MIU, iv, t.i.w., weeks 1—3 or IL-2 1.0 MIU, iv, t.i.w., weeks 1—3 plus IFN 5 MIU, sc, t.i.w, weeks 1—3 or biochemotherapy group 5-FU, 500 mg/m2, iv, once a week, weeks 1—3 plus IL-2 1.0 MIU, iv, t.i.w., weeks 1—3 plus IFN 5 MIU, sc, t.i.w., weeks 1—3. Courses were repeated every three weeks. A response was assessed according to the RECIST every 2 courses.Results: 64 pts were enrolled, of whom 63 were analyzed. Their median age was 55.4 years (range 16—74. 42.9% of the patients had pre- viously received chemo- or immunotherapy. 55.6 percent of the pts had poor prognosis (according to Motzer et al., 2002. Bone metastases were present in 52.4% of the pts. Sixteen patients treated with IL-2 alone showed no CR, PR, 2 SD, or 14 PD. Of 23 patients in the IL-2+IFN group, there were 5 PR, 8 SD, and 10 PD, with a response rate of 21.7%. Amongst 24 patients in the 5-FU+IL-2+IFN group, there were 1 CR, 3 PR, 10 SD, and 10 PD, with a response rate of 16.7%. One-year survival was 20.0%, 81.3% and 81.0%, respectively. The influenza-like syndrome was the most common side effect in the pts who received IFN (89.1%, grade 1, CTC. Hypotension associated with IL-2 (all groups was seen in 56.3% (50%, grade 1 and 6.3%, grade 2. The other adverse reactions were 12.7% grade 1 neutropenia and vomiting in 4.7% pts (Group 3.Conclusion: All regimens are well tolerated. Small-dose IL-2

  13. Critical dose and toxicity index of organs at risk in radiotherapy: Analyzing the calculated effects of modified dose fractionation in non–small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pedicini, Piernicola, E-mail: ppiern@libero.it [Service of Medical Physics, I.R.C.C.S. Regional Cancer Hospital C.R.O.B, Rionero in Vulture (Italy); Strigari, Lidia [Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome (Italy); Benassi, Marcello [Service of Medical Physics, Scientific Institute of Tumours of Romagna I.R.S.T., Meldola (Italy); Caivano, Rocchina [Service of Medical Physics, I.R.C.C.S. Regional Cancer Hospital C.R.O.B, Rionero in Vulture (Italy); Fiorentino, Alba [U.O. of Radiotherapy, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy); Nappi, Antonio [U.O. of Nuclear Medicine, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy); Salvatore, Marco [U.O. of Nuclear Medicine, I.R.C.C.S. SDN Foundation, Naples (Italy); Storto, Giovanni [U.O. of Nuclear Medicine, I.R.C.C.S. Regional Cancer Hospital C.R.O.B., Rionero in Vulture (Italy)

    2014-04-01

    To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volume histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.

  14. Effect of lung and target density on small-field dose coverage and PTV definition

    Energy Technology Data Exchange (ETDEWEB)

    Higgins, Patrick D., E-mail: higgi010@umn.edu; Ehler, Eric D.; Cho, Lawrence C.; Dusenbery, Kathryn E.

    2015-04-01

    We have studied the effect of target and lung density on block margin for small stereotactic body radiotherapy (SBRT) targets. A phantom (50 × 50 × 50 cm{sup 3}) was created in the Pinnacle (V9.2) planning system with a 23-cm diameter lung region of interest insert. Diameter targets of 1.6, 2.0, 3.0, and 4.0 cm were placed in the lung region of interest and centered at a physical depth of 15 cm. Target densities evaluated were 0.1 to 1.0 g/cm{sup 3}, whereas the surrounding lung density was varied between 0.05 and 0.6 g/cm{sup 3}. A dose of 100 cGy was delivered to the isocenter via a single 6-MV field, and the ratio of the average dose to points defining the lateral edges of the target to the isocenter dose was recorded for each combination. Field margins were varied from none to 1.5 cm in 0.25-cm steps. Data obtained in the phantom study were used to predict planning treatment volume (PTV) margins that would match the clinical PTV and isodose prescription for a clinical set of 39 SBRT cases. The average internal target volume (ITV) density was 0.73 ± 0.17, average local lung density was 0.33 ± 0.16, and average ITV diameter was 2.16 ± 0.8 cm. The phantom results initially underpredicted PTV margins by 0.35 cm. With this offset included in the model, the ratio of predicted-to-clinical PTVs was 1.05 ± 0.32. For a given target and lung density, it was found that treatment margin was insensitive to target diameter, except for the smallest (1.6-cm diameter) target, for which the treatment margin was more sensitive to density changes than the larger targets. We have developed a graphical relationship for block margin as a function of target and lung density, which should save time in the planning phase by shortening the design of PTV margins that can satisfy Radiation Therapy Oncology Group mandated treatment volume ratios.

  15. Development of immunity against viral and bacterial antigens after repeated exposures to suberythemal doses of ultraviolet light

    Directory of Open Access Journals (Sweden)

    S. A. Snopov

    2012-01-01

    Full Text Available The effects of ultraviolet (UV radiation on human infectious immunity are not well studied. On the one hand, solar and artificial UU sources have been shown to change cytokine levels in human skin, lymphocyte subpopulation counts in parepheral blood, lymphocyte DNA synthesis and prolifarative response to mitogens. On the other hand, there are just only one or two observations suggesting an influence of UV radiation on human infection course. For instance, UV irradiations have been reported to induce a reccurence of orofacial vesicular lesions caused by herpes siplex virus. Moreover, there is a lack of data concerning immune effects of suberythtemal doses of UV in spite of a long history of using them by Russian prophylactic medicine. In this work we questioned whether such suberythemal UV exposures can affect the immune responses of children to infectious conjunctivitis, to simultaneous measles and polio vaccinations and to simultaneous polio and diphtheria-tetanus vaccinations. In peripheral blood of vaccinated children we examined leukocyte counts (monocytes, neutrophils, eosinophils, lymphocytes, percentages of lymphocyte subpopulations (CD3+, CD20+, CD4+, CD8+, CD25+, HLADR+, concentrations of cytokines (IL-1 beta, TNF-alpha, IFN- amma и IL-10, DNA-synthetic activity of lymphocytes and titres of antibodies against measles and diphtheria toxin. We observed no local or systemic reactions to the vaccines in the UV-group while a moderate rise in body temperature occured in several children from unexposed group. In the blood of childeren from UV-group we found increases in CD25+ и HLADR+ cell percentages, IL- 1 beta and IL-10 concentrations, PWMinduced DNA synthesis in mononuclears, and no decreases in formation of antibodies against measles and diphreria. We concluded that suberythemal UV exposures of children modulated their further responses to imminisations perhaps through the activation of a T helper 2-like

  16. Deployment Repeatability

    Science.gov (United States)

    2016-04-01

    controlled to great precision, but in a Cubesat , there may be no attitude determination at all. Such a Cubesat might treat sun angle and tumbling rates as...could be sensitive to small differences in motor controller timing. In these cases, the analyst might choose to model the entire deployment path, with...knowledge of the material damage model or motor controller timing precision. On the other hand, if many repeated and environmentally representative

  17. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    Science.gov (United States)

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  18. Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, R.A.; Albertini, F.; Koch, T.; Ares, C.; Lomax, A.; Goitein, G. [Paul Scherrer Institute PSI, Villigen (Switzerland). Center for Proton Therapy; Vitolo, V. [Fondazione CNAO, Pavia (Italy); Hug, E.B. [Paul Scherrer Institute PSI, Villigen (Switzerland). Center for Proton Therapy; ProCure Proton Therapy Centers, New York, NY (United States)

    2013-12-15

    Purpose: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). Patients and methods: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81 %), sarcomas (16 %) and meningiom (3 %). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. Results: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm{sup 3}. A mean of 93.2 % of the PTV was covered by at least 90 % of the prescribed dose. SB volumes (cm{sup 3}) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5 = 0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of > 70 Gy (RBE), SB received > 50 and > 60 Gy (RBE) in only 61 and 54 % of patients, respectively. Mean SB volumes (cm{sup 3}) covered by different dose levels (Gy, RBE) were: V20 (n = 24): 45.1, V50 (n = 19): 17.7, V60 (n = 17): 7.6 and V70 (n = 12): 2.4. No acute toxicity {>=} grade 2 or late SB sequelae were observed. Conclusion: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology. (orig.)

  19. Thirty Cases of Obsession Treated by Point-Stimulation and with Small Dose of Chlorimipramine

    Institute of Scientific and Technical Information of China (English)

    Feng Bin; Liu Lanying; Xu Fangzhong; Chen Jiong; Wang Peirong; Chen Wensong; Yu Enyan; Chen Zhengqiu

    2007-01-01

    Objective: To investigate the clinical therapeutic effects of point-stimulation for obsession. Methods: Sixty cases of obsession were divided into two groups: a control group of 30 cases treated with chlorimipramine (Ch1), and a treatment group of 30 cases treated by point-stimulation (PS) plus chlorimipramine (PS+Ch1). The therapeutic effects and side-effect were evaluated according to the criteria set in Yale-Brown Obsession Scale (Y-BOCS), Hamilton's depression scale (HAMD), brief psychiatric rating scale (BPRS) and treatment emergent symptom scale (TESS). Results: The cure rate and markedly effective rate were respectively 26.7% and 56.6% in the control group, and 43.3% and 50% in the treatment group, suggesting that the therapeutic effect in the treatment group was better than that in the control group. The incidence of adverse side-effects was 73.33% in the control group and 46.67% in the treatment group, with a significant difference between the two groups (P<0.05). Conclusion:Point-stimulation plus small dose of chlorimipramine was superior to the simple chlorimipramine treatment, indicating that the combined method was more effective and safe for obsession with less side effects.

  20. Estimating Effective Dose from Phantom Dose Measurements in Atrial Fibrillation Ablation Procedures and Comparison of MOSFET and TLD Detectors in a Small Animal Dosimetry Setting

    Science.gov (United States)

    Anderson-Evans, Colin David

    Two different studies will be presented in this work. The first involves the calculation of effective dose from a phantom study which simulates an atrial fibrillation (AF) ablation procedure. The second involves the validation of metal-oxide semiconducting field effect transistors (MOSFET) for small animal dosimetry applications as well as improved characterization of the animal irradiators on Duke University's campus. Atrial Fibrillation is an ever increasing health risk in the United States. The most common type of cardiac arrhythmia, AF is associated with increased mortality and ischemic cerebrovascular events. Managing AF can include, among other treatments, an interventional procedure called catheter ablation. The procedure involves the use of biplane fluoroscopy during which a patient can be exposed to radiation for as much as two hours or more. The deleterious effects of radiation become a concern when dealing with long fluoroscopy times, and because the AF ablation procedure is elective, it makes relating the risks of radiation ever more essential. This study hopes to quantify the risk through the derivation of dose conversion coefficients (DCCs) from the dose-area product (DAP) with the intent that DCCs can be used to provide estimates of effective dose (ED) for typical AF ablation procedures. A bi-plane fluoroscopic and angiographic system was used for the simulated AF ablation procedures. For acquisition of organ dose measurements, 20 diagnostic MOSFET detectors were placed at selected organs in a male anthropomorphic phantom, and these detectors were attached to 4 bias supplies to obtain organ dose readings. The DAP was recorded from the system console and independently validated with an ionization chamber and radiochromic film. Bi-plane fluoroscopy was performed on the phantom for 10 minutes to acquire the dose rate for each organ, and the average clinical procedure time was multiplied by each organ dose rate to obtain individual organ doses. The

  1. A randomised controlled trial evaluating IGF1 titration in contrast to current GH dosing strategies in children born small for gestational age

    DEFF Research Database (Denmark)

    Jensen, Rikke Beck; Thankamony, Ajay; O'Connell, Susan M

    2014-01-01

    BACKGROUND: Short children born small for gestational age (SGA) are treated with a GH dose based on body size, but treatment may lead to high levels of IGF1. The objective was to evaluate IGF1 titration of GH dose in contrast to current dosing strategies. METHODS: In the North European Small-for-...

  2. Optimizing Collimator Margins for Isotoxically Dose-Escalated Conformal Radiation Therapy of Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Panettieri, Vanessa [William Buckland Radiotherapy Centre, Alfred Hospital, Commercial Road, Melbourne (Australia); Panakis, Niki; Bates, Nicholas [Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Lester, Jason F. [Velindre Cancer Centre, Velindre Road, Whitchurch, Cardiff (United Kingdom); Jain, Pooja [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Landau, David B. [Department of Radiotherapy, Guy' s and St. Thomas' NHS Foundation Trust, London (United Kingdom); Nahum, Alan E.; Mayles, W. Philip M. [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Fenwick, John D. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom)

    2014-04-01

    Purpose: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. Methods and Materials: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D{sub 99}) delivered to 99% of the planning target volume (PTV) was determined. Results: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D{sub 99}, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). Conclusions: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

  3. Concentration of metallothionein in mice livers after a small dose of irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Saitou, Mikio; Yanai, Takanori; Hasegawa, Hidenao; Otsu, Hiroshi; Sato, Fumiaki [Inst. for Environmental Sciences, Rokkasho, Aomori (Japan); Akata, Naofumi; Kanaiwa-Kudo, Shouko; Matsumoto, Tsuneya; Noda, Yuko

    1998-12-01

    This study was made to determine whether metallothionein (MT) is induced by a small dose (0.5 Gy) irradiation. One hundred B6C3F1/Nrs mice of each sex, 8-10 weeks old, were used in the sham study (unirradiated controls) and experimental (irradiated) groups. Eighty mice of each sex were given acute whole body irradiation with {sup 197}Cs{gamma}-rays under SPF conditions; two doses of 0.5 and 5.0 Gy at 30 cm distance from the source at the rate of 0.563 Gy/min. Twenty mice of each sex were used in the sham study. Every ten male and female mouse was killed by cervical dislocation on days 1, 7, 14 and 21 after irradiation. The same numbers of male and female control mice were killed on days 0 and 21. Livers were removed immediately after death, and concentration of MT was examined. In both the males and females, the MT concentration of the 5 Gy-group peaked on the first day after irradiation, and there was no difference in comparison with the control values between the 7th and 21st days. In contrast, on no day did the MT concentration for the 0.5 Gy-group showed a significant difference from the control group. The time dependency patterns of the female and male mice also showed no significant differences for 5 Gy- and 0.5 Gy-groups, but the mean values of the MT concentration was lower in the males than in the females on the 1st day. Results of the direct quantitation of MT by the enzyme-linked immunoabsorbent assay (ELISA) also showed peak MT accumulation on the 1st day for both male and female mice. These were also shown by the atomic absorption spectrometry (AAS) and the inductively coupled plasma mass spectrometry (ICP-MS) analyses. But peak heights for the males and females showed a tendency inverse to that of the AAS and ICP-MS analyses. This discrepancy is attributable to the technical problem encountered in the experiment. On the basis of our findings, MT does not seem to be related to acquired radioresistance in mice. (K.H.)

  4. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex

    NARCIS (Netherlands)

    Eleveld, Douglas J.; Kuizenga, Karel; Proost, Johannes H.; Wierda, J. Mark K. H.

    BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was > 0.9, and the

  5. An approach for online evaluations of dose consequences caused by small rotational setup errors in intracranial stereotactic radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lu Bo; Li, Jonathan; Kahler, Darren; Yan Guanghua; Mittauer, Kathryn; Shi Wenyin; Okunieff, Paul; Liu, Chihray [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida 32607 (United States)

    2011-11-15

    Purpose: The purpose of this work is to investigate the impact of small rotational errors on the magnitudes and distributions of spatial dose variations for intracranial stereotactic radiotherapy (SRT) treatment setups, and to assess the feasibility of using the original dose map overlaid with rotated contours (ODMORC) method as a fast, online evaluation tool to estimate dose changes (using DVHs) to clinical target volumes (CTVs) and organs-at-risks (OARs) caused by small rotational setup errors. Methods: Fifteen intracranial SRT cases treated with either three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) techniques were chosen for the study. Selected cases have a variety of anatomical dimensions and pathologies. Angles of {+-}3 deg. and {+-}5 deg. in all directions were selected to simulate the rotational errors. Dose variations in different regions of the brain, CTVs, and OARs were evaluated to illustrate the various spatial effects of dose differences before and after rotations. DVHs accounting for rotations that were recomputed by the treatment planning system (TPS) and those generated by the ODMORC method were compared. A framework of a fast algorithm for multicontour rotation implemented by ODMORC is introduced as well. Results: The average values of relative dose variations between original dose and recomputed dose accounting for rotations were greater than 4.0% and 10.0% in absolute mean and in standard deviation, respectively, at the skull and adjacent regions for all cases. They were less than 1.0% and 2.5% in absolute mean and in standard deviation, respectively, for dose points 3 mm away from the skull. The results indicated that spatial dose to any part of the brain organs or tumors separated from the skull or head surface would be relatively stable before and after rotations. Statistical data of CTVs and OARs indicate the lens and cochleas have the large dose variations before and after rotations

  6. New observations on chronic intoxication by very small doses of sodium fluosilicate

    Energy Technology Data Exchange (ETDEWEB)

    Cristiani, H.; Chausse, P.

    1927-01-01

    It was determined that daily doses of approximately 0.1 of the lethal dose of sodium fluoride produced a fluoric cachexia in guinea pigs which caused the death of the animals in 2 or 3 months. Animals which were given 0.02 of the lethal dose of sodium fluoride were apparently in good health for a period of 10 months. However, after two or three years cachexia was likely to appear.

  7. Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management.

    Science.gov (United States)

    Dambach, Donna M; Simpson, Natalie E; Jones, Thomas W; Brennan, Richard J; Pazdur, Richard; Palmby, Todd R

    2016-06-01

    Multidisciplinary approaches that incorporate nonclinical pharmacologic and toxicologic characterization of small-molecule oncology drugs into clinical development programs may facilitate improved benefit-risk profiles and clinical toxicity management in patients. The performance of the current nonclinical safety-testing scheme was discussed, highlighting current strengths and areas for improvement. While current nonclinical testing appears to predict the clinical outcome where the prevalence of specific adverse effects are high, nonclinical testing becomes less reliable for predicting clinical adverse effects that occur infrequently, as with some kinase inhibitors. Although adverse effects associated with kinase inhibitors can often be predicted on the basis of target biology, drugs can be promiscuous and inhibit targets with poorly defined function and associated risks. Improvements in adverse effect databases and better characterization of the biologic activities of drug targets may enable better use of computational modeling approaches in predicting adverse effects with kinase inhibitors. Assessing safety of a lead candidate in parallel with other drug properties enables incorporation of a molecule's best features during chemical design, eliminates the worst molecules early, and permits timely investigation/characterization of toxicity mechanisms for identified liabilities. A safety lead optimization and candidate identification strategy that reduces intrinsic toxicity and metabolic risk and enhances selectivity can deliver selective kinase inhibitors that demonstrate on-target adverse effects identified nonclinically. Integrating clinical and nonclinical data during drug development can facilitate better identification and management of oncology drugs. Follow-up nonclinical studies may be used to better understand the risks in a given patient population and minimize or manage these risks more appropriately. Clin Cancer Res; 22(11); 2618-22. ©2016 AACR SEE ALL

  8. Small doses from artificial UV sources elucidate the photo-production of vitamin D.

    Science.gov (United States)

    McKenzie, Richard; Liley, Ben; Johnston, Paul; Scragg, Robert; Stewart, Alistair; Reeder, Anthony I; Allen, Martin W

    2013-09-01

    To clarify the relation between UV exposure and vitamin D status, 201 volunteers wore personal electronic UV dosimeters during daylight hours, to record their UV exposure over a 10 week period when ambient UV levels were significantly less than the summer maxima. Blood samples to determine serum 25-hydroxyvitamin D3 [25(OH)D3] levels were taken at the end of week 4 and week 8. Participants were then given a single full-body exposure of approximately 2 SED from one of four artificial UV sources with different spectral outputs and a further blood sample taken at study completion, nominally week 10. The artificial UV exposure reversed the mean seasonal decline in 25(OH)D3. Increases in 25(OH)D3 from week 8 to week 10 were related to total UV exposure, including the ambient sun exposures. These exposures were weighted by the erythemal action spectrum and separately for three different action spectra for pre-vitamin D production. For the erythema weighting function, 25(OH)D3 increased 1.78 ± 0.25 nmol per litre per SED, a value consistent with other studies. Any differences due to age, BMI, gender, and skin reflectance were not statistically significant. Ethnicity differences were the only significant factor, with Asians producing the least vitamin D, and Maori the most. There was no statistically significant improvement in consistency between sources for any of the three pre-vitamin weightings compared with that for erythema. Further work is needed to verify which vitamin D action spectrum is most appropriate. Nevertheless, these small doses of UV from artificial sources were helpful in quantifying the relationship between UV exposure and vitamin D status among the New Zealand population.

  9. Dosimetric Feasibility of Dose Escalation Using SBRT Boost for Stage III Non-Small Cell Lung Cancer

    Science.gov (United States)

    Hepel, Jaroslaw T.; Peter, Justin; Hiatt, Jessica R.; Patel, Salil; Osibanjo, Oluwademilade; Safran, Howard; Curran, Bruce; DiPetrillo, Thomas

    2012-01-01

    Purpose: Standard chemoradiation therapy for stage III non-small cell lung cancer (NSCLCa) results in suboptimal outcomes with a high rate of local failure and poor overall survival. We hypothesize that dose escalation using stereotactic body radiotherapy (SBRT) boost could improve upon these results. We present here a study evaluating the dosimetric feasibility of such an approach. Methods: Anonymized CT data sets from five randomly selected patients with stage III NSCLCa undergoing definitive chemoradiation therapy in our department with disease volumes appropriate for SBRT boost were selected. Three-dimensional conformal radiation therapy (3D-CRT) plans to 50.4 Gy in 28 fractions were generated follow by SBRT plans to two dose levels, 16 Gy in two fractions and 28 Gy in two fractions. SBRT plans and total composite (3D-CRT and SBRT) were optimized and evaluated for target coverage and dose to critical structures; lung, esophagus, cord, and heart. Results: All five plans met predetermined target coverage and normal tissue dose constraints. PTV V95 was equal to or greater than 95% in all cases. The cumulative lung V20 and V5 of the combined 3D-CRT and SBRT plans were less than or equal to 30 and 55%, respectively. The 5 cc esophageal dose was less than 12 Gy for all low and high dose SBRT plans. The cumulative dose to the esophagus was also acceptable with less than 10% of the esophagus receiving doses in excess of 50 Gy. The cumulative spinal cord dose was less than 33 Gy and heart V25 was less than 5%. Conclusion: The combination of chemoradiation to 50.4 Gy followed by SBRT boost to gross disease at the primary tumor and involved regional lymph nodes is feasible with respect to normal tissue dose constraints in this dosimetric pilot study. A phase I/II trial to evaluate the clinical safety and efficacy of this approach is being undertaken. PMID:23057009

  10. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  11. Effects of repeated high-dose methamphetamine and ceftriaxone post-treatments on tissue content of dopamine and serotonin as well as glutamate and glutamine.

    Science.gov (United States)

    Althobaiti, Yusuf S; Almalki, Atiah H; Das, Sujan C; Alshehri, Fahad S; Sari, Youssef

    2016-11-10

    Repeated exposure to high doses of methamphetamine (METH) is known to alter several neurotransmitters in certain brain regions. Little is known about the effects of ceftriaxone (CEF), a β-lactam antibiotic, known to upregulate glutamate transporter subtype 1, post-treatment on METH-induced depletion of dopamine and serotonin (5-HT) tissue content in brain reward regions. Moreover, the effects of METH and CEF post-treatment on glutamate and glutamine tissue content are not well understood. In this study, Wistar rats were used to investigate the effects of METH and CEF post-treatment on tissue content of dopamine/5-HT and glutamate/glutamine in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats received either saline or METH (10mg/kg, i.p. every 2h×4) followed by either saline or CEF (200mg/kg, i.p, every day×3) post-treatment. METH induced a significant depletion of dopamine and 5-HT in the NAc and PFC. Importantly, dopamine tissue content was completely restored in the NAc following CEF post-treatment. Additionally, METH caused a significant decrease in glutamate and glutamine tissue content in PFC, and this effect was attenuated by CEF post-treatment. These findings demonstrate for the first time the attenuating effects of CEF post-treatment on METH induced alterations in the tissue contents of dopamine, glutamate, and glutamine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  13. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    Science.gov (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  14. 氟氯氰菊酯亚急性吸入毒性实验研究%Inhalation toxicity of cyfluthrin for 28-day repeated dose in rats

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民

    2012-01-01

    Objective To determine the inhalation toxicity and find the non -observed adverse effect level (NOAEL) of cyfluthrin for a 28-day repeated dose in rats. Methods Clean-grade SD rats were randomly divided into 5 groups with 5 females and 5 males in each. The animals inhaled DMSO or cyfluthrin at the concentration of 0, 7. 81 , 9. 05 and 18. 98 mg/m for 4 weeks (6 h/d, 5 d/w). At the end of inhalation , all the animals were kindly sacrificed. Their organs were collected for histopathological examination . Blood samples were collected for analysis of complete blood count , biochemistry and coagulation. Results The animals in 18. 98 mg/m3 group were found scratching repeatedly around the mouth, listless, fidgeting, trembling, discharging blood around the mouth and nose . However, symptoms in females were less serious than in males. Furthermore , the body mass , feed efficiency , weight of kidney of animals in this dose male group were found decreased compared with the control group . Biochemistry detection revealed that serum AST was elevated markedly in both genders of 18. 98 mg/m3 group and in males of 9. 05 mg/m3 group. No obvious abnormity was found in 7.81 mg/m3 group or control group. Conclusion Based on the results above, the non-observed adverse effect level (NOAEL) of cyfluthrin in SD rats is 7. 81 mg/m3 for 28 d repeated inhalation in this study.%目的 观察氟氯氰菊酯染毒大鼠亚急性吸入毒性.方法 7周龄清洁级SD大鼠随机分成5组,每组雌雄各5只,分别吸入氟氯氰菊酯0,7.81,9.05,18.98 mg/m3及溶剂二甲亚砜,每天6 h,每周5 d,共28 d.实验结束时取血液做常规生化指标、血细胞指标、血凝学指标检测.取心、肝、脾等8种主要脏器称重并做病理组织学检查.结果 18.98 mg/m3组动物在染毒中呈现反复抓挠口周、烦躁不安、鼻有血性分泌物、颤抖,染毒结束后呈现萎靡、蜂腰、四肢无力的体征.雌性动物的毒性表现较雄性低.与溶剂对照组相

  15. Percentage depth dose distributions in inhomogeneous phantoms with lung and bone equivalent media for small fields of CyberKnife

    CERN Document Server

    Lee, Chung Il; Yoon, Sei-Chul; Suh, Tae Suk; Hong, Seung-Woo; Min, Kyung Joo; Lee, Sang Deok; Chung, Su Mi; Jung, Jae-Yong

    2014-01-01

    The percentage depth dose distributions in inhomogeneous phantoms with lung and bone equivalent media are studied. For lung equivalent media a Balsa wood is used, and for a soft bone equivalent media a compound material with epoxy resin, hardener and calcium carbonate is used. Polystyrene slabs put together with these materials are used as an inhomogeneous phantom. Dose measurements are performed with Gafchromic EBT film by using photon beams from 6MV CyberKnife at the Seoul Uridul Hospital. The cone sizes of the photon beams are varied from 5, 10 to 30 mm. As a simulation tool GEANT4 Monte Carlo code v9.4.p02 is used. When the Balsa wood is inserted in the phantom, the dose measured with EBT film is found to be significantly different from the dose without the EBT film in and beyond the Balsa wood region, particularly for small field sizes. On the other hand, when the soft bone equivalent material is inserted in the phantom, discrepancy between the dose measured with EBT film and the dose without EBT film ca...

  16. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial

    Directory of Open Access Journals (Sweden)

    Barry Aichatou

    2011-08-01

    Full Text Available Abstract Background The use of artemisinin-based combination therapy (ACT is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT - artesunate plus amodiaquine (ASAQ and artemether-lumefantrine (AL - in subsequent episodes of Plasmodium falciparum malaria. Methods A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR after polymerase chain reaction (PCR correction on day 28 for the first episode. Results A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182 and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182, PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03. No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during

  17. IMRT and IMRS Checking the Dose Distribution in the Small Field Evaluation of Measurement by Changes in SAD

    Energy Technology Data Exchange (ETDEWEB)

    Ko, Seung Young; Kim, Sung Joon; Park, Gir Yong; Son, Mi Suk; Lee, Nam Ki; Kim, Jin Soo [Dept. of Radiation Oncology, CHA Bundang medical Center, Seongnam (Korea, Republic of)

    2010-03-15

    It is very important to confirm conformance of dose distribution that is formed with treatment planning from IMRS or IMRT. It has been a problem dropped accuracy and conformance when the field size is getting smaller because of character of the 2D ion chamber. Verification of MatriXX Phantom dose distribution with a change in the SAD. Dose distribution measurement and analysis to improve the accuracy and should be useful to evaluate the award. A use of Novalis linear accelerator 6 MV photon beams. In general, IMRS were 25 patients with small field size. The selected patients were divided into three groups on the basis of the field size. SAD was changed from 80 to 130 cm and field size to determine the dose distribution to the change, each dose was measured using MatriXX Phantom. Analysis of measured values obtained from the program for each patient through the treatment planning system comparison and analysis of the dose distribution and gamma values were expressed. SAD 80, 100, and 120 cm in size in the gamma value to the investigation of patients less than 3 cm{sup 2} average 0.939, 0.969, and 0.979, respectively. Patients with more than 5 cm{sup 2} 0.962, 0.983, and 0.988, respectively. 5 cm{sup 2} or more patients 0.982, 0.990, and 0.992, respectively. The error rate of less than 3 cm{sup 2} field size is increased rapidly. If the field size is increased, resolution is increased by 2D ion chambers. It has been approved that it can be credible if it is around 3 cm{sup 2} when measuring dose distribution using MatriXX. Adjusting geometric field size by changing SAD is likely to be very useful when you measure dose distribution using MatriXX.

  18. Using Generalized Equivalent Uniform Dose Atlases to Combine and Analyze Prospective Dosimetric and Radiation Pneumonitis Data From 2 Non-Small Cell Lung Cancer Dose Escalation Protocols

    Energy Technology Data Exchange (ETDEWEB)

    Liu Fan; Yorke, Ellen D. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Belderbos, Jose S.A.; Borst, Gerben R. [The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam (Netherlands); Rosenzweig, Kenneth E. [Mount Sinai School of Medicine, New York, New York (United States); Lebesque, Joos V. [The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam (Netherlands); Jackson, Andrew, E-mail: jacksona@mskcc.org [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-01-01

    Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate {>=}20% were plotted. Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.

  19. Comparison of gonadal radiation doses from CT enterography and small-bowel follow-through in pediatric patients.

    Science.gov (United States)

    Reid, Janet R; Pozzuto, Jessica; Morrison, Stuart; Obuchowski, Nancy; Davros, William

    2015-03-01

    OBJECTIVE. CT enterography is superior to small-bowel follow-through (SBFT) for diagnosis of inflammatory bowel disease (IBD). It is widely assumed that the radiation dose from CT enterography is greater than that from SBFT in the pediatric patient. This study was designed to compare gonadal doses from CT enterography and SBFT to verify the best imaging choice for IBD evaluation in children. This study also challenges the assumption that CT enterography imparts a higher radiation dose through comparison of calculated radiation doses from CT enterography and SBFT. MATERIALS AND METHODS. Patients 0-18 years old who underwent either CT enterography or SBFT over a 2-year period were included. The CT enterography group consisted of 39 boys and 51 girls, whereas the SBFT group consisted of 89 boys and 113 girls. CT enterography was performed at 120 kVp and approximately 132 mAs (range, 54-330 mAs) using weight-based protocols. SBFT used automated control of kilovoltage and tube current-exposure time product. Patient demographics and technical parameters were collected for CT enterography and SBFT, data were cross-paired between CT enterography and SBFT, and gonadal dose was calculated. RESULTS. Mean (± SD) CT enterography testis and ovarian doses were 0.93 ± 0.3 cGy (n = 39) and 0.64 ± 0.2 cGy (n = 51), respectively. Mean SBFT testis and ovarian doses were 2.3 ± 1.6 cGy (n = 89) and 1.49 ± 0.3 cGy (n = 113), respectively. Mean fluoroscopy time for SBFT was 2.6 ± 2 minutes. Gonadal dose for CT enterography was significantly lower than that for SBFT in boys and girls (p enterography dose was higher in boys than girls (p enterography was lower than that for SBFT for boys and girls of all sizes and age. Controlled exposure time made CT enterography dose more consistent, whereas the range of dose for SBFT was highly operator dependent and related to extent of disease. Thus, for IBD, CT enterography is preferred over SBFT for all children.

  20. Low-dose ouabain constricts small arteries from ouabain-hypertensive rats: implications for sustained elevation of vascular resistance

    OpenAIRE

    Zhang, Jin; Hamlyn, John M.; Karashima, Eiji; Raina, Hema; Mauban, Joseph R. H.; Izuka, Michelle; Berra-Romani, Roberto; Zulian, Alessandra; Wier, W. Gil; Blaustein, Mordecai P.

    2009-01-01

    Prolonged ouabain administration to normal rats causes sustained blood pressure (BP) elevation. This ouabain-induced hypertension (OH) has been attributed, in part, to the narrowing of third-order resistance arteries (∼320 μm internal diameter) as a result of collagen deposition in the artery media (see Ref. 6). Here we describe the structural and functional properties of fourth-order mesenteric small arteries from control and OH rats, including the effect of low-dose ouabain on myogenic tone...

  1. Organellar genome, nuclear ribosomal DNA repeat unit, and microsatellites isolated from a small-scale of 454 GS FLX sequencing on two mosses.

    Science.gov (United States)

    Liu, Yang; Forrest, Laura L; Bainard, Jillian D; Budke, Jessica M; Goffinet, Bernard

    2013-03-01

    Recent innovations in high-throughput DNA sequencing methodology (next generation sequencing technologies [NGS]) allow for the generation of large amounts of high quality data that may be particularly critical for resolving ambiguous relationships such as those resulting from rapid radiations. Application of NGS technology to bryology is limited to assembling entire nuclear or organellar genomes of selected exemplars of major lineages (e.g., classes). Here we outline how organellar genomes and the entire nuclear ribosomal DNA repeat can be obtained from minimal amounts of moss tissue via small-scale 454 GS FLX sequencing. We sampled two Funariaceae species, Funaria hygrometrica and Entosthodon obtusus, and assembled nearly complete organellar genomes and the whole nuclear ribosomal DNA repeat unit (18S-ITS1-5.8S-ITS2-26S-IGS1-5S-IGS2) for both taxa. Sequence data from these species were compared to sequences from another Funariaceae species, Physcomitrella patens, revealing low overall degrees of divergence of the organellar genomes and nrDNA genes with substitutions spread rather evenly across their length, and high divergence within the external spacers of the nrDNA repeat. Furthermore, we detected numerous microsatellites among the 454 assemblies. This study demonstrates that NGS methodology can be applied to mosses to target large genomic regions and identify microsatellites.

  2. THE ONE CINETIC MODEL DAMAGE OF CELL BY SMALL DOSES OF RADIATION

    Directory of Open Access Journals (Sweden)

    A. T. Gubin

    2015-01-01

    Full Text Available To explain the known differences in the dose and age dependences of radiogenic mortality from leukemia and solid tumors after single exposure, a model was developed, which is a modification of the Kellerer-Rossi theory of dual radiation action. The model assumes formation in a cell of both single and double primary damages due to radiation and other carcinogens, while the recovery rate of single damages (φ significantly exceeds that for double ones (ψ. Upon achieving a certain stage of the cell cycle (the critical age of cell – T, double damages become permanent and with probability of А can be inherited to daughter cells as “premalignant” defects. In contrast, in the Kellerer-Rossi theory, permanent damage is formed immediately after formation of the second damage at the next energy absorption event in the cell, i.e. ψ=0 .On the assumption that the premalignant defects only occur based on the double primary damages, i.e. φ>>ψ, the expressions for А were derived for the prompt radiation exposure and radiation exposure at a constant dose rate. They reproduce the effect increasing with decreasing of T, whereas the influence of T on the linear term of the dose expression in both cases is the same, but with decreasing of T the quadratic term increases faster for exposure at a constant dose rate than that for the prompt one. Thus, presence of the quadratic term in the dose expression for leukemia and its virtual complete absence for solid tumors may be due to lower T-value for hemopoietic stem cells. Predicted by the model dose rate influence on the quadratic term does not depend on the dose, so the reduction factor should be only applied to the quadratic term of the dose expression. This follows as well from the original version of the Kellerer-Rossi theory.

  3. A Monte Carlo approach to lung dose calculation in small fields used in intensity modulated radiation therapy and stereotactic body radiation therapy

    Directory of Open Access Journals (Sweden)

    Asghar Mesbahi

    2014-01-01

    Conclusion: Our study showed that the dose reduction with small fields in the lung was very enormous. Thus, inaccurate prediction of absorbed dose inside lung and also lung soft-tissue interfaces with small photon beams may lead to critical consequences for treatment outcome.

  4. Seismic activities of earthquake clusters and small repeating earthquakes in Japan before and after the 2011 off the Pacific coast of Tohoku earthquake

    Science.gov (United States)

    Igarashi, T.

    2011-12-01

    The 2011 off the Pacific coast of Tohoku earthquake (M9.0) had a great effect on seismic activities over vast areas. In this study, we investigated spatio-temporal changes of seismic activities of earthquake clusters and small repeating earthquakes before and after the main shock. We have already reported many small repeating earthquakes occur at the upper boundary of the subducting plates in Japan. From these sequences, we can estimate the space-time characteristics of the inter-plate slip. In the 21st century, the resultant slip-rates correspond to relative plate motion in the Ryukyu-arc. In contrast, the shallow part and the southern part of the northeastern Japan arc indicated slip deficits. There were few after-slips following the 2005 off Miyagi earthquake (M7.2), which located near the hypocenter of the 2011 main shock. On the other hand, slip deficits of the southern shallow part were slightly decreased by after-slips following the 2003 and 2008 M7 class earthquakes. We also identified quasi-static slips associated with foreshocks off Miyagi that started from February 2011. After the main shock, we detect many small repeating earthquakes in the aftershocks. The distributions suggest after-slips near the trench of the southeastern part as well as in the deep part of the source region estimated by GPS data analysis. However, some of them are burst-type repeating sequences which occurred only after the main shock. Many continual-type repeating sequences are distributed in the southern part of the source region, and it is difficult to estimate slip-rates in the northern part at present. This uneven distribution may have been caused because observed seismograms are distorted by the multiplicity of the waves to come from various locations, the seismic velocity changes at the propagation path or site, or changes of physical properties at the plate interface. Furthermore, we automatically extracted earthquake clusters by using the unified JMA hypocenter catalogue

  5. Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease

    Directory of Open Access Journals (Sweden)

    Lähdeaho Marja-Leena

    2011-11-01

    Full Text Available Abstract Background Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient. We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. Methods Twenty-five celiac disease adults were challenged with low (1-3 g or moderate (3-5g doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs and celiac serology were determined. Results Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. Conclusions Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.

  6. Entrance surface dose measurements using a small OSL dosimeter with a computed tomography scanner having 320 rows of detectors.

    Science.gov (United States)

    Takegami, Kazuki; Hayashi, Hiroaki; Yamada, Kenji; Mihara, Yoshiki; Kimoto, Natsumi; Kanazawa, Yuki; Higashino, Kousaku; Yamashita, Kazuta; Hayashi, Fumio; Okazaki, Tohru; Hashizume, Takuya; Kobayashi, Ikuo

    2017-03-01

    Entrance surface dose (ESD) measurements are important in X-ray computed tomography (CT) for examination, but in clinical settings it is difficult to measure ESDs because of a lack of suitable dosimeters. We focus on the capability of a small optically stimulated luminescence (OSL) dosimeter. The aim of this study is to propose a practical method for using an OSL dosimeter to measure the ESD when performing a CT examination. The small OSL dosimeter has an outer width of 10 mm; it is assumed that a partial dose may be measured because the slice thickness and helical pitch can be set to various values. To verify our method, we used a CT scanner having 320 rows of detectors and checked the consistencies of the ESDs measured using OSL dosimeters by comparing them with those measured using Gafchromic™ films. The films were calibrated using an ionization chamber on the basis of half-value layer estimation. On the other hand, the OSL dosimeter was appropriately calibrated using a practical calibration curve previously proposed by our group. The ESDs measured using the OSL dosimeters were in good agreement with the reference ESDs from the Gafchromic™ films. Using these data, we also estimated the uncertainty of ESDs measured with small OSL dosimeters. We concluded that a small OSL dosimeter can be considered suitable for measuring the ESD with an uncertainty of 30 % during CT examinations in which pitch factors below 1.000 are applied.

  7. Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease

    Science.gov (United States)

    2011-01-01

    Background Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient. We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. Methods Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined. Results Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. Conclusions Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis. PMID:22115041

  8. Cyclophosphamide-induced lung damage in mice: protection by a small preliminary dose.

    Science.gov (United States)

    Collis, C. H.; Wilson, C. M.; Jones, J. M.

    1980-01-01

    Cycylphosphamide (Cy) produces an interstitial pneumonitis in CBA mice. The extent of the lung damage has been quantified by measuring the increase in ventilation rate over 6 weeks after an i.p. injection of Cy 200, 250 and 300 mg/kg. A dose-dependent response was found. When a preliminary ("priming") dose of Cy at 50 mg/kg was given 7, 9 or 14 days before a single large dose of 250 mg/kg, lung damage was reduced, as shown by a smaller increase in ventilation rate than in those receiving 250 mg/kg alone, and this difference was significant (P less than 0.01) in the Day-14-and highly significant (P<0.001) in the Day-7-"primed" groups. When primed less than 7 days before, there was a relative increase in ventilation rate, which was statistically significant (P less than 0.01) in the Day-1-primed group. Similar effects were also seen in the survival of the mice. PMID:7426315

  9. Dose-related carcinogenic effects of water-borne benzo(a)pyrene on livers of two small fish species

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, W.E.; Walker, W.W.; Overstreet, R.M.; Lytle, T.F.; Lytle, J.S.

    1988-12-01

    Benzo(a)pyrene (BaP) administered by water-borne exposures caused dose-related carcinogenic effects in livers of two small fish species, the Japanese medaka (Oryzias latipes) and the guppy (Poecilia reticulata). Medaka and guppies each were given two 6-h exposures. The first exposure was conducted on 6- to 10-day-old specimens. The second exposure was given 7 days later. The tests incorporated five treatment groups: (1) control, (2) carrier (dimethylformamide) control, (3) low BaP dose (not detectable--4 ppb), (4) intermediate BaP dose (about 8-47 ppb BaP), and (5) high BaP dose (200-270 ppb). Following the high-dose exposure, hepatocellular lesions classified as foci of cellular alteration (altered foci), adenomas, and hepatocellular carcinomas occurred in both species. In medaka, the lesions appeared to develop sequentially with the appearance of altered foci followed by adenomas and then hepatocellular carcinomas. Most lesions in guppies, however, were classified as altered foci although a few adenomas occurred in the early (24-week) sample and hepatocellular carcinomas occurred in the late (52-week) sample. When total lesions were combined, medaka had an 11% incidence at 24 weeks after the initial exposure and 36% incidence at 36 weeks. In guppies, 8% had liver lesions at 24 weeks, 19% at 36 weeks, and 20% at 52 weeks. A single extrahepatic neoplasm, a capillary hemangioma in a gill filament, occurred in a medaka from the 36-week high-dose sample. The results suggest that the medaka and guppy are capable of metabolizing water-borne BaP to carcinogenic metabolites which initiate hepatic tumor development.

  10. Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, Daniel R., E-mail: dgomez@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gillin, Michael [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liao, Zhongxing [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wei, Caimiao [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Lin, Steven H.; Swanick, Cameron; Alvarado, Tina; Komaki, Ritsuko; Cox, James D.; Chang, Joe Y. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-07-15

    Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

  11. Effect of small-dose levosimendan on mortality rates and organ functions in Chinese elderly patients with sepsis

    Directory of Open Access Journals (Sweden)

    Wang X

    2017-05-01

    Full Text Available Xin Wang,1,* Shikui Li2,* 1Intensive Care Unit, 2Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Aim: As a primary cause of death not only in Western countries but also in the People’s Republic of China, sepsis is diagnosed as abnormal organ functions as a result of a disordered response to a severe infection. This study was designed to assess the effect of small-dose levosimendan without a loading dose on mortality rates and organ functions in Chinese elderly patients with sepsis.Methods: Following a prospective, randomized, and double-blinded design, 240 Chinese elderly patients with sepsis shock were admitted to the intensive care unit (ICU. All patients were randomly and evenly assigned into a levosimendan group (number of patients =120 and a control group (number of patients =120. The control group underwent standard care, and the levosimendan group was administered levosimendan in addition to standard care.Results: All participants, comprising 134 males (55.8% and 106 females (44.2%, were 70 (67–73 years old. Baseline characteristics, preexisting illnesses, initial infections, organ failures, and additional agents and therapies showed no significant difference between the two groups (P>0.05 for all. There were no significant differences in mortality rates at 28 days, at ICU discharge, and at hospital discharge between the two groups (P>0.05 for all. The number of days of ICU and hospital stay in the levosimendan group was significantly less than for those in the control group (P<0.05 for all. Mean daily total sequential organ failure assessment score and all organ scores except the cardiovascular scores showed no significant difference between the two groups (P>0.05 for all. Cardiovascular scores in the levosimendan group were significantly higher than those in the control group (P<0.05 for all.Conclusion: Small-dose

  12. Strategies of dose escalation in the treatment of locally advanced non-small cell lung cancer: image guidance and beyond

    Directory of Open Access Journals (Sweden)

    Alexander eChi

    2014-06-01

    Full Text Available Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG-PET incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

  13. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  14. Prognostic significance of telomeric repeat length alterations in pathological stage I-IIIA non-small cell lung cancer.

    Science.gov (United States)

    Hirashima, T; Komiya, T; Nitta, T; Takada, Y; Kobayashi, M; Masuda, N; Matui, K; Takada, M; Kikui, M; Yasumitu, T; Ohno, A; Nakagawa, K; Fukuoka, M; Kawase, I

    2000-01-01

    This study was performed to evaluate the prognostic significance of alteration in telomere length in pathological stage (p-stage) I-IIIA non-small cell lung cancer (NSCLC). Paired cancer and normal lung tissues were obtained from 72 patients with histologically confirmed p-stage I-IIIA NSCLC. Terminal restriction fragment (TRF) length, which indicates telomere length, was measured by Southern blot analysis. Tumor telomerase activity was also assayed by non-radioactive PCR-ELISA in 55 patients. TRF length (mean +/- SD) in normal tissue was 6.2 +/- 1.1 Kb. Therefore, upper and lower limits of normal range in TRF length was set at 8.4 (mean + 2SD) Kb and 4.0 (mean-2SD) Kb, respectively. A tumor showing TRF length over normal range was defined as positive for the alteration. In 72 patients, 25 (34.7%) with alteration in TRF length had significantly shorter survival durations than those of the others. Telomerase activity did not correlate with survival duration. In multivariate analysis, alteration in TRF length (P = 0.0033) was second to p-stage (P = 0.0004) in importance among the various parameters.

  15. Small irregular pulmonary nodules in low-dose CT : observer detection sensitivity and volumetry accuracy

    NARCIS (Netherlands)

    Xie, Xueqian; Willemink, Martin J.; de Jong, Pim A.; van Ooijen, Peter M. A.; Oudkerk, Matthijs; Vliegenthart, Rozemarijn; Greuter, Marcel J. W.

    2014-01-01

    OBJECTIVE: The purpose of this study is to evaluate observer detection and volume measurement of small irregular solid artificial pulmonary nodules on 64-MDCT in an anthropomorphic thoracic phantom. MATERIALS AND METHODS: Forty in-house-made solid pulmonary nodules (lobulated and spiculated; actual

  16. Detecting small-scale spatial heterogeneity and temporal dynamics of soil organic carbon (SOC) stocks: a comparison between automatic chamber-derived C budgets and repeated soil inventories

    Science.gov (United States)

    Hoffmann, Mathias; Jurisch, Nicole; Garcia Alba, Juana; Albiac Borraz, Elisa; Schmidt, Marten; Huth, Vytas; Rogasik, Helmut; Rieckh, Helene; Verch, Gernot; Sommer, Michael; Augustin, Jürgen

    2017-03-01

    Carbon (C) sequestration in soils plays a key role in the global C cycle. It is therefore crucial to adequately monitor dynamics in soil organic carbon (ΔSOC) stocks when aiming to reveal underlying processes and potential drivers. However, small-scale spatial (10-30 m) and temporal changes in SOC stocks, particularly pronounced in arable lands, are hard to assess. The main reasons for this are limitations of the well-established methods. On the one hand, repeated soil inventories, often used in long-term field trials, reveal spatial patterns and trends in ΔSOC but require a longer observation period and a sufficient number of repetitions. On the other hand, eddy covariance measurements of C fluxes towards a complete C budget of the soil-plant-atmosphere system may help to obtain temporal ΔSOC patterns but lack small-scale spatial resolution. To overcome these limitations, this study presents a reliable method to detect both short-term temporal dynamics as well as small-scale spatial differences of ΔSOC using measurements of the net ecosystem carbon balance (NECB) as a proxy. To estimate the NECB, a combination of automatic chamber (AC) measurements of CO2 exchange and empirically modeled aboveground biomass development (NPPshoot) were used. To verify our method, results were compared with ΔSOC observed by soil resampling. Soil resampling and AC measurements were performed from 2010 to 2014 at a colluvial depression located in the hummocky ground moraine landscape of northeastern Germany. The measurement site is characterized by a variable groundwater level (GWL) and pronounced small-scale spatial heterogeneity regarding SOC and nitrogen (Nt) stocks. Tendencies and magnitude of ΔSOC values derived by AC measurements and repeated soil inventories corresponded well. The period of maximum plant growth was identified as being most important for the development of spatial differences in annual ΔSOC. Hence, we were able to confirm that AC-based C budgets are able

  17. Detecting small-scale spatial differences and temporal dynamics of soil organic carbon (SOC) stocks: a comparison between automatic chamber-derived C budgets and repeated soil inventories

    Science.gov (United States)

    Hoffmann, Mathias; Jurisch, Nicole; Garcia Alba, Juana; Albiac Borraz, Elisa; Schmidt, Marten; Huth, Vytas; Rogasik, Helmut; Rieckh, Helene; Verch, Gernot; Sommer, Michael; Augustin, Jürgen

    2017-04-01

    Carbon (C) sequestration in soils plays a key role in the global C cycle. It is therefore crucial to adequately monitor dynamics in soil organic carbon (ΔSOC) stocks when aiming to reveal underlying processes and potential drivers. However, small-scale spatial and temporal changes in SOC stocks, particularly pronounced on arable lands, are hard to assess. The main reasons for this are limitations of the well-established methods. On the one hand, repeated soil inventories, often used in long-term field trials, reveal spatial patterns and trends in ΔSOC but require a longer observation period and a sufficient number of repetitions. On the other hand, eddy covariance measurements of C fluxes towards a complete C budget of the soil-plant-atmosphere system may help to obtain temporal ΔSOC patterns but lack small-scale spatial resolution. To overcome these limitations, this study presents a reliable method to detect both short-term temporal as well as small-scale spatial dynamics of ΔSOC. Therefore, a combination of automatic chamber (AC) measurements of CO2 exchange and empirically modeled aboveground biomass development (NPPshoot) was used. To verify our method, results were compared with ΔSOC observed by soil resampling. AC measurements were performed from 2010 to 2014 under a silage maize/winter fodder rye/sorghum-Sudan grass hybrid/alfalfa crop rotation at a colluvial depression located in the hummocky ground moraine landscape of NE Germany. Widespread in large areas of the formerly glaciated Northern Hemisphere, this depression type is characterized by a variable groundwater level (GWL) and pronounced small-scale spatial heterogeneity in soil properties, such as SOC and nitrogen (Nt). After monitoring the initial stage during 2010, soil erosion was experimentally simulated by incorporating topsoil material from an eroded midslope soil into the plough layer of the colluvial depression. SOC stocks were quantified before and after soil manipulation and at the end

  18. Effect of small-dose mifepristone in combined with Gongxuening capsule on perimenopasual dysfunctional uterine bleeding and sex hormone levels

    Institute of Scientific and Technical Information of China (English)

    Wei-Feng Zhang

    2016-01-01

    Objective:To explore the clinical efficacy of small-dose mifepristone in combined with Gongxuening capsule in the treatment of perimenopasual dysfunctional uterine bleeding and their effects on sex hormone levels. Methods: The perimenopasual women with dysfunctional uterine bleeding who were admitted in our hospital from October, 2014 to October, 2015 and received small-dose mifepristone in combined with Gongxuening capsule were served as the observation group. They were orally administered with mifepristone, 6.25 mg/time, 1 time/d, taken before bedtime, and Gongxuening capsule, 2 pills/time, 3 times/d, for 7 d after each menstruation, and continuously for 3 months. The perimenopasual women with dysfunctional uterine bleeding who were received mifepristone were served as the control group. They were orally administered with mifepristone, 12.5 mg/time, 1 time/d, taken before bedtime, and continuously for 3 months. The HGB level and endometrial thickness before and after treatment were detected. The bleeding control time, total blood stopping time, and adverse reactions in the two groups were compared. The levels of FSH, E2, P, and LH before and after treatment in the two groups were determined. Results:After treatment, HGB level in the observation group was elevated, and the altered degree of endometrial thickness was significantly superior to that in the control group (P0.05). Conclusions: Small-dose mifepristone in combined with Gongxuening capsule in the treatment of perimenopasual dysfunctional uterine bleeding can effectively improve the endometrial thickness, timely control bleeding, and improve the serum sex hormone levels, with a satisfactory effect;therefore, it deserves to be widely recommended in the clinic.

  19. Isolation and Characterization of Simple Sequence Repeats (SSR Markers from the Moss Genus Orthotrichum Using a Small Throughput Pyrosequencing Machine

    Directory of Open Access Journals (Sweden)

    Vítězslav Plášek

    2012-06-01

    Full Text Available Here, we report the results of next-generation sequencing on the GS Junior system to identify a large number of microsatellites from the epiphytic moss Orthotrichum speciosum. Using a combination of a total (non-enrichment genomic library and small-scale 454 pyrosequencing, we determined 5382 contigs whose length ranged from 103 to 5445 bp. In this dataset we identified 92 SSR (simple sequence repeats motifs in 89 contigs. Forty-six of these had flanking regions suitable for primer design. We tested PCR amplification, reproducibility, and the level of polymorphism of 46 primer pairs for Orthotrichum speciosum using 40 individuals from two populations. As a result, the designed primers revealed 35 polymorphic loci with more than two alleles detected. This method is cost- and time-effective in comparison with traditional approaches involving cloning and sequencing.

  20. The canine prostate cancer cell line CHP-1 shows over-expression of the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α.

    Science.gov (United States)

    Azakami, D; Nakahira, R; Kato, Y; Michishita, M; Kobayashi, M; Onozawa, E; Bonkobara, M; Kobayashi, M; Takahashi, K; Watanabe, M; Ishioka, K; Sako, T; Ochiai, K; Omi, T

    2017-06-01

    Although androgen therapy resistance and poor clinical outcomes are seen in most canine prostate cancer cases, there are only a few tools for analysing canine prostate cancer by using a cell biological approach. Therefore, to evaluate androgen-independent neoplastic cell growth, a new canine prostate cancer cell line (CHP-1) was established in this study. CHP-1 over-expressed the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), which is over-expressed in human androgen-independent prostate cancer. The CHP-1 xenograft also showed SGTA over-expression. Although CHP-1 shows poor androgen receptor (AR) signalling upon dihydrotestosterone stimulation, forced expression of AR enabled evaluation of AR signalling. Taken together, these results suggest that CHP-1 will be a useful model for investigating the pathogenesis of androgen-dependent and androgen-independent canine prostate cancer. © 2016 John Wiley & Sons Ltd.

  1. Back-traceable measurement of very small doses; Rueckfuehrbare Messung sehr kleiner Dosen

    Energy Technology Data Exchange (ETDEWEB)

    Balg, Sabrina [Physikalisch-Technische Bundesanstalt (PTB), Braunschweig (Germany). Fachbereich 6.3 ' Strahlenschutzdosimetrie'

    2012-07-01

    A 1-litre ionization chamber (HSO1-chamber) to measure the ambient dose equivalent by means of additional coating was optimized by Ankerhold, especially for low-energy photon beams below 40 keV. This should be done also for the similar 10-litre ionization chamber (HS10-chamber). A casing of the HS10-ionization chamber with 4.5 mm thick Ultraform half-shells was shown to be optimal for this purpose. The core of this paper is the choice of material and the determination of the thickness of the half-shell production by measuring the response of the ionization chamber at different photon energies. Furthermore, the influence of the series dispersion of HS10-chambers on the optimization is checked. The results are then compared with those of the optimized HS01-chamber. (orig.)

  2. A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial.

    Science.gov (United States)

    Leyvraz, Serge; Pampallona, Sandro; Martinelli, Giovanni; Ploner, Ferdinand; Perey, Lucien; Aversa, Savina; Peters, Solange; Brunsvig, Paal; Montes, Ana; Lange, Andrzej; Yilmaz, Ugur; Rosti, Giovanni

    2008-04-16

    The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe

  3. Prolonged perturbation of the oscillations of hepatoma Fao cell proliferation by a single small dose of methotrexate.

    Science.gov (United States)

    Guerroui, S; Deschatrette, J; Wolfrom, C

    2005-06-01

    The proliferation rate of various cell types in vitro, including hepatoma Fao cells, displays aperiodic oscillations. The frequency of these oscillations is about one every 3-5 weeks, and there are variations in cell functions and polarity. Topological analysis has showed that these oscillations in growth rate are determined, and presumably chaotic. One characteristic of complex chaotic systems is that their dynamics can be persistently modified by a small external perturbation. We show that treatment with a single small dose of the anticancer drug methotrexate causes long-term stable alteration of the oscillatory dynamics of Fao cell proliferation. The oscillations of growth rate are shifted, and their mean level decreased according to a fractal pattern.

  4. Phase I Study of Concurrent High-Dose Three-Dimensional Conformal Radiotherapy With Chemotherapy Using Cisplatin and Vinorelbine for Unresectable Stage III Non-Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sekine, Ikuo, E-mail: isekine@ncc.go.jp [Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan); Sumi, Minako; Ito, Yoshinori [Division of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Horinouchi, Hidehito; Nokihara, Hiroshi; Yamamoto, Noboru; Kunitoh, Hideo; Ohe, Yuichiro; Kubota, Kaoru; Tamura, Tomohide [Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan)

    2012-02-01

    Purpose: To determine the maximum tolerated dose in concurrent three-dimensional conformal radiotherapy (3D-CRT) with chemotherapy for unresectable Stage III non-small-cell lung cancer (NSCLC). Patients and Methods: Eligible patients with unresectable Stage III NSCLC, age {>=}20 years, performance status 0-1, percent of volume of normal lung receiving 20 GY or more (V{sub 20}) {<=}30% received three to four cycles of cisplatin (80 mg/m{sup 2} Day 1) and vinorelbine (20 mg/m{sup 2} Days 1 and 8) repeated every 4 weeks. The doses of 3D-CRT were 66 Gy, 72 Gy, and 78 Gy at dose levels 1 to 3, respectively. Results: Of the 17, 16, and 24 patients assessed for eligibility, 13 (76%), 12 (75%), and 6 (25%) were enrolled at dose levels 1 to 3, respectively. The main reasons for exclusion were V{sub 20} >30% (n = 10) and overdose to the esophagus (n = 8) and brachial plexus (n = 2). There were 26 men and 5 women, with a median age of 60 years (range, 41-75). The full planned dose of radiotherapy could be administered to all the patients. Grade 3-4 neutropenia and febrile neutropenia were noted in 24 (77%) and 5 (16%) of the 31 patients, respectively. Grade 4 infection, Grade 3 esophagitis, and Grade 3 pulmonary toxicity were noted in 1 patient, 2 patients, and 1 patient, respectively. The dose-limiting toxicity was noted in 17% of the patients at each dose level. The median survival and 3-year and 4-year survival rates were 41.9 months, 72.3%, and 49.2%, respectively. Conclusions: 72 Gy was the maximum dose that could be achieved in most patients, given the predetermined normal tissue constraints.

  5. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354 in subjects with asthma

    Directory of Open Access Journals (Sweden)

    Roskos Lorin

    2010-01-01

    Full Text Available Abstract Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354 in adults with asthma. Methods This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] ≥ 80% predicted. Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. Results Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted received ≥ 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg and volume of distribution (44-57 mL/kg were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. Trial registration NCT00974675.

  6. Detector dose response in megavoltage small photon beams. II. Pencil beam perturbation effects

    Energy Technology Data Exchange (ETDEWEB)

    Bouchard, Hugo, E-mail: hugo.bouchard@npl.co.uk; Duane, Simon [Acoustics and Ionising Radiation Team, National Physical Laboratory, Hampton Road, Teddington TW11 0LW (United Kingdom); Kamio, Yuji [Centre hospitalier de l’Université de Montréal (CHUM), 1560 Sherbrooke Est, Montréal, Québec H2L 4M1 (Canada); Palmans, Hugo [Acoustics and Ionising Radiation Team, National Physical Laboratory, Hampton Road, Teddington TW11 0LW (United Kingdom); Medical Physics, EBG MedAustron GmbH, Wiener Neustadt A-2700 (Austria); Seuntjens, Jan [Medical Physics Unit, McGill University, Montréal, Québec H3G 1A4 (Canada)

    2015-10-15

    Purpose: To quantify detector perturbation effects in megavoltage small photon fields and support the theoretical explanation on the nature of quality correction factors in these conditions. Methods: In this second paper, a modern approach to radiation dosimetry is defined for any detector and applied to small photon fields. Fano’s theorem is adapted in the form of a cavity theory and applied in the context of nonstandard beams to express four main effects in the form of perturbation factors. The pencil-beam decomposition method is detailed and adapted to the calculation of perturbation factors and quality correction factors. The approach defines a perturbation function which, for a given field size or beam modulation, entirely determines these dosimetric factors. Monte Carlo calculations are performed in different cavity sizes for different detection materials, electron densities, and extracameral components. Results: Perturbation effects are detailed with calculated perturbation functions, showing the relative magnitude of the effects as well as the geometrical extent to which collimating or modulating the beam impacts the dosimetric factors. The existence of a perturbation zone around the detector cavity is demonstrated and the approach is discussed and linked to previous approaches in the literature to determine critical field sizes. Conclusions: Monte Carlo simulations are valuable to describe pencil beam perturbation effects and detail the nature of dosimetric factors in megavoltage small photon fields. In practice, it is shown that dosimetric factors could be avoided if the field size remains larger than the detector perturbation zone. However, given a detector and beam quality, a full account for the detector geometry is necessary to determine critical field sizes.

  7. Clinical Observation on Treatment of Senile Rheumatoid Arthritis by Tripterygium Polyglycosides Combined with Small Dose of Methotrexate

    Institute of Scientific and Technical Information of China (English)

    沈杰; 张之澧

    2004-01-01

    Objective: To observe the effect and adverse reaction of tripterygium polyglycosides (TP) combined with small dose of methotrexate (MTX) in treating senile rheumatoid arthritis (RA). Methods: Sixty old patients with RA were equally divided into two groups, the treated group was treated with oral intake of TP (10 mg three times per day) plus MTX (7. 5 mg, once per week), and the control group was treated with MTX (15 mg per week) respectively for 3 months. The changes from before to after treatment in resting pain, morning rigidity, bilateral grip strength, local tenderness index, arthroncus index, patient's evaluation, doctor's evaluation, erythrocyte sedimentation rate (ESR), C-reaction protein (CRP) and rheumatoid factor(RF) titre were observed and the clinical therapeutic effect assessed. Results: The total effective rate in the treated group was 86.67% and that in the control group 83.33%, showing insignificant difference between them ( P>0.05). But the improvement in local tenderness index, arthroncus index, morning rigidity and ESR in the treated group was significantly better than those in the control group (P<0.01 or P<0.05).The occurrence rate of adverse reaction in the treated group was 26.67 %, which was lower than that in the control group (43.33%), showing significant difference (P<0.01). Conclusion: TP combined with small dose of MTX is a favorable therapeutic method for treating senile RA.

  8. Effect of small dose of EPO after PCI on cardiac function and myocardial injury in patients with acute myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    Guo-Min Li

    2016-01-01

    Objective:To study the effect of small dose of erythropoietin (EPO) after PCI on cardiac function and myocardial injury in patients with acute myocardial infarction.Methods:A total of 86 patients with acute ST-elevation myocardial infarction who received percutaneous coronary intervention in our hospital from April 2012 to June 2015 were selected and randomly divided into EPO group and control group, serum was collected 1 week after operation to determine myocardial injury indexes, inflammation indexes, oxidative stress indexes and ventricular remodeling indexes, and color Doppler echocardiography was conducted 6 months after surgery to determine ventricular systolic and diastolic function indexes.Results:One week after operation, serum LDH, CK, CK-MB, cTnI, cTnT, sCD40L, E-selectin, P-selectin, sICAM-1, MDA, O2-, ox-LDL, PICP, CITP and PIIINP levels of EPO group were significantly lower than those of control group while GSH-Px and SOD levels were significantly higher than those of control group; 6 months after operation, LVEF of EPO group was significantly higher than that of control group while LVEDVI and LVESVI were significantly lower than those of control group.Conclusions:Small dose of EPO after PCI can alleviate myocardial damage, relieve inflammation and oxidative stress, and improve myocardial remodeling and cardiac diastolic and systolic function in patients with AMI.

  9. Micro-feeding and dosing of powders via a small-scale powder pump.

    Science.gov (United States)

    Besenhard, M O; Fathollahi, S; Siegmann, E; Slama, E; Faulhammer, E; Khinast, J G

    2017-03-15

    Robust and accurate powder micro-feeding (micro-dosing (micro-feeders that yield feed rates below 5mg/s use gravimetric feeding principles, feed rates depend primarily on powder properties. In contrast, volumetric powder feeders do not require regular calibration because their feed rates are primarily determined by the feeder's characteristic volume replacement. In this paper, we present a volumetric micro-feeder based on a cylinder piston system (i.e., a powder pump), which allows accurate micro-feeding and feed rates of a few grams per hours even for very fine powders. Our experimental studies addressed the influence of cylinder geometries, the initial conditions of bulk powder, and the piston speeds. Additional computational studies via Discrete Element Method simulations offered a better understanding of the feeding process, its possible limitations and ways to overcome them. The powder pump is a simple yet valuable tool for accurate powder feeding at feed rates of several orders of magnitude. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Pulmonary Artery Invasion, High-Dose Radiation, and Overall Survival in Patients With Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Han, Cheng-Bo [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Oncology, Shengjing Hospital of China Medical University, Shenyang (China); Wang, Wei-Li [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Fourth Hospital of China Medical University, Shenyang (China); Quint, Leslie [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Xue, Jian-Xin [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Matuszak, Martha; Ten Haken, Randall [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Kong, Feng-Ming, E-mail: fkong@gru.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2014-06-01

    Purpose: To investigate whether high-dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Patients with medically inoperable/unresectable NSCLC treated with definitive radiation therapy in prospective studies were eligible for this study. Pulmonary artery involvement was defined on the basis of pretreatment chest CT and positron emission tomography/CT fusion. Pulmonary artery was contoured according to the Radiation Therapy Oncology Group protocol 1106 atlas, and dose-volume histograms were generated. Results: A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiation therapy. Radiation dose ranged from 60 to 85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤2, 3, 4, and 5 had 1-year OS and median survival of 67% and 25.4 months (95% confidence interval [CI] 15.7-35.1), 62% and 22.2 months (95% CI 5.8-38.6), 90% and 35.8 months (95% CI 28.4-43.2), and 50% and 7.0 months, respectively (P=.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of radiation therapy. Maximum and mean doses to PA were not significantly associated with OS. The V45, V50, V55, and V60 of PA were correlated significantly with a worse OS (P<.05). Patients with V45 >70% or V60 >37% had significantly worse OS (13.3 vs 37.9 months, P<.001, and 13.8 vs 37.9 months, P=.04, respectively). Conclusions: Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.

  11. Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

    Energy Technology Data Exchange (ETDEWEB)

    Westover, Kenneth D. [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Loo, Billy W. [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Gerber, David E. [Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Iyengar, Puneeth; Choy, Hak [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Diehn, Maximilian [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Hughes, Randy; Schiller, Joan; Dowell, Jonathan [Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Wardak, Zabi [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Sher, David [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States); Christie, Alana; Xie, Xian-Jin [Department of Clinical Science, Southwestern Medical Center, Dallas, Texas (United States); Corona, Irma [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Sharma, Akanksha [School of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Wadsworth, Margaret E. [Radiation Oncology of Mississippi, Jackson, Mississippi (United States); Timmerman, Robert, E-mail: Robert.Timmerman@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2015-09-01

    Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long

  12. Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer.

    NARCIS (Netherlands)

    Timmer-Bonte, J.N.H.; Punt, C.J.A.; Heijden, H.F.M. van der; Die, C.E. van; Bussink, J.; Beijnen, J.H.; Huitema, A.D.; Tjan-Heijnen, V.C.

    2008-01-01

    In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a

  13. Dose-volume histogram constrains for small intestine in postoperative transcutaneous radiotherapy of endometrial carcinoma: comparison between conventional and conformal techniques

    Directory of Open Access Journals (Sweden)

    Anela Ramić

    2013-09-01

    Full Text Available Introduction: The aim of this study was to determine the dose-volume histogram (DVH constrains of conventional and conformal transcutaneous radiotherapy for small intestine and perform their comparison.Methods: This retrospective-prospective study included patients who were treated for endometrial cancer using conventional transcutaneous radiotherapy at the Department of Radiotherapy Clinic of Oncology,Hematology and Radiotherapy, University Clinical Center Tuzla in the period from 2009 to 2011. The study was performed on patients of all ages suffering from this condition. The study involved 35 patients. DVHparameters which were analyzed are: minimum dose (Dmin, maximum dose (Dmax, medium dose (Daver of the small intestine, as well as the volume of the small intestine, which is included in 75%, 95% and 100%dose (V33,75Gy, V42,75Gy, V45Gy expressed in percentages and cubic centimeters of the affected organ. Working hypothesis was tested with paired t test. The difference between the variables at the level of p Results: DVH constrains of transcutaneous conformal radiotherapy showed signifi cantly smaller dose contribution on small intestine than DVH parameters of conventional transcutaneous radiotherapy (pConclusion: The dose contribution on small intestine was signifi cantly lower by planning three-dimensional conformal transcutaneous radiotherapy in comparison to the conventional planning.

  14. Dose-volume histogram constrains for small intestine in postoperative transcutaneous radiotherapy of endometrial carcinoma: comparison between conventional and conformal techniques

    Directory of Open Access Journals (Sweden)

    Anela Ramić

    2013-09-01

    Full Text Available Introduction: The aim of this study was to determine the dose-volume histogram (DVH constrains of conventional and conformal transcutaneous radiotherapy for small intestine and perform their comparison.Methods: This retrospective-prospective study included patients who were treated for endometrial cancer using conventional transcutaneous radiotherapy at the Department of Radiotherapy Clinic of Oncology,Hematology and Radiotherapy, University Clinical Center Tuzla in the period from 2009 to 2011. The study was performed on patients of all ages suffering from this condition. The study involved 35 patients. DVHparameters which were analyzed are: minimum dose (Dmin, maximum dose (Dmax, medium dose (Daver of the small intestine, as well as the volume of the small intestine, which is included in 75%, 95% and 100%dose (V33,75Gy, V42,75Gy, V45Gy expressed in percentages and cubic centimeters of the affected organ. Working hypothesis was tested with paired t test. The difference between the variables at the level of p <0.05 was considered statistically significant.Results: DVH constrains of transcutaneous conformal radiotherapy showed signifi cantly smaller dose contribution on small intestine than DVH parameters of conventional transcutaneous radiotherapy (p<0.0001.Conclusion: The dose contribution on small intestine was signifi cantly lower by planning three-dimensional conformal transcutaneous radiotherapy in comparison to the conventional planning.

  15. Cardiac toxicity and radiation dose to the heart in definitive treated non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schytte, Tine; Hansen, Olfred (Dept. of Oncology, Odense Univ. Hospital, 5000 Odense C (Denmark)), E-mail: tine.schytte@dadlnet.dk; Stolberg-Rohr, Thomine; Brink, Carsten (Radiophysic Laboratory, Odense Univ. Hospital, 5000 Odense C (Denmark))

    2010-10-15

    large doses to the heart are associated with higher risk of cardiac toxicity. This is why the upper quartile was chosen to be definition of high mean dose in this study. In addition, it is not known which part of the heart which is the most radiosensitive part, nor which structures at risk should be chosen as a reference point for tolerance doses in clinical practice. In the present study, the endpoint was cardiac event. When analysing larger cohorts the primary end point is often cardiac death. This was not appropriate here because the sample size was too small. This study did not find a relation between high mean-dose to different volumes of the heart and cardiac toxicity defined as cardiac event. This means that one should not compromise on dose to the tumour in order to reduce dose to the heart, when treating NSCLC patients with definitive radiotherapy.

  16. Accuracy of Acuros XB and AAA dose calculation for small fields with reference to RapidArc stereotactic treatments

    Energy Technology Data Exchange (ETDEWEB)

    Fogliata, Antonella; Nicolini, Giorgia; Clivio, Alessandro; Vanetti, Eugenio; Cozzi, Luca [Oncology Institute of Southern Switzerland, Medical Physics Unit, CH-6500 Bellinzona (Switzerland)

    2011-11-15

    Purpose: To assess the accuracy against measurements of two photon dose calculation algorithms (Acuros XB and the Anisotropic Analytical algorithm AAA) for small fields usable in stereotactic treatments with particular focus on RapidArc. Methods: Acuros XB and AAA were configured for stereotactic use. Baseline accuracy was assessed on small jaw-collimated open fields for different values for the spot sizes parameter in the beam data: 0.0, 0.5, 1, and 2 mm. Data were calculated with a grid of 1 x 1 mm{sup 2}. Investigated fields were: 3 x 3, 2 x 2, 1 x 1, and 0.8 x 0.8 cm{sup 2} with a 6 MV photon beam generated from a Clinac2100iX (Varian, Palo Alto, CA). Profiles, PDD, and output factors were measured in water with a PTW diamond detector (detector size: 4 mm{sup 2}, thickness 0.4 mm) and compared to calculations. Four RapidArc test plans were optimized, calculated and delivered with jaw settings J3 x 3, J2 x 2, and J1 x 1 cm{sup 2}, the last was optimized twice to generate high (H) and low (L) modulation patterns. Each plan consisted of one partial arc (gantry 110 deg. to 250 deg.), and collimator 45 deg. Dose to isocenter was measured in a PTW Octavius phantom and compared to calculations. 2D measurements were performed by means of portal dosimetry with the GLAaS method developed at authors' institute. Analysis was performed with gamma pass-fail test with 3% dose difference and 2 mm distance to agreement thresholds. Results: Open square fields: penumbrae from open field profiles were in good agreement with diamond measurements for 1 mm spot size setting for Acuros XB, and between 0.5 and 1 mm for AAA. Maximum MU difference between calculations and measurements was 1.7% for Acuros XB (0.2% for fields greater than 1 x 1 cm{sup 2}) with 0.5 or 1 mm spot size. Agreement for AAA was within 0.7% (2.8%) for 0.5 (1 mm) spot size. RapidArc plans: doses were evaluated in a 4 mm diameter structure at isocenter and computed values differed from measurements by 0.0, -0

  17. Accuracy of Acuros XB and AAA dose calculation for small fields with reference to RapidArc(®) stereotactic treatments.

    Science.gov (United States)

    Fogliata, Antonella; Nicolini, Giorgia; Clivio, Alessandro; Vanetti, Eugenio; Cozzi, Luca

    2011-11-01

    To assess the accuracy against measurements of two photon dose calculation algorithms (Acuros XB and the Anisotropic Analytical algorithm AAA) for small fields usable in stereotactic treatments with particular focus on RapidArc(®). Acuros XB and AAA were configured for stereotactic use. Baseline accuracy was assessed on small jaw-collimated open fields for different values for the spot sizes parameter in the beam data: 0.0, 0.5, 1, and 2 mm. Data were calculated with a grid of 1 × 1 mm(2). Investigated fields were: 3 × 3, 2 × 2, 1 × 1, and 0.8 × 0.8 cm(2) with a 6 MV photon beam generated from a Clinac2100iX (Varian, Palo Alto, CA). Profiles, PDD, and output factors were measured in water with a PTW diamond detector (detector size: 4 mm(2), thickness 0.4 mm) and compared to calculations. Four RapidArc test plans were optimized, calculated and delivered with jaw settings J3 × 3, J2 × 2, and J1 × 1 cm(2), the last was optimized twice to generate high (H) and low (L) modulation patterns. Each plan consisted of one partial arc (gantry 110° to 250°), and collimator 45°. Dose to isocenter was measured in a PTW Octavius phantom and compared to calculations. 2D measurements were performed by means of portal dosimetry with the GLAaS method developed at authors' institute. Analysis was performed with gamma pass-fail test with 3% dose difference and 2 mm distance to agreement thresholds. Open square fields: penumbrae from open field profiles were in good agreement with diamond measurements for 1 mm spot size setting for Acuros XB, and between 0.5 and 1 mm for AAA. Maximum MU difference between calculations and measurements was 1.7% for Acuros XB (0.2% for fields greater than 1 × 1 cm(2)) with 0.5 or 1 mm spot size. Agreement for AAA was within 0.7% (2.8%) for 0.5 (1 mm) spot size. RapidArc plans: doses were evaluated in a 4 mm diameter structure at isocenter and computed values differed from measurements by 0.0, -0.2, 5.5, and

  18. Evaluation of the dose calculation accuracy for small fields defined by jaw or MLC for AAA and Acuros XB algorithms.

    Science.gov (United States)

    Fogliata, Antonella; Lobefalo, Francesca; Reggiori, Giacomo; Stravato, Antonella; Tomatis, Stefano; Scorsetti, Marta; Cozzi, Luca

    2016-10-01

    Small field measurements are challenging, due to the physical characteristics coming from the lack of charged particle equilibrium, the partial occlusion of the finite radiation source, and to the detector response. These characteristics can be modeled in the dose calculations in the treatment planning systems. Aim of the present work is to evaluate the MU calculation accuracy for small fields, defined by jaw or MLC, for anisotropic analytical algorithm (AAA) and Acuros XB algorithms, relative to output measurements on the beam central axis. Single point output factor measurement was acquired with a PTW microDiamond detector for 6 MV, 6 and 10 MV unflattened beams generated by a Varian TrueBeam STx equipped with high definition-MLC. Fields defined by jaw or MLC apertures were set; jaw-defined: 0.6 × 0.6, 0.8 × 0.8, 1 × 1, 2 × 2, 3 × 3, 4 × 4, 5 × 5, and 10 × 10 cm(2); MLC-defined: 0.5 × 0.5 cm(2) to the maximum field defined by the jaw, with 0.5 cm stepping, and jaws set to: 2 × 2, 3 × 3, 4 × 4, 5 × 5, and 10 × 10 cm(2). MU calculation was obtained with 1 mm grid in a virtual water phantom for the same fields, for AAA and Acuros algorithms implemented in the Varian eclipse treatment planning system (version 13.6). Configuration parameters as the effective spot size (ESS) and the dosimetric leaf gap (DLG) were varied to find the best parameter setting. Differences between calculated and measured doses were analyzed. Agreement better than 0.5% was found for field sizes equal to or larger than 2 × 2 cm(2) for both algorithms. A dose overestimation was present for smaller jaw-defined fields, with the best agreement, averaged over all the energies, of 1.6% and 4.6% for a 1 × 1 cm(2) field calculated by AAA and Acuros, respectively, for a configuration with ESS = 1 mm for both X and Y directions for AAA, and ESS = 1.5 and 0 mm for X and Y directions for Acuros. Conversely, a calculated dose underestimation was found for small MLC-defined fields, with the

  19. A prospective study of differences in duodenum compared to remaining small bowel motion between radiation treatments: Implications for radiation dose escalation in carcinoma of the pancreas

    Directory of Open Access Journals (Sweden)

    Wahab Sasha H

    2006-09-01

    Full Text Available Abstract Purpose As a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy. Patients and methods Nine patients (4 women, 5 men undergoing radiation therapy were enrolled in this prospective study. The patients had up to four weekly CT scans performed during their course of radiation therapy. Pancreas, duodenum and non-duodenal small bowel were then contoured for each CT scan. On the initial scan, a four-field plan was generated to fully cover the pancreas. This plan was registered to each subsequent CT scan. Dose-volume histogram (DVH analyses were performed for the duodenum, non-duodenal small bowel, large bowel, and pancreas. Results With significant individual variation, the volume of duodenum receiving at least 80% of the prescribed dose was consistently greater than the remaining small bowel. In the patient with the largest inter-fraction variation, the fractional volume of non-duodenal small bowel irradiated to at least the 80% isodose line ranged from 1% to 20%. In the patient with the largest inter-fraction variation, the fractional volume of duodenum irradiated to at least the 80% isodose line ranged from 30% to 100%. Conclusion The volume of small bowel irradiated during four-field pancreatic radiation therapy changes substantially between fractions. This suggests dose escalation may be possible. However, dose limits to the duodenum should be stricter than for other segments of small bowel.

  20. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster

    DEFF Research Database (Denmark)

    Langkilde, Søren; Mandimika, T.; Schrøder, Malene

    2009-01-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine...... to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity...... of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios...

  1. Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial.

    Science.gov (United States)

    Choi, Clara Y H; Wakelee, Heather A; Neal, Joel W; Pinder-Schenck, Mary C; Yu, Hsiang-Hsuan Michael; Chang, Steven D; Adler, John R; Modlin, Leslie A; Harsh, Griffith R; Soltys, Scott G

    2017-09-01

    To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates. In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days. From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS. The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Estimation of effective dose caused by stray radiations of photons, electrons and positrons around a small storage ring for a synchrotron radiation facility

    Science.gov (United States)

    Takashima, Y.; Oki, S.; Sugiyama, H.; Kobayakawa, H.

    2005-10-01

    The spatial distribution of the effective dose of photons, electrons and positrons caused by beam loss around a small electron storage ring in a synchrotron radiation source is calculated. We propose a simple formula applicable to calculate the effective dose for storage rings for beam energies ranging from 200 MeV to 5 GeV. The formula is derived from Monte Carlo calculations of radiation flux using the simulation code EGS4. We apply the formula to estimate the effective dose distribution in a small synchrotron radiation facility planned by the Nagoya University.

  3. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

    Science.gov (United States)

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

    2014-05-01

    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

  4. Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas. Ablative dose PBT for NSCLC

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sung Uk; Cho, Kwan Ho; Kim, Joo Young; Kim, Dae Yong; Kim, Tae Hyun; Suh, Yang-Gun; Kim, Yeon-Joo [Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Goyang (Korea, Republic of); Moon, Sung Ho [Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Goyang (Korea, Republic of); Research Institute and Hospital, National Cancer Center, Center for Lung Cancer, Goyang (Korea, Republic of); Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769 (Korea, Republic of); Pyo, Hong Ryull [Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Radiation Oncology, Seoul (Korea, Republic of)

    2016-09-15

    To evaluate the efficacy and safety of ablative dose hypofractionated proton beam therapy (PBT) for patients with stage I and recurrent non-small cell lung carcinoma (NSCLC). A total of 55 patients with stage I (n = 42) and recurrent (n = 13) NSCLC underwent hypofractionated PBT and were retrospectively reviewed. A total dose of 50-72 CGE (cobalt gray equivalent) in 5-12 fractions was delivered. The median follow-up duration was 29 months (range 4-95 months). There were 24 deaths (43.6%) during the follow-up period: 11 died of disease progression and 13 from other causes. Kaplan-Meier overall survival rate (OS) at 3 years was 54.9% and the median OS was 48.6 months (range 4-95 months). Local progression was observed in 7 patients and the median time to local progression was 9.3 months (range 5-14 months). Cumulative actuarial local control rate (LCR), lymph node metastasis-free survival, and distant metastasis-free survival rates at 3 years were 85.4, 78.4, and 76.5%, respectively. Larger tumor diameter was significantly associated with poorer LCR (3-year: 94% for ≤3 cm vs. 65% for >3 cm, p = 0.006) on univariate analysis and also an independent prognostic factor for LCR (HR 6.9, 95% CI = 1.3-37.8, p = 0.026) on multivariate analysis. No grade 3 or 4 treatment-related toxicities developed. One grade 5 treatment-related adverse event occurred in a patient with symptomatic idiopathic pulmonary fibrosis. Ablative dose hypofractionated PBT was safe and promising for stage I and recurrent NSCLC. (orig.) [German] Beurteilung von Wirksamkeit und Sicherheit hypofraktionierter Protonentherapie (PBT) mit ablativen Dosen fuer nichtkleinzellige Lungenkarzinome (NSCLC) im Stadium I und rekurrierende NSCLC. Retrospektiv wurden insgesamt 55 NSCLC-Patienten (Stadium I: n = 42; rekurrierender Tumor: n = 13), analysiert. Sie waren mit einer Gesamtdosis von 50-72 CGE (''cobalt gray equivalent'') in 5-12 Fraktionen behandelt worden. Der Median der Follow

  5. Comparison of single-grain and small-aliquot OSL dose estimates in < 3000 years old river sediments from South India

    DEFF Research Database (Denmark)

    Thomas, P.J.; Jain, M.; Juyal, N.;

    2005-01-01

    We report on OSL dose distributions derived from small-aliquot and single grains of quartz in young fluvial sediments sampled from the Penner River basin, South India. The single-grain dose distributions suggest that 13 out of 19 samples were well bleached. In many well-bleached samples, there wa......We report on OSL dose distributions derived from small-aliquot and single grains of quartz in young fluvial sediments sampled from the Penner River basin, South India. The single-grain dose distributions suggest that 13 out of 19 samples were well bleached. In many well-bleached samples......, there was an underestimation in the single-aliquot dose estimates as compared to those from the single grain-the difference between average dose estimates determined by the two methods ranged from similar to 1% to 31%. Such a dose underestimation was not detectable in poorly bleached samples. Various possible reasons...... for the discrepancy between single-grain and small-aliquot dose estimates are discussed. Although there is no satisfactory explanation for this discrepancy, we speculate that the difference in the stimulation wavelengths, 470 +/- 130 nm in the case of single-aliquot and 532 nm in the case of single grains, could...

  6. [Metabolic effect of amaranth oil and impulse hypoxic training under chronic fluoride intoxication and small doses of ionizing radiation].

    Science.gov (United States)

    Konyk, U V; Hzhehots'kyĭ, M P; Koval'chuk, S M

    2002-01-01

    Lipid peroxidation and antioxidative defence system in blood, liver and heart tissues, nitric oxide metabolites content in brain tissue of rats under binary action of small-doses of ionizing radiation and fluoride intoxication treated by amaranth oil and interval hypoxic training have been studied. Complex using of amaranth oil and interval hypoxic training result in increase both enzymatic, as nonezymatic links of antioxidant defence in all investigated tissues. It was revealed also enhance of NO system metabolites content in brain gomogenate. In this conditions lipid peroxidation processes in liver and heart tissues normalize comparison with essential increase level LPO under binary action influence. On the basis of obtained results LPO metabolites content we can suppossed that complex using of amaranth oil and interval hypoxic training result in increase of organism adaptative possibility. This complex can be using for binary action of ionizing radiation and fluoride intoxication correction.

  7. Phase 3 Randomized Low-Dose Paclitaxel Chemoradiotherapy Study for Locally Advanced Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hongmei Lin

    2016-12-01

    Full Text Available Introduction: Concurrent chemoradiotherapy (CCRT is the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC, but is associated with poor chest tumor control. Here we report results of a randomized phase 3 study comparing two CCRT regimens in improving chest tumor control by low-dose paclitaxel chemoradiation for LA-NSCLC. Methods: Due to the logistics of local referral pattern, the study was designed to enroll patients with stage III LA-NSCLC who had completed 2-4 cycles of full-dose chemotherapy. One hundred thirty four were randomized to either Arm 1 (paclitaxel at 15 mg/m2, three times/wk [M, W, F] for 6 weeks, n=74, or Arm 2 (weekly paclitaxel at 45 mg/m2 for 6 weeks, n=60. Chest RT was 60-70 Gy in standard fractionation. Response rate was the primary endpoint, with recurrence-free survival (RFS as the secondary endpoint. Results: From March 2006 to February 2013, seventy-one patients completed Arm 1 treatment, and 59 completed Arm 2 treatment. The response rate for Arm 1 was significantly higher (83.1% than Arm 2 (54.2% (p=0.001. RFS was superior in Arm 1: median 14.6 months vs. 9.4 months, p=0.005, Hazard ratio (HR 1.868 (95% CI 1.203, 2.901. Overall survival was not significantly different: median 32.6 months in Arm 1 vs. 31.3 months in Arm 2, p = 0.91, HR 0.969 (95% CI 0.552, 1.703. Toxicity was significantly lower in Arm 1 for grade 3 and 4 leucopenia/neutropenia (p<0.001.Conclusions: Pulsed low-dose paclitaxel CCRT resulted in significantly better RFS and tumor response rate, and less hematologic toxicities than weekly CCRT for LA-NSCLC.

  8. Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine

    Directory of Open Access Journals (Sweden)

    Karaca Omer

    Full Text Available Abstract Objectives: The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anaesthesia on tourniquet-induced ischaemia-reperfusion injury. Methods: 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2 mg·kg-1 followed by infusion at a rate of 2 mg·kg-1·h-1. In the ketamine group, a continuous infusion of ketamine 0.5 mg·kg-1·h-1 was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1, at 30 minutes (min of tourniquet ischaemia (T2, and 5 min after tourniquet deflation (T3 for malondialdehyde (MDA measurements. Results: No differences were noted between the groups in haemodynamic (p > 0.05 and demographic data (p > 0.05. There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p > 0.05. There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95 ± 0.59, 2.31 ± 0.48 and pre-ischaemia (1.41 ± 0.38, 1.54 ± 0.45, and ischaemia (1.76 ± 0.70, 1.71 ± 0.38 (µmoL-1 periods (p < 0.05. Conclusions: Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischaemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anaesthesia.

  9. [Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine].

    Science.gov (United States)

    Omer, Karaca; Nermin, Gogus; Ali, Ahiskalioglu; Mehmet, Aksoy; Unal, Dogus; Sezen, Kumas Solak; Hakan, Kalafat

    The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anesthesia on tourniquet-induced ischemia-reperfusion injury. 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2mg.kg(-1) followed by infusion at a rate of 2mg.kg(-1).h(-1). In the ketamine group, a continuous infusion of ketamine 0.5mg.kg(-1).h(-1) was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1), at 30minutes (min) of tourniquet ischemia (T2), and 5min after tourniquet deflation (T3) for malondialdehyde (MDA) measurements. No differences were noted between the groups in hemodynamic (p>0.05) and demographic data (p>0.05). There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p>0.05). There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95±0.59, 2.31±0.48) and pre-ischemia (1.41±0.38, 1.54±0.45), and ischemia (1.76±0.70, 1.71±0.38) (μmoL(-1)) periods (p<0.05). Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anesthesia. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  10. Effect of Small-dose of Ephedrine Administered Prior to Induction of Anesthesia on the Onset Time of Succinylcholine

    Directory of Open Access Journals (Sweden)

    S Atashkhoyi

    2007-10-01

    Full Text Available Introduction & Objective: Onset of action of relaxants is influenced by cardiac output and muscle blood flow. Ephedrine increases blood flow to muscles and may shorten the onset of action of succinylcholine. The aim of this study was to evaluate the effect of small-dose of ephedrine administered prior to rapid-sequence induction of anesthesia on the onset time of succinylcholine for endotracheal intubation. Materials & Methods: In this randomized clinical trial, 60 patients scheduled for elective gynecologic surgeries in Alzahra hospital in Tabriz 1385, were selected. In these patients ephedrine, 70 µg/kg (study group, n=30, or saline (placebo group, n=30 was administered 3 minutes before induction of anesthesia with thiopentone/fentanyl. Succinylcholine, 0.6 mg/kg, was administrated to facilitate the tracheal intubation. Onset of succinylcholine, intubating conditions and hemodynamic variables were recorded in the subjects. Results: Fasciculation was absent in 60% (36 of the patients. No significant differences were found between the onsets of fasciculation between two groups. Moreover, the difference in duration of fasciculation in two groups was not significant. Onset time of succinylcholine was significantly shorter in study group (19.53±3.91 second, compared with placebo group (25.87±7.11 second (p<0.0001. Patients in study group were intubated in 47.07±4.51 seconds compared with 58.73±9.04 seconds in placebo group (p<0.0001. Intubation conditions were similar in both groups. Heart rate was slightly increased in study patients in the first and 3rd minutes after ephedrine administration, but there was no significant difference in systolic blood pressure values compared with the baseline value between two groups. Conclusion: The onset time of succinylcholine is shortened with small-dose of ephedrine pretreatment without significant adverse heamodynamic effects.

  11. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.

    Science.gov (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane W; Palyada, Kiran; Shrewsbury, Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.

  12. Effects of a small-sided game-based training programme on repeated sprint and change of direction abilities in recreationally-trained football players.

    Science.gov (United States)

    Bujalance-Moreno, Pascual; García-Pinillos, Felipe; Latorre-Román, Pedro Á

    2017-02-21

    To examine the effects of 6-week periodized small-sided game (SSG) training intervention on change of direction [COD], sprint and repeated sprint ability [RSA] in recreational male football players. Twenty-three young football players (age: 20.86 years) were randomized in a control group (n = 11) and an experimental group (n = 12). The SSG programme was included in the experimental group's training sessions. The players completed two variations of a SSG (i.e. 2 vs. 2 and 4 vs. 4 players) during intervention. To examine the changes in physical performance after the 6-week periodized SSG training intervention, all players were tested 6 weeks apart (i.e. pre-test and post-test) in sprint, COD ability test, and RSA shuttle test. A 2x2 ANOVA showed that 6-week SSG training intervention induced significant improvements (P0.7) in COD ability test, and variables related to both sprint test and RSA in the experimental group, whereas the control group remained unchanged (P≥0.05, ESsprint in recreationally trained football players.

  13. Collagen triple helix repeat containing 1 (Cthrc1) is an independently prognostic biomarker of non-small cell lung cancers with cigarette smoke.

    Science.gov (United States)

    Liu, Xiaojun; Liu, Beiyan; Cui, Ying; Wang, Fengping; Sun, Hui; Lv, Fuzhen

    2014-11-01

    Collagen triple helix repeat containing 1 (Cthrc1) has been recently documented in various malignancies, but its role in non-small cell lung cancer (NSCLC) remains uncertain. In the current study, we investigated the level of Cthrc1 in NSCLC tissues by immunohistochemistry. Results revealed that Cthrc1 overexpression was significantly associated with differentiation (P=0.039), tumor-node-metastasis (TNM) stage (P=0.035), lymph node status (P=0.001), and cigarette smoke (P=0.037). Furthermore, it was shown that patients with high Cthrc1 expression had significantly poorer overall survival (OS) and disease-free survival (DFS; P=0.004 and P=0.010, respectively). Interestingly, high Cthrc1 expression was an independent prognostic factor for both OS and DFS (P=0.010 and P=0.005, respectively) only in NSCLCs with cigarette smoke. These results indicated and suggested that Cthrc1 could be used as a prognostic marker for NSCLC, and it may play an important role in the smoked-related NSCLC.

  14. Small repeating earthquake activity, interplate quasi-static slip, and interplate coupling in the Hyuga-nada, southwestern Japan subduction zone

    Science.gov (United States)

    Yamashita, Yusuke; Shimizu, Hiroshi; Goto, Kazuhiko

    2012-04-01

    Small repeating earthquake (RE) analysis is a useful method for estimating interplate quasi-static slip, which is a good indicator of interplate coupling. We detected 170 continual-type interplate RE groups and then estimated the spatial variation in quasi-static slip in the Hyuga-nada over the past 17 years. The RE activity in this region has different characteristics compared with that in the northeast Japan subduction zone, presumably reflecting differences in the subduction properties. Our results revealed that interplate coupling spatially changes along the trench-axis and dip-direction—a phenomenon that cannot be resolved by land-based Global Positioning System (GPS) analysis. By comparing seismicity, the low-slip-rate areas correspond with the location of hypocenters and asperities for large- and moderate-sized interplate earthquakes, suggesting strong interplate coupling at these sites. These results indicate that the slip rate distribution estimated from RE activity is reliable and useful for assessing the potential of future large earthquakes.

  15. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

    Science.gov (United States)

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-04-01

    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  16. A 28-day repeat dose toxicity study of steroidal glycoalkaloids a-solanine and a-chaconine in the Syrian Golden Hamster

    NARCIS (Netherlands)

    Langkilde, S.; Mandimika, T.; Schroder, M.; Meyer, O.; Slob, W.; Peijnenburg, A.A.C.M.; Poulsen, M.

    2009-01-01

    Glycoalkaloids ¿-solanine and ¿-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of ¿-solanine to ¿-chaconine m

  17. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    Science.gov (United States)

    2016-06-28

    Adenocarcinoma of the Lung; Recurrent Non-small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  18. Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Shank, B.; Natale, R.B.; Hilaris, B.S.; Wittes, R.E.

    1981-04-01

    Survival of patients with small cell carcinoma of lung, treated on a new combined radiotherapy-chemotherapy protocol, compares favorably with other regimens in the literature and our own previous combined approaches. Radiation, given after induction chemotherapy, consisted of whole brain prophylaxis in all 44 evaluable patients. Patients with limited disease were also treated to the primary and mediastinum to a high dose (5000 rad equivalent) using multiple fields. The new chemotherapy regimen consisted of induction with cyclophosphamide, doxorubicin, and vincristine alternated with cis-platinum and VP-16 (an epipodophyllotoxin) for two cycles, followed by consolidation with low dose cyclophosphamide and vincristine concurrent with irradiation. Patients with limited disease who achieved less than complete response, and all patients with extensive disease were not continued on maintenance chemotherapy. Out of 24 evaluable patients with limited disease, there was 73% survival at 1 year by life-table analysis, measured from treatment initiation. After induction, 16/24 of these limited disease patients were CR (complete responders): 20/24 were CR at completion of their irradiation. Out of 20 evaluable patients with extensive disease, there was 59% survival at 1 year by life-table analysis. Only 4/44 (9%) brain parenchymal relapses occurred, one at 3 months and one at 6 months after local failure and two in patients who did not become CRs, implicating a possible re-seeding mechanism. Five patients had central nervous system relapses outside of brain parenchyma (spinal epidural and leptomeningeal); in three patients this was the initial site of failure. Significant complications included leukopenia (50%) and thrombocytopenia (24%) primarily during induction, and chronic pulmonary fibrosis (25%), possibly contributing to two deaths.

  19. Assessing mixed dose distributions in young sediments identified using small aliquots and a simple two-step SAR procedure: the F-statistic as a diagnostic tool

    Energy Technology Data Exchange (ETDEWEB)

    Spencer, J.Q. E-mail: joel.spencer@st-andrews.ac.uk; Sanderson, D.C.W.; Deckers, Katleen; Sommerville, A.A

    2003-10-01

    In this study we have investigated the apparent dose (D{sub e}*) distribution in four samples of young sedimentary quartz from different depositional environments, and on standard quartz comprised of artificial binary-dose mixtures. We have used a simplified two-step single-aliquot regenerative-dose (SAR) approach to rapidly measure D{sub e}* from a large number of small aliquots ({approx}50-100 grains), with a small sub-set subjected to routine SAR measurements to enable monitoring of luminescence characteristics. We have used an F-ratio analysis to interpret D{sub e}* distributions. This analysis is sensitive to structure, the leading edge and modal data in D{sub e}* distributions, indicated by inflections and plateaux in F-ratio plots. We cautiously suggest that F-ratios at or approaching unity may indicate a single dose component.

  20. An empirical formula to obtain tissue-phantom ratios from percentage depth-dose curves for small fields

    Science.gov (United States)

    Ding, George X.; Krauss, Rob

    2013-07-01

    For small photon fields, accurate values of a tissue-phantom ratio (TPR) are difficult to obtain either by direct measurement or by the conventional method of converting from measured percentage depth doses (%dd). This study aims to develop an empirical method to accurately obtain TPRs from %dd curves for small radiosurgery beams. The Monte Carlo simulation codes BEAMnrc/DOSXYZnrc were used to simulate the accelerator head and small, collimated fields including the circular cone accessory. The Monte Carlo directly calculated TPR values as a function of depth were compared with TPRs converted from %dd curves in a water phantom for field sizes ranging from 4 mm diameter to 10 × 10 cm2 fields. Direct measurements of TPRs were performed with the detector remaining fixed at a SAD of 100 cm and increasing the detector depth by adding water. The %dd curves were measured at 100 cm SSD in a 50 × 50 × 50 cm3 water tank. Using the Monte Carlo values, we developed an empirical formula to obtain TPRs from %dd and validated its accuracy. The conventional method of obtaining TPRs from %dd underestimate TPR by 3.4% and 0.6% at a depth 1.5 cm and overestimate TPR by 6.4% and 1.7% at a depth of 25 cm for 4 mm and 30 mm diameter circular fields, respectively. The empirical formula is derived from realistic Monte Carlo simulations using field sizes ranging from 4 to 30 mm and depth ranging from 1.5 to 25 cm. TPRs calculated using this function deviate from TPRs directly calculated from Monte Carlo by less than 0.5%. The accuracy of this empirical formula is validated against the directly measured TPRs in water. The developed empirical method has the potential to greatly simply the work in obtaining TPRs from measured %dd curves for small fields. By using this developed empirical formula the uncertainties between directly measured TPRs and converted TPRs from measured %dd curves are within 1%.

  1. Clinical introduction of Monte Carlo treatment planning: a different prescription dose for non-small cell lung cancer according to tumor location and size.

    Science.gov (United States)

    van der Voort van Zyp, Noëlle C; Hoogeman, Mischa S; van de Water, Steven; Levendag, Peter C; van der Holt, Bronno; Heijmen, Ben J M; Nuyttens, Joost J

    2010-07-01

    To provide a prescription dose for Monte Carlo (MC) treatment planning in patients with non-small-cell lung cancer according to tumor size and location. Fifty-three stereotactic radiotherapy plans designed using the equivalent path-length (EPL) algorithm were re-calculated using MC. Plans were compared by the minimum dose to 95% of the PTV (D95), the heterogeneity index (HI) and the mean dose to organs at risk (OARs). Based on changes in D95, the prescription dose was converted from EPL to MC. Based on changes in HI, we examined the feasibility of MC prescription to plans re-calculated but not re-optimized with MC. The MC fraction dose for peripheral tumors is 16-18 Gy depending on tumor size. For central tumors the MC dose was reduced less than for peripheral tumors. The HI decreased on average by 4-9% in peripheral tumors and 3-5% in central tumors. The mean dose to OARs was lower for MC than EPL, and correlated strongly (R(2)=0.98-0.99). For the conversion from EPL to MC we recommend a separate prescription dose according to tumor size. MC optimization is not required if a HI > or = 70% is accepted. Dose constraints to OARs can be easily converted due to the high EPL-MC correlation. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  2. Rapid Prenatal Diagnosis of Trisomy 21 by Real-time Quantitative Polymerase Chain Reaction with Amplification of Small Tandem Repeats and S100B in Chromosome 21

    Science.gov (United States)

    Nam, Mi Suk; Yang, Eun Suk

    2005-01-01

    Trisomy 21 (Down syndrome) is the most common congenital anomaly, and it occurs in one out of 700-1000 births. Current techniques such as amniocentesis and chorionic villi sampling (CVS) require lengthy laboratory culture procedures and high costs. This study was undertaken to establish a rapid prenatal diagnosis of trisomy 21 using real-time quantitative polymerase chain reaction (PCR) of fetal DNA from amniotic fluid. Real-time quantitative PCR was performed with DNA templates obtained from 14 normal blood samples, 10 normal amniotic fluid samples, 14 Down syndrome blood samples, and 7 Down syndrome amniotic fluid samples. Primers for D21S167 and S100B of chromosome 21 were used. Primers that direct the amplification of the 165-bp fragment of the insulin-like growth factor (IGF)-1 gene on chromosome 12 using a PCR primer were included to generate an internal standard for quantitation. The relative levels of D21S167 and S100B were 2.6 and 2.4 times higher in the blood of Down syndrome patients than those in the control group. The differences between these two groups were statistically significant (p-values were 0.0012 and 0.0016, respectively). The relative levels of D21S167 and S100B were 2.1 and 2.7 times higher in the amniotic fluid of Down syndrome fetuses than those in the control group. The difference between these two groups was statistically significant (p-values were 0.0379 and 0.0379, respectively). Prenatal diagnosis of trisomy 21 by real-time quantitative PCR using STR (small tandem repeats) amplification of D21S167 and S100B is a useful, accurate and rapid diagnostic method. Furthermore, it may also be useful for prenatal diagnosis with fetal DNA from maternal blood, and for preimplantation genetic diagnosis and prenatal counseling. PMID:15861490

  3. Small kernel 1 encodes a pentatricopeptide repeat protein required for mitochondrial nad7 transcript editing and seed development in maize (Zea mays) and rice (Oryza sativa).

    Science.gov (United States)

    Li, Xiao-Jie; Zhang, Ya-Feng; Hou, Mingming; Sun, Feng; Shen, Yun; Xiu, Zhi-Hui; Wang, Xiaomin; Chen, Zong-Liang; Sun, Samuel S M; Small, Ian; Tan, Bao-Cai

    2014-09-01

    RNA editing modifies cytidines (C) to uridines (U) at specific sites in the transcripts of mitochondria and plastids, altering the amino acid specified by the DNA sequence. Here we report the identification of a critical editing factor of mitochondrial nad7 transcript via molecular characterization of a small kernel 1 (smk1) mutant in Zea mays (maize). Mutations in Smk1 arrest both the embryo and endosperm development. Cloning of Smk1 indicates that it encodes an E-subclass pentatricopeptide repeat (PPR) protein that is targeted to mitochondria. Loss of SMK1 function abolishes the C → U editing at the nad7-836 site, leading to the retention of a proline codon that is edited to encode leucine in the wild type. The smk1 mutant showed dramatically reduced complex-I assembly and NADH dehydrogenase activity, and abnormal biogenesis of the mitochondria. Analysis of the ortholog in Oryza sativa (rice) reveals that rice SMK1 has a conserved function in C → U editing of the mitochondrial nad7-836 site. T-DNA knock-out mutants showed abnormal embryo and endosperm development, resulting in embryo or seedling lethality. The leucine at NAD7-279 is highly conserved from bacteria to flowering plants, and analysis of genome sequences from many plants revealed a molecular coevolution between the requirement for C → U editing at this site and the existence of an SMK1 homolog. These results demonstrate that Smk1 encodes a PPR-E protein that is required for nad7-836 editing, and this editing is critical to NAD7 function in complex-I assembly in mitochondria, and hence to embryo and endosperm development in maize and rice.

  4. Overexpression of collagen triple helix repeat containing 1 (CTHRC1) is associated with tumour aggressiveness and poor prognosis in human non-small cell lung cancer.

    Science.gov (United States)

    Ke, Zunfu; He, Weiling; Lai, Yuanhui; Guo, Xuefeng; Chen, Sharon; Li, Shuhua; Wang, Yuefeng; Wang, Liantang

    2014-10-15

    Collagen triple helix repeat-containing 1 (CTHRC1), a novel oncogene, was identified to be aberrantly overexpressed in several malignant tumors. However, the expression profile of CTHRC1 and its clinical significance in non-small cell lung cancer (NSCLC) remain unknown. In this study, we showed that CTHRC1 was evidently overexpressed in human NSCLC tissues and NSCLC cell lines at the protein and mRNA level. Ectopic up-regulation of CTHRC1 in cancer cells resulted in elevated invasive and proliferative abilities, which were attenuated by the specific CTHRC1 siRNA. The biological effect of CTHRC1 on metastasis and proliferation was mediated by the activation of the Wnt/β-catenin pathway. Furthermore, CTHRC1 immunoreactivity was evidently overexpressed in paraffin-embedded NSCLC tissues (212/292, 72.60%) in comparison to corresponding adjacent non-cancerous tissues (6/66, 9.09%) (p<0.001). Clinicopathologic analysis showed that CTHRC1 expression was significantly correlated with differentiation degree (p<0.001), clinical stage (p<0.001), T classification (p<0.001), lymph node metastasis (p=0.013) and distant metastasis (p<0.001). Kaplan-Meier analysis revealed that patients with high CTHRC1 expression had poorer overall survival rates than those with low CTHRC1 expression. Multivariate analysis indicated that CTHRC1 expression was an independent prognostic factor for the overall survival of NSCLC patients. Collectively, CTHRC1 plays important roles in NSCLC progression, and the evaluation of CTHRC1 expression could serve as a potential marker for metastasis progression and prognosis in NSCLC patients.

  5. Concerted evolution of the tandemly repeated genes encoding primate U2 small nuclear RNA (the RNU2 locus) does not prevent rapid diversification of the (CT){sub n} {center_dot} (GA){sub n} microsatellite embedded within the U2 repeat unit

    Energy Technology Data Exchange (ETDEWEB)

    Liao, D.; Weiner, A.M. [Yale Univ., New Haven, CT (United States)

    1995-12-10

    The RNU2 locus encoding human U2 small nuclear RNA (snRNA) is organized as a nearly perfect tandem array containing 5 to 22 copies of a 5.8-kb repeat unit. Just downstream of the U2 snRNA gene in each 5.8-kb repeat unit lies a large (CT){sub n}{center_dot}(GA){sub n} dinucleotide repeat (n {approx} 70). This form of genomic organization, in which one repeat is embedded within another, provides an unusual opportunity to study the balance of forces maintaining the homogeneity of both kinds of repeats. Using a combination of field inversion gel electrophoresis and polymerase chain reaction, we have been able to study the CT microsatellites within individual U2 tandem arrays. We find that the CT microsatellites within an RNU2 allele exhibit significant length polymorphism, despite the remarkable homogeneity of the surrounding U2 repeat units. Length polymorphism is due primarily to loss or gain of CT dinucleotide repeats, but other types of deletions, insertions, and substitutions are also frequent. Polymorphism is greatly reduced in regions where pure (CT){sub n} tracts are interrupted by occasional G residues, suggesting that irregularities stabilize both the length and the sequence of the dinucleotide repeat. We further show that the RNU2 loci of other catarrhine primates (gorilla, chimpanzee, ogangutan, and baboon) contain orthologous CT microsatellites; these also exhibit length polymorphism, but are highly divergent from each other. Thus, although the CT microsatellite is evolving far more rapidly than the rest of the U2 repeat unit, it has persisted through multiple speciation events spanning >35 Myr. The persistence of the CT microsatellite, despite polymorphism and rapid evolution, suggests that it might play a functional role in concerted evolution of the RNU2 loci, perhaps as an initiation site for recombination and/or gene conversion. 70 refs., 5 figs.

  6. Small pulmonary nodules in baseline and incidence screening rounds of low-dose CT lung cancer screening.

    Science.gov (United States)

    Walter, Joan E; Heuvelmans, Marjolein A; Oudkerk, Matthijs

    2017-02-01

    Currently, lung cancer screening by low-dose computed tomography (LDCT) is widely recommended for high-risk individuals by US guidelines, but there still is an ongoing debate concerning respective recommendations for European countries. Nevertheless, the available data regarding pulmonary nodules released by lung cancer screening studies could improve future screening guidelines, as well as the clinical practice of incidentally detected pulmonary nodules on routine CT scans. Most lung cancer screening trials present results for baseline and incidence screening rounds separately, clustering pulmonary nodules initially found at baseline screening and newly detected pulmonary nodules after baseline screening together. This approach does not appreciate possible differences among pulmonary nodules detected at baseline and firstly detected at incidence screening rounds and is heavily influenced by methodological differences of the respective screening trials. This review intends to create a basis for assessing non-calcified pulmonary nodules detected during LDCT lung cancer screening in a more clinical relevant manner. The aim is to present data of non-calcified pulmonary baseline nodules and new non-calcified pulmonary incident nodules without clustering them together, thereby also simplifying translation to the clinical practice of incidentally detected pulmonary nodules. Small pulmonary nodules newly detected at incidence screening rounds of LDCT lung cancer screening may possess a greater lung cancer probability than pulmonary baseline nodules at a smaller size, which is essential for the development of new guidelines.

  7. Active detection of small quantities of shielded highly-enriched uranium using low-dose 60-kev neutron interrogation

    Science.gov (United States)

    Kerr, Phil; Rowland, Mark; Dietrich, Dan; Stoeffl, Wolfgang; Wheeler, Boyd; Nakae, Les; Howard, Doug; Hagmann, Chris; Newby, Jason; Porter, Robert

    2007-08-01

    Active interrogation with low-energy neutrons provides a search technique for highly-enriched uranium concealed in cargo. We describe the technique and show initial results using a low-dose 60-keV neutron beam. This technique produces a clear induced fission signal in the presence of small quantities of 235U. The technique has been validated with low-Z and high-Z cargo materials. The technique uses a forward-directed beam of 60-keV neutrons to induce fission in 235U. Detection of the fast fission neutrons with pulse-shape discriminating scintillators is then the signature for 235U. The beam of neutrons is generated with a 1.93 MeV proton beam impinging on a natural lithium target. The proton beam is produced by a radio-frequency quadrupole LINAC. The 60 keV neutron beam is forward-directed because the 7Li(p, n) reaction is just above threshold for a proton energy of 1.93 MeV.

  8. Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats.

    Science.gov (United States)

    Liu, Liangming; Tian, Kunlun; Xue, Mingying; Zhu, Yu; Lan, Dan; Peng, Xiaoyong; Wu, Yue; Li, Tao

    2013-11-01

    Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.

  9. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

    Science.gov (United States)

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

    2009-01-01

    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  10. Low-dose ouabain constricts small arteries from ouabain-hypertensive rats: implications for sustained elevation of vascular resistance

    Science.gov (United States)

    Zhang, Jin; Hamlyn, John M.; Karashima, Eiji; Raina, Hema; Mauban, Joseph R. H.; Izuka, Michelle; Berra-Romani, Roberto; Zulian, Alessandra; Wier, W. Gil; Blaustein, Mordecai P.

    2009-01-01

    Prolonged ouabain administration to normal rats causes sustained blood pressure (BP) elevation. This ouabain-induced hypertension (OH) has been attributed, in part, to the narrowing of third-order resistance arteries (∼320 μm internal diameter) as a result of collagen deposition in the artery media (see Ref. 6). Here we describe the structural and functional properties of fourth-order mesenteric small arteries from control and OH rats, including the effect of low-dose ouabain on myogenic tone in these arteries. Systolic BP in OH rats was 138 ± 3 versus 124 ± 4 mmHg in controls (P < 0.01). Pressurized (70 mmHg) control and OH arteries, with only a single layer of myocytes, both had ∼165-μm internal diameters and ∼20-μm wall thicknesses. Even after fixation, despite vasoconstriction, the diameters and wall thicknesses did not differ between control and OH fourth-order arteries, whereas in third-order arteries, both parameters were significantly smaller in OH than in controls. Myogenic reactivity was significantly augmented in OH fourth-order arteries. Nevertheless, phenylephrine- (1 μM) and high K+-induced vasoconstrictions and acetylcholine-induced vasodilation were comparable in control and OH arteries. Vasoconstrictions induced by 5 μM phenylephrine and by 10 mM caffeine in Ca2+-free media indicated that releasable sarcoplasmic reticulum Ca2+ stores were normal in OH arteries. Importantly, 100 nM ouabain constricted both control and OH arteries by ∼26 μm, indicating that this response was not downregulated in OH rats. This maximal ouabain-induced constriction corresponds to a ∼90% increase in resistance to flow in these small arteries; thus ouabain at EC50 of ∼0.66 nM should raise resistance by ∼35%. We conclude that dynamic constriction in response to circulating nanomolar ouabain in small arteries likely makes a major contribution to the increased vascular tone and BP in OH rats. PMID:19617413

  11. Lack of a Dose-Effect Relationship for Pulmonary Function Changes After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guckenberger, Matthias, E-mail: Guckenberger_M@klinik.uni-wuerzburg.de [Department of Radiation Oncology, University Hospital Wuerzburg, Wuerzburg (Germany); Klement, Rainer J. [Department of Radiation Oncology, University Hospital Wuerzburg, Wuerzburg (Germany); Kestin, Larry L. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Hope, Andrew J. [Princess Margaret Hospital, University of Toronto, Toronto, ON (Canada); Belderbos, Jose [The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Werner-Wasik, Maria [Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Yan, Di [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Sonke, Jan-Jakob [The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Bissonnette, Jean-Pierre [Princess Margaret Hospital, University of Toronto, Toronto, ON (Canada); Xiao, Ying [Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Grills, Inga S. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States)

    2013-03-15

    Purpose: To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). Methods and Materials: The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses. Results: Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by −1.4% (95% confidence interval [CI], −3.4% to 0) and −7.6% (95% CI, −10.2% to −3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of −8.1% (95% CI, −13.3% to −5.3%) and −12.4% (95% CI, −15.5% to −6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship. Conclusions: This study failed to demonstrate a significant dose-effect relationship for

  12. Unexpectedly frequent occurrence of very small repeating earthquakes (5.1=Mw=3.6) in a South African gold mine: Implications for monitoring intraplate faults

    CSIR Research Space (South Africa)

    Naoi, M

    2015-12-01

    Full Text Available loaded by the surrounding aseismic slip (background creep). Application of the Nadeau and Johnson (1998) empirical formula (NJ formula), which relates the amount of background creep and repeater activity and is well established for plate boundary faults...

  13. Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol.

    Science.gov (United States)

    Hassan, H; Pohle, W; Rüthrich, H; Brödemann, R; Krug, M

    2000-04-01

    Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.

  14. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R

    1998-07-01

    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  15. Intensity modulated radiation therapy (IMRT: differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

    Directory of Open Access Journals (Sweden)

    Delclos Marc E

    2011-06-01

    Full Text Available Abstract Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT, to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1 or node-positive (N = 9, and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005, bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005, pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005, and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005, with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005. We found that the IMRT treatment volumes were typically larger than that

  16. Mating competitiveness of male Anopheles arabiensis mosquitoes irradiated with a partially or fully sterilizing dose in small and large laboratory cages.

    Science.gov (United States)

    Helinski, M E H; Knols, B G J

    2008-07-01

    Male mating competitiveness is a crucial parameter in many genetic control programs including the sterile insect technique (SIT). We evaluated competitiveness of male Anopheles arabiensis Patton as a function of three experimental variables: (1) small or large cages for mating, (2) the effects of either a partially sterilizing (70 Gy) or fully sterilizing (120 Gy) dose, and (3) pupal or adult irradiation. Irradiated males competed for females with an equal number of unirradiated males. Competitiveness was determined by measuring hatch rates of individually laid egg batches. In small cages, pupal irradiation with the high dose resulted in the lowest competitiveness, whereas adult irradiation with the low dose gave the highest, with the latter males being equal in competitiveness to unirradiated males. In the large cage, reduced competitiveness of males irradiated in the pupal stage was more pronounced compared with the small cage; the males irradiated as adults at both doses performed similarly to unirradiated males. Unexpectedly, males irradiated with the high dose performed better in a large cage than in a small one. A high proportion of intermediate hatch rates was observed for eggs collected in the large cage experiments with males irradiated at the pupal stage. It is concluded that irradiation of adult An. arabiensis with the partially sterilizing dose results in the highest competitiveness for both cage designs. Cage size affected competitiveness for some treatments; therefore, competitiveness determined in laboratory experiments must be confirmed by releases into simulated field conditions. The protocols described are readily transferable to evaluate male competitiveness for other genetic control techniques.

  17. A planning study of radiotherapy dose escalation of PET-active tumour volumes in non-small cell lung cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Sloth Moeller, Ditte; Hoffmann, Lone (Dept. of Medical Physics, Aarhus Univ. Hospital, Aarhus (Denmark)), e-mail: dittmoel@rm.dk; Khalil, Azza Ahmed; Marquard Knap, Marianne (Dept. of Oncology, Aarhus Univ. Hospital, Aarhus (Denmark)); Muren, Ludvig Paul (Dept. of Medical Physics, Aarhus Univ. Hospital, Aarhus (Denmark); Dept. of Oncology, Aarhus Univ. Hospital, Aarhus (Denmark))

    2011-08-15

    Background. Patients with non-small cell lung cancer (NSCLC) have poor prognosis partly because of high local failure rates. Escalating the dose to the tumour may decrease the local failure rates and thereby, improve overall survival, but the risk of complications will limit the possibility to dose-escalate a broad range of patients. Escalating only PET-active areas of the tumour may increase the potential for reaching high doses for a variety of tumour sizes and locations. Material and methods. Ten patients were randomly chosen for a dose escalation planning study. A planning target volume (PTV) was defined on the mid-ventilation scan of a four-dimensional computed tomography (4D-CT) scan and a boost planning target volume (PTV-boost) was defined based on a positron emission tomography computed tomography (PET-CT) scan. Treatment plans were created aiming to reach the highest achievable of 74 Gy, 78 Gy or 82 Gy in 2 Gy per fraction prescribed to the PTV-boost without compromising normal tissue constraints and with the PTV prescribed in all cases a biological equivalent dose in 2 Gy fractions of 66 Gy. Results. Nine of ten patients could be escalated to the highest dose level (82 Gy), while one patient was limited by the oesophagus dose constraint and could only reach 74 Gy. Four patients could be dose-escalated above 82 Gy without compromising normal tissue constraints. Conclusion. Dose-escalating only the PET-active areas of lung tumours to doses of 82 Gy while respecting normal tissue constraints is feasible, also in a series of unselected patients including cases with relatively large tumours

  18. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    Science.gov (United States)

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  19. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  20. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  1. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat.

    Science.gov (United States)

    Antkiewicz-Michaluk, Lucyna; Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy

    2014-07-01

    Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both

  2. Repeated low-dose 17β-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia.

    Science.gov (United States)

    Stanojlović, Miloš; Zlatković, Jelena; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zarić, Marina; Horvat, Anica; Drakulić, Dunja

    2015-01-01

    Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.

  3. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    Science.gov (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  4. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko

    2011-01-01

    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  5. Normal tissue tolerance to external beam radiation therapy: Small bowel; Dose de tolerance a l'irradiation des tissus sains: intestin grele

    Energy Technology Data Exchange (ETDEWEB)

    Martin, E. [Departement de radiotherapie, centre Georges-Francois-Leclerc, 21 - Dijon (France); Pointreau, Y.; Barillot, I. [Service de radiotherapie, centre regional universitaire de cancerologie Henry-S.-Kaplan, hopital Bretonneau, CHRU de Tours, 37 - Tours (France); Roche-Forestier, S. [Centre Jean-Bernard, 72 - Le Mans (France); Barillot, I. [Universite Francois-Rabelais, centre de cancerologie Henry-S.-Kaplan, CHU de Tours, 37 - Tours (France)

    2010-07-15

    The small bowel is a hollow organ involved in the transit and absorption of food. In relation to its anatomical location, a significant amount of this organ is exposed in whole or in part to ionizing radiation in external radiotherapy during abdominal or pelvic irradiation either for primary cancers or metastasis. The acute functional changes during external beam radiation are mainly leading to diarrhea, abdominal pain and bloating. The main late side effects of irradiation of the small intestine are chronic diarrhea, malabsorption with steatorrhoea, abdominal spasms, intestinal obstruction, bleeding and fistulas. The architecture of the small intestine may be considered as parallel with a significant correlation between the irradiated volume of small bowel and the likelihood of acute toxicity, whatever the dose. The literature analysis recommends to consider the volume of small bowel receiving 15 Gy (threshold of 100 to 200 cm{sup 3}) but also 30 and 50 Gy (thresholds of 35 to 300 cm{sup 3}, depending on the level of dose considered). Modern techniques of conformal radiotherapy with modulated intensity will probably have beneficial impact on small bowel toxicity. (authors)

  6. A temporary decrease in twitch response following reversal of rocuronium-induced neuromuscular block with a small dose of sugammadex in a pediatric patient.

    Science.gov (United States)

    Iwasaki, Hajime; Takahoko, Kenichi; Otomo, Shigeaki; Sasakawa, Tomoki; Kunisawa, Takayuki; Iwasaki, Hiroshi

    2014-04-01

    We report a temporary decrease in twitch response following reversal of rocuronium-induced neuromuscular block with a small dose of sugammadex in our dose-finding study in pediatric patients. A 19-month-old female infant (9.6 kg, 80 cm) was scheduled for elective cheiloplasty surgery. Anesthesia was induced with nitrous oxide 50% and sevoflurane 5% and maintained with air, oxygen, sevoflurane 3%, and fentanyl (total, 3 μg/kg). Neuromuscular monitoring was performed at the adductor pollicis muscle after induction of anesthesia but before the administration of rocuronium. Total dose of rocuronium during the surgery was 0.9 mg/kg. Neuromuscular block was reversed with 0.5 mg/kg sugammadex when one response was observed with post-tetanic count stimulation. Twitch responses after sugammadex administration showed a temporary decrease after its initial recovery. Maximum decreases in twitch responses were observed 17 min after initial dose of sugammadex. Twitch responses recovered to their control values after additional doses of 3.5 mg/kg sugammadex (4 mg/kg in total). Time from sugammadex administration to maximum decreases in twitch responses is earlier than has been reported in adults (20-70 min). It is demonstrated that following neuromuscular block reversal with insufficient dose of sugammadex, there is a possibility of the recurrence of residual paralysis within less than 20 min in pediatric patients.

  7. SU-E-T-108: Development of a Novel Clinical Neutron Dose Monitor for Proton Therapy Based On Twin TLD500 Chips in a Small PE Moderator

    Energy Technology Data Exchange (ETDEWEB)

    Hentschel, R; Mukherjee, B [Westdeutsches Protonentherapiezentrum Essen (WPE)gGmbH, Essen (Germany)

    2014-06-01

    Purpose: In proton therapy, it could be desirable to measure out-of-field fast neutron doses at critical locations near and outside the patient body. Methods: The working principle of a novel clinical neutron dose monitor is verified by MCNPX simulation. The device is based on a small PE moderator of just 5.5cm side length for easy handling covered with a thermal neutron suppression layer. In the simulation, a polystyrene phantom is bombarded with a standard proton beam. The secondary thermal neutron flux produced inside the moderator by the impinging fast neutrons from the treatment volume is estimated by pairs of α-Al2O3:C (TLD500) chips which are evaluated offline after the treatment either by TL or OSL methods. The first chip is wrapped with 0.5mm natural Gadolinium foil converting the thermal neutrons to gammas via (n,γ) reaction. The second chip is wrapped with a dummy material. The chip centers have a distance of 2cm from each other. Results: The simulation shows that the difference of gamma doses in the TLD500 chips is correlated to the mean fast neutron dose delivered to the moderator material. Different outer shielding materials have been studied. 0.5mm Cadmium shielding is preferred for cost reasons and convenience. Replacement of PE moderator material by other materials like lead or iron at any place is unfavorable. The spatial orientation of the moderator cube is uncritical. Using variance reduction techniques like splitting/Russian roulette, the TLD500 gamma dose simulation give positive differences up to distances of 0.5m from the treatment volume. Conclusion: Applicability and basic layout of a novel clinical neutron dose monitor are demonstrated. The monitor measures PE neutron doses at locations outside the patient body up to distances of 0.5m from the treatment volume. Tissue neutron doses may be calculated using neutron kerma factors.

  8. TU-F-BRE-09: Towards the Establishment of Dosimetric References in Small Fields Using the New Concept of Dose-Area Product

    Energy Technology Data Exchange (ETDEWEB)

    Dufreneix, S; Bordy, J; Delaunay, F; Delaunay, F; Daures, J; Gouriou, J; Le Roy, M; Ostrowsky, A; Rapp, B; Sommier, L [CEA, LIST, Laboratoire National Henri Becquerel, Gif-sur-Yvette (France)

    2014-06-15

    Purpose: To establish dosimetric references of absorbed dose in water in radiation fields smaller than 2 cm used in radiotherapy thanks to a new methodology based on the use of dosimeters larger than the field size. Methods: A new graphite calorimeter was constructed with a large sensitive volume (diameter of the core: 30 mm). This primary dosimeter was fully characterized and compared to previous LNE-LNHB graphite calorimeters in a 60Co large field. A specially designed graphite parallel-plate ionization chamber with a 30 mm collecting electrode was also assembled and tested. Measurements were then conducted in two 6 MV small circular fields of 2 cm and 1 cm diameter respectively, using the new concept of dose-area product instead of punctual dose commonly used in radiotherapy. Results: The dose rate established in a large 60Co field with the new calorimeter is in agreement within 0.4% with previous calorimeters. The ionization chamber shows good characteristics except for a 0.06% drift per hour in water. The ratio of calorimetric against ionometric measurements in the 2 cm diameter field is 1.1% higher than the one in the 1 cm diameter field (with respectively 0.30% and 1.03% type A uncertainty for each field). Conclusion: Results presented here highlight the possibility of measuring dose-area products in small fields with a graphite calorimeter and a parallel-plate ionization chamber. Measurements in a 0.75 cm diameter field are already underway to confirm the trend observed in the 2 cm and 1 cm diameter fields. The last step to establish precise dosimetric references in small fields is to calculate correction factors thanks to Monte Carlo simulations.

  9. Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure

    Energy Technology Data Exchange (ETDEWEB)

    Maier, Joscha, E-mail: joscha.maier@dkfz.de [Medical Physics in Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Sawall, Stefan; Kachelrieß, Marc [Medical Physics in Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and Institute of Medical Physics, University of Erlangen–Nürnberg, 91052 Erlangen (Germany)

    2014-05-15

    Purpose: Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Methods: Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Results: Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the

  10. Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer.

    Science.gov (United States)

    Stiff, P; Chen, B; Franklin, W; Oldenberg, D; Hsi, E; Bayer, R; Shpall, E; Douville, J; Mandalam, R; Malhotra, D; Muller, T; Armstrong, R D; Smith, A

    2000-03-15

    The collection of small aliquots of bone marrow (BM), followed by ex vivo expansion for autologous transplantation may be less morbid, and more cost-effective, than typical BM or blood stem cell harvesting. Passive elimination of contaminating tumor cells during expansion could reduce reinoculation risks. Nineteen breast cancer patients underwent autotransplants exclusively using ex vivo expanded small aliquot BM cells (900-1200 x 10(6)). BM was expanded in media containing recombinant flt3 ligand, erythropoietin, and PIXY321, using stromal-based perfusion bioreactors for 12 days, and infused after high-dose chemotherapy. Correlations between cell dose and engraftment times were determined, and immunocytochemical tumor cell assays were performed before and after expansion. The median volume of BM expanded was 36.7 mL (range 15.8-87.0). Engraftment of neutrophils greater than 500/microL and platelets greater than 20,000/microL were 16 (13-24) and 24 (19-45) days, respectively; 1 patient had delayed platelet engraftment, even after infusion of back-up BM. Hematopoiesis is maintained at 24 months, despite posttransplant radiotherapy in 18 of the 19 patients. Transplanted CD34(+)/Lin(-) (lineage negative) cell dose correlated with neutrophil and platelet engraftment, with patients receiving greater than 2.0 x 10(5) CD34(+)/Lin(-) cells per kilogram, engrafting by day 28. Tumor cells were observed in 1 of the 19 patients before expansion, and in none of the 19 patients after expansion. It is feasible to perform autotransplants solely with BM cells grown ex vivo in perfusion bioreactors from a small aliquot. Engraftment times are similar to those of a typical 1000 to 1500 mL BM autotransplant. If verified, this procedure could reduce the risk of tumor cell reinoculation with autotransplants and may be valuable in settings in which small stem cell doses are available, eg, cord blood transplants. (Blood. 2000;95:2169-2174)

  11. SU-F-P-29: Impact of Oral Contrast Agent for Assisting in Outlining Small Intestine On Pelvic IMAT Dose in Patients with Cervical Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, R; Bai, W; Fan, X [The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei (China)

    2016-06-15

    Purpose: As the advanced intensity modulated arc therapy(IMAT) delivery systems becoming a main role of treatment ways, which places even greater demands on delivering accuracy. The impact of oral contrast agent (meglumine diatrizoate) for assisting in outlining the small intestine on pelvic IMAT dose in patients with cervical cancer was investigated. Methods: Ten cervical cancer patients for postoperative radiotherapy underwent CT scans, and the planning target volumes (PTV) and organs at risk (including the small intestine, rectum, bladder, colon and the left and right femoral head) were contoured. The IMAT plans were generated on Oncentra v4.1 planning system for each case, PTV was prescribed to 50.4 Gy in 28 fractions. Then another plan was generated by re-calculating the radiation dose after changing the electron density of the small bowel. The first plan (plan A) was the conventional IMAT plan (with oral contrast agent), and the second one (plan B) specified the electron density of the small bowel (without oral contrast agent). Paired t-test was used to compare the dose distribution between the two plans. Results: The PTV’s D2, D50, D95, V110, conformity index, and homogeneity index of plans A and B were 5610.5 vs. 5611.4 cGy (P=0.175), 5348.5 vs. 5348.0 cGy (P=0.869), 5039 vs. 5042.3 (P=0.518), 6.0% vs. 6.1 %( P=0.886), 0.1269 vs. 0.1271 (P=0.34) and 0.8421 vs. 0.8416 (P=0.598), respectively. The volumes of the small bowel receiving at least 30 Gy (V30) and the minimum dose of 2% volume accepted (D2) for plans A and B were 31.6% vs. 31.9% (P=0.371) and 5067.8 vs. 5085.4 cGy (P=0.377), while rectum V50 of the two plans was 12.4% vs. 12.1% (P=0.489). Conclusion: The oral contrast agent (meglumine diatrizoate) filling the small intestine does not lead to a significant increase in the pelvic IMAT dose in patients with cervical cancer.

  12. Effect on thyroid function and serum PTH, BGP, CT of small dose of iodine 131 combined with Methimazole in patients with hyperthyroidism

    Institute of Scientific and Technical Information of China (English)

    Jia-Yin Qiu; Yan Zhu; Qing-Hong Xi

    2016-01-01

    Objective:To observe the effect Effect on thyroid function and serum PTH, BGP, CT of small dose of iodine 131 combined with Methimazole in patients with hyperthyroidism. Methods:A total of 104 patients with hyperthyroidism willing be incorporated into the study were randomly divided into the observation group (54 cases) and the control group (50 cases). The control group was treated with Methimazole, and the observation group was given a small dose of iodine 131 the basised on the control group. For 2 months, to observe the changes of thyroid function (TT3, TT4, FT3, FT4 and TSH) and bone metabolism related indexes (PTH, BGP and CT) of the two groups. Results:(1) After treatment, TT3, FT3, TT4 and FT4 of the two groups decreased with before, and the observation group improved more significantly than the control group, with statistical difference;TSH of the two groups had no significant change. (2) After treatment, BGP and CT of the two groups decreased and PTH increased, the observation group improved more significantly than the control group, with statistical difference. Conclusion:small dose of iodine 131 combined with Methimazole can correct thyroid function and bone metabolism quickly in patients with hyperthyroidism.

  13. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  14. Small pulmonary nodules in baseline and incidence screening rounds of low-dose CT lung cancer screening

    NARCIS (Netherlands)

    Walter, Joan E; Heuvelmans, Marjolein A; Oudkerk, Matthijs

    Currently, lung cancer screening by low-dose computed tomography (LDCT) is widely recommended for high-risk individuals by US guidelines, but there still is an ongoing debate concerning respective recommendations for European countries. Nevertheless, the available data regarding pulmonary nodules

  15. Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

    Science.gov (United States)

    Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

  16. A small peptide modeled after the NRAGE repeat domain inhibits XIAP-TAB1-TAK1 signaling for NF-κB activation and apoptosis in P19 cells.

    Directory of Open Access Journals (Sweden)

    Jennifer A Rochira

    Full Text Available In normal growth and development, apoptosis is necessary to shape the central nervous system and to eliminate excess neurons which are not required for innervation. In some diseases, however, apoptosis can be either overactive as in some neurodegenerative disorders or severely attenuated as in the spread of certain cancers. Bone morphogenetic proteins (BMPs transmit signals for regulating cell growth, differentiation, and apoptosis. Responding to BMP receptors stimulated from BMP ligands, neurotrophin receptor-mediated MAGE homolog (NRAGE binds and functions with the XIAP-TAK1-TAB1 complex to activate p38(MAPK and induces apoptosis in cortical neural progenitors. NRAGE contains a unique repeat domain that is only found in human, mouse, and rat homologs that we theorize is pivotal in its BMP MAPK role. Previously, we showed that deletion of the repeat domain inhibits apoptosis, p38(MAPK phosphorylation, and caspase-3 cleavage in P19 neural progenitor cells. We also showed that the XIAP-TAB1-TAK1 complex is dependent on NRAGE for IKK-α/β phosphorylation and NF-κB activation. XIAP is a major inhibitor of caspases, the main executioners of apoptosis. Although it has been shown previously that NRAGE binds to the RING domain of XIAP, it has not been determined which NRAGE domain binds to XIAP. Here, we used fluorescence resonance energy transfer (FRET to determine that there is a strong likelihood of a direct interaction between NRAGE and XIAP occurring at NRAGE's unique repeat domain which we also attribute to be the domain responsible for downstream signaling of NF-κB and activating IKK subunits. From these results, we designed a small peptide modeled after the NRAGE repeat domain which we have determined inhibits NF-κB activation and apoptosis in P19 cells. These intriguing results illustrate that the paradigm of the NRAGE repeat domain may hold promising therapeutic strategies in developing pharmaceutical solutions for combating harmful

  17. Comparison in the calculation of committed effective dose using the ICRP 30 and ICRP 60 models for a repeated incorporation by inhalation of I-125; Comparacion en el calculo de la dosis efectiva comprometida usando los modelos del ICRP 30 y del ICRP 60 para una incorporacion repetida por inhalacion de I-125

    Energy Technology Data Exchange (ETDEWEB)

    Carreno P, A.L.; Cortes C, A. [CNSNS, Dr. Barragan 779, Col. Narvarte, Mexico D.F. (Mexico); Alonso V, G.; Serrano P, F. [IPN, Edificio de Fisica Avanzada Zacatenco, 07300 Mexico D.F. (Mexico)

    2005-07-01

    Presently work, a comparison in the calculation of committed effective dose using the models of the ICRP 30 and those of the ICRP 60 for the analysis of internal dose due to repeated incorporation of I-125 is shown. The estimations of incorporated activity are obtained starting from the proportionate data for an exercise of inter comparison, with which it should be determined the internal dose later on. For to estimate the initial activity incorporated by repeated dose was assumed that this it was given through of multiple individual incorporations which happened in the middle points of the monitoring periods. The results using the models of the ICRP 30 and of the ICRP 60 are compared and the causes of the differences are analyzed. (Author)

  18. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer.

    Science.gov (United States)

    Dickhoff, C; Dahele, M; Paul, M A; van de Ven, P M; de Langen, A J; Senan, S; Smit, E F; Hartemink, K J

    2016-04-01

    Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery. Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed. A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60-70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. Increasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing Stereotactic Body Radiation Therapy for Stage I Non–Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Koshy, Matthew, E-mail: mkoshy@radonc.uchicago.edu [Department of Radiation Oncology, University of Illinois at Chicago, Chicago, Illinois (United States); Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois (United States); Malik, Renuka [Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois (United States); Weichselbaum, Ralph R. [Department of Radiation Oncology, University of Illinois at Chicago, Chicago, Illinois (United States); Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois (United States); Sher, David J. [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States)

    2015-02-01

    Purpose: To determine the comparative effectiveness of different stereotactic body radiation therapy (SBRT) dosing regimens for early-stage non–small-cell lung cancer, using a large national database, focusing on the relative impact of dose as a function of tumor stage. Methods and Materials: The study included patients in the National Cancer Database from 2003 to 2006 with T1-T2N0M0 inoperable lung cancer (n=498). The biologically effective dose (BED) was calculated according to the linear quadratic formula using an α/β ratio of 10. High versus lower-dose (HD vs LD) SBRT was defined as a calculated BED above or below 150 Gy. Overall survival was estimated using Kaplan-Meier methods and Cox proportional hazard regression. Results: The 5 most common dose fractionation schemes (percentage of cohort) used were 20 Gy × 3 (34%), 12 Gy × 4 (16%), 18 Gy × 3 (10%), 15 Gy × 3 (10%), and 16 Gy × 3 (4%). The median calculated BED was 150 Gy (interquartile range 106-166 Gy). The 3-year overall survival (OS) for patients who received HD versus LD was 55% versus 46% (log–rank P=.03). On subset analysis of the T1 cohort there was no association between calculated BED and 3-year OS (61% vs 60% with HD vs LD, P=.9). Among the T2 cohort, patients receiving HD experienced superior 3-year OS (37% vs 24%, P=.01). On multivariable analysis, factors independently prognostic for mortality were female gender (hazard ratio [HR] 0.76, P=.01), T2 tumor (HR 1.99, P=.0001), and HD (HR 0.68, P=.001). Conclusions: This comparative effectiveness analysis of SBRT dose for patients with stage I non–small-cell lung cancer suggests that higher doses (>150 Gy BED) are associated with a significant survival benefit in patients with T2 tumors.

  20. [The effect of small doses of ionizing radiation on the physico-chemical characteristics of the membranes of peripheral blood lymphocytes of rats].

    Science.gov (United States)

    Prishchep, S G; Gerasimovich, N V; Bulanova, K Ia; Miliutin, A A

    2000-01-01

    The fluorescence probe method was used for investigating the physical state of a total lipid phase of a bi-layer and an annular (near-protein) zone of the membrane lipids of lymphocytes in a peripheral blood of rats on the 10th day after a whole-body acute and chronic gamma-exposure to doses of 0.25, 0.5, and 1.0 Gy. It was discovered that exposure to doses of 0.25, 0.5, and 1.0 Gy revealed no reliable distinctions in the parameters of a physical state of the lipid component of membranes within the given period of observation if compared with those of controls. However chronic exposure to the same doses caused the increase in hydrophobicity of the total lipid phase of the membrane bi-layer with no change in the polarity of an annular lipid. The near-protein zone of lipids revealed a local decrease in microviscosity while the fluidity of total lipids of a membrane bi-layer remained unaltered. A detected change of tryptophan fluorescence of the membrane proteins after exposing them to small dosed has also been carried out.

  1. Use of mass vaccination with a reduced dose of REV 1 vaccine for Brucella melitensis control in a population of small ruminants.

    Science.gov (United States)

    Scharp, D W; al Khalaf, S A; al Muhanna, M W; Cheema, R A; Godana, W

    1999-06-01

    Mass vaccination with reduced dose 1/50 Rev 1 strain live vaccine (1-2 10(9) colony forming units), administered subcutaneously, over a four and a half year period reduced the prevalence of Brucella melitensis in Kuwait's small ruminant population from 5.8% in 1993 to 2.02% in 1997. Serological test results using the Rose Bengal Plate Test, Rivanol Agglutination Test and Complement Fixation showed no evidence of persistence of positive serology in animals nine or more months after vaccination. Questionnaires and post-vaccination flock inspections found that the effects on gestation (abortions) were minimal--and not proven to be due to the vaccine. The conclusion from these findings is that mass vaccination with reduced dose Rev 1 administered by the subcutaneous route is a practical field strategy for control of Brucella melitensis.

  2. Analysis of incidental radiation dose to uninvolved mediastinal/supraclavicular lymph nodes in patients with limited-stage small cell lung cancer treated without elective nodal irradiation.

    Science.gov (United States)

    Ahmed, Irfan; DeMarco, Marylou; Stevens, Craig W; Fulp, William J; Dilling, Thomas J

    2011-01-01

    Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENI(off)) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENI(on)). Nodal stations were contoured using published guidelines, then placed into 4 "bins" (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENI(on) plans demonstrated a statistically significant degradation in dose coverage compared with the ENI(off) plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the "1 echelon away" nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to anatomically distant lymph nodes

  3. Analysis of Incidental Radiation Dose to Uninvolved Mediastinal/Supraclavicular Lymph Nodes in Patients with Limited-Stage Small Cell Lung Cancer Treated Without Elective Nodal Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Irfan; DeMarco, Marylou; Stevens, Craig W. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL (United States); Fulp, William J. [Biostatistics Core, H. Lee Moffitt Cancer Center, Tampa, FL (United States); Dilling, Thomas J., E-mail: Thomas.Dilling@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL (United States)

    2011-01-01

    Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENI{sub off}) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENI{sub on}). Nodal stations were contoured using published guidelines, then placed into 4 'bins' (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENI{sub on} plans demonstrated a statistically significant degradation in dose coverage compared with the ENI{sub off} plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the '1 echelon away' nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to

  4. Analysis of small field percent depth dose and profiles: Comparison of measurements with various detectors and effects of detector orientation with different jaw settings

    Directory of Open Access Journals (Sweden)

    Henry Finlay Godson

    2016-01-01

    Full Text Available The advent of modern technologies in radiotherapy poses an increased challenge in the determination of dosimetric parameters of small fields that exhibit a high degree of uncertainty. Percent depth dose and beam profiles were acquired using different detectors in two different orientations. The parameters such as relative surface dose (DS, depth of dose maximum (Dmax, percentage dose at 10 cm (D10, penumbral width, flatness, and symmetry were evaluated with different detectors. The dosimetric data were acquired for fields defined by jaws alone, multileaf collimator (MLC alone, and by MLC while the jaws were positioned at 0, 0.25, 0.5, and 1.0 cm away from MLC leaf-end using a Varian linear accelerator with 6 MV photon beam. The accuracy in the measurement of dosimetric parameters with various detectors for three different field definitions was evaluated. The relative DS(38.1% with photon field diode in parallel orientation was higher than electron field diode (EFD (27.9% values for 1 cm ×1 cm field. An overestimation of 5.7% and 8.6% in D10depth were observed for 1 cm ×1 cm field with RK ion chamber in parallel and perpendicular orientation, respectively, for the fields defined by MLC while jaw positioned at the edge of the field when compared to EFD values in parallel orientation. For this field definition, the in-plane penumbral widths obtained with ion chamber in parallel and perpendicular orientation were 3.9 mm, 5.6 mm for 1 cm ×1 cm field, respectively. Among all detectors used in the study, the unshielded diodes were found to be an appropriate choice of detector for the measurement of beam parameters in small fields.

  5. Effectiveness of polaprezinc for low-dose aspirin-induced small-bowel mucosal injuries as evaluated by capsule endoscopy: a pilot randomized controlled study.

    Science.gov (United States)

    Watari, Ikue; Oka, Shiro; Tanaka, Shinji; Aoyama, Taiki; Imagawa, Hiroki; Shishido, Takayoshi; Yoshida, Shigeto; Chayama, Kazuaki

    2013-07-04

    Treatment of low-dose aspirin (LDA)-induced small-bowel injury has not been established. Polaprezinc, a chelate of zinc and L-carnosine, may be efficacious for such injury. We conducted a pilot randomized controlled study to investigate whether polaprezinc is effective against LDA-induced small-bowel injuries. Consecutive patients under long-term (>3 months) LDA treatment and who agreed to participate in our study underwent initial capsule endoscopy (CE). Patients with LDA-induced small-bowel injury apparent upon initial CE (n = 20) were randomized into a polaprezinc (150 mg/day for 4 weeks) group and a control (no polaprezinc treatment) group. All underwent follow-up CE after 4 weeks. Changes in the number and characteristics of small-bowel mucosal injuries were compared within and between the two groups. The median number of reddened lesions and erosions/ulcers upon follow-up CE in the polaprezinc group significantly decreased (P < 0.05). However, there was no significant difference in the median number of reddened lesions and erosions/ulcers upon follow-up CE in the control group. Co-administration of polaprezinc may be effective against small-bowel mucosal injury associated with long-term LDA therapy.

  6. Comparison of small-bowel mucosal injury between low-dose aspirin and non-aspirin non-steroidal anti-inflammatory drugs: a capsule endoscopy study.

    Science.gov (United States)

    Watari, Ikue; Oka, Shiro; Tanaka, Shinji; Igawa, Atsushi; Nakano, Makoto; Aoyama, Taiki; Yoshida, Shigeto; Chayama, Kazuaki

    2014-01-01

    The differences in the severity of small-bowel toxicity induced by aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) remain unclear. This study aimed at clarifying these differences in small-bowel mucosal injury by using capsule endoscopy (CE). We retrospectively compared the records of 78 and 40 obscure gastrointestinal bleeding patients receiving low-dose aspirin (LDA) and non-aspirin NSAIDs, respectively. All patients were found to have small-bowel mucosal injuries on CE. The two groups were compared for the number of small-bowel mucosal injuries and CE scores on the basis of the findings of CE. The mean numbers of reddened lesions in the LDA group and non-aspirin NSAID group were 2.49 ± 3.15 and 1.65 ± 3.04; the mean numbers of erosions/ulcers 1.56 ± 3.75 and 6.08 ± 10.4, and the mean CE scores 154 ± 294 and 520 ± 758, respectively. The mean number of reddened lesions was significantly higher and the mean number of erosions/ulcers and CE scores significantly lower in the LDA group than in the other non-aspirin NSAID group. Small-bowel mucosal injuries were significantly milder in the LDA group than in the non-aspirin NSAID group, though reddened lesions were more frequent in the LDA group.

  7. Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin in the treatment of stage III non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Tianlin XIAO

    2008-02-01

    Full Text Available Background and objective Concurrent chemoradiotherapy is regarded as the standard care for locally advanced non-small cell lung cancer at present. This paper is designed to evaluate the efficacy and toxicity of low-dose weekly docetaxel (DTX with concurrent chemoradiotherapy followed by consolidation chemotherapy with DTX and cisplatin for unresectable stage III non-small cell lung cancer(NSCLC. Methods 44 previously untreated patients with stage III NSCLC were randomized into low-dose weekly DTX group and control group concomitant with radiotherapy. Both groups were treated by the standard fractionation schedule with three-dimensional conformal radiotherapy. An involved-field irradiation technique was performed. Gross tumor and metastatic lymph nodes were irradiated to a total dose of 66 Gy~70 Gy. Patients in the former group received chemotherapy with DTX 20mg. m-2.w-1,and the other group patients received DTX 60 mg/m2 on day 1 and DDP 30 mg/m2 on day 1~3 every 21 days. All patients received consolidation chemotherapy with DP regime after chemoradiotherapy for no more than 4 cycles. Results The overall response rates of patients in the low-dose weekly DTX group and control group were 81.8% with 27.3% CR(complete response and 86.4% with 27.3% CR respectively (Chisquare=0.120, P=0.942. After a median follow-up of 20months, the median survival time was 20 months and 17 months respectively. The 1-, 2- year survival rates of patients in low-dose weekly DTX group and control group were 69.8%, 48.1% versus 66.5%, 40.2% respectively;there was no difference between two groups. Grade 3 or 4 neutropenia and esophagitis occurred in 26.3%, 14.3% and 15.8%, 28.6% respectively (Chiquare=0.765,P =0.382(Chiquare=1.108,P =0.292.Grade 3 and 4 pulmonary toxicity was unusual.Conclusion Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin is highly active with manageable toxicity in patients

  8. Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

    Science.gov (United States)

    Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

    2015-03-01

    Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days.

  9. [Role of emotional stress in development of somatic injuries in liquidators of the Chernobyl power plant accident irradiated with small doses].

    Science.gov (United States)

    Moroz, B B; Deshevoĭ, Iu B

    1999-01-01

    In the light of modern beliefs about emotional stress are considered available in the literature given on changing a picture of health beside persons, taken part in liquidations of consequences of damage on Chernobil atomic stations. Results of psychological, psychophysiological and endocrinological examinations point to that beside significant numbers of liquidators of damage was developed chronic emotional stress. Expected presence of feedforward between the emotional stress and development beside liquidators of psychic frustrations, cardiovascular pathology, peptic ulcer of stomach and duodenum. Is discussed problem of combining action on the organism of ionizing radiating in small doses and long emotional stress.

  10. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Jong-Hyuk [KAERI; Byun, Thak Sang [ORNL; Maloy, S [Los Alamos National Laboratory (LANL); Toloczko, M [Pacific Northwest National Laboratory (PNNL)

    2014-01-01

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3 145 dpa at 380 503 C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm 3mm 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than the irradiation dose. At an irradiation temperature <430 C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180 200 MPa ffiffiffiffiffi m p at 350 450 C, and then decreased with the test temperature. At an irradiation temperatureP430 C, the fracture toughness was nearly unchanged up to about 450 C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.

  11. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Jong-Hyuk, E-mail: jhbaek@kaeri.re.kr [Korea Atomic Energy Research Institute, Daejeon 305-353 (Korea, Republic of); Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Byun, Thak Sang [Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States); Maloy, Start A. [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Toloczko, Mychailo B. [Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2014-01-15

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3–145 dpa at 380–503 °C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm × 3 mm × 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than the irradiation dose. At an irradiation temperature <430 °C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180–200MPa√(m) at 350–450 °C, and then decreased with the test temperature. At an irradiation temperature ⩾430 °C, the fracture toughness was nearly unchanged up to about 450 °C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.

  12. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, Stuart A.; Toloczko, Mychailo B.

    2014-01-01

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3–145 dpa at 380–503 degrees*C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm *3mm* 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than the irradiation dose. At an irradiation temperature <430 *degreesC, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180—200 MPa*m^.5 at 350–450 degrees*C, and then decreased with the test temperature. At an irradiation temperature >430 degrees*C, the fracture toughness was nearly unchanged up to about 450 *degreesC and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.

  13. Dosimetry for small size beams such as IMRT and stereotactic radiotherapy, is the concept of the dose at a point still relevant? proposal for a new methodology; Dosimetrie pour les faisceaux de petites dimensions pour la RCMI et la stereotaxie. Le concept de dose en un point est il adapte? proposition pour une nouvelle methodologie

    Energy Technology Data Exchange (ETDEWEB)

    Ostrowsky, A.; Bordy, J.M.; Daures, J.; De Carlan, L.; Delaunay, F.

    2010-07-01

    Solving the problem of traceability of the absorbed dose to the tumour for the radiation fields of small and very small dimensions, like those used for new treatment modality usually results in the use of dosemeters of much smaller size than those of the beam. For the realisation of the reference in primary standards laboratories, the absence of technology likely to produce absolute small-size dosemeters leaves no possibility for the direct measurement of the absorbed dose at a point and implies the use of passive or active small-size transfer dosemeters. This report intends to introduce a new kind of dose quantity for radiotherapy similar do the Dose Area Product concept used in radiology. Such a new concept has to be propagated through the metrology chain, including the TPS, to the calculation of the absorbed dose to the tumour. (authors)

  14. Karnosky Performance Score and Radiation Dose Predict Survival of Patients Re-irradiated for a Locoregional Recurrence of Small Cell Lung Cancer.

    Science.gov (United States)

    Käsmann, Lukas; Janssen, Stefan; Schild, Steven E; Rades, Dirk

    2016-02-01

    When patients with small cell lung cancer (SCLC) experience locoregional recurrence, surgery is often not employed as salvage therapy. Systemic chemotherapy and radiotherapy are often used. Many radiation oncologists are reluctant to deliver a second course of radiotherapy. However, select patients may benefit from re-irradiation. This study aimed to identify these patients. In patients receiving re-irradiation for a locoregional recurrence of SCLC, 11 potential prognostic factors were analyzed for survival. Survival was positively associated with a Karnofsky performance score ≥80 (p=0.003) and a cumulative dose >90 Gy (p=0.026). A trend was observed for younger age, longer interval between first course of radiotherapy and re-irradiation, a greater dose of re-irradiation and for concurrent chemotherapy. Significant predictors of survival in patients re-irradiated for a locoregional recurrence of SCLC were identified. Patients with a good performance status can benefit from re-irradiation if administered in sufficient doses. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Variation of kQclin,Qmsrfclin,fmsr for the small-field dosimetric parameters percentage depth dose, tissue-maximum ratio, and off-axis ratio

    Science.gov (United States)

    Francescon, Paolo; Beddar, Sam; Satariano, Ninfa; Das, Indra J.

    2014-01-01

    Purpose: Evaluate the ability of different dosimeters to correctly measure the dosimetric parameters percentage depth dose (PDD), tissue-maximum ratio (TMR), and off-axis ratio (OAR) in water for small fields. Methods: Monte Carlo (MC) simulations were used to estimate the variation of kQclin,Qmsrfclin,fmsr for several types of microdetectors as a function of depth and distance from the central axis for PDD, TMR, and OAR measurements. The variation of kQclin,Qmsrfclin,fmsr enables one to evaluate the ability of a detector to reproduce the PDD, TMR, and OAR in water and consequently determine whether it is necessary to apply correction factors. The correctness of the simulations was verified by assessing the ratios between the PDDs and OARs of 5- and 25-mm circular collimators used with a linear accelerator measured with two different types of dosimeters (the PTW 60012 diode and PTW PinPoint 31014 microchamber) and the PDDs and the OARs measured with the Exradin W1 plastic scintillator detector (PSD) and comparing those ratios with the corresponding ratios predicted by the MC simulations. Results: MC simulations reproduced results with acceptable accuracy compared to the experimental results; therefore, MC simulations can be used to successfully predict the behavior of different dosimeters in small fields. The Exradin W1 PSD was the only dosimeter that reproduced the PDDs, TMRs, and OARs in water with high accuracy. With the exception of the EDGE diode, the stereotactic diodes reproduced the PDDs and the TMRs in water with a systematic error of less than 2% at depths of up to 25 cm; however, they produced OAR values that were significantly different from those in water, especially in the tail region (lower than 20% in some cases). The microchambers could be used for PDD measurements for fields greater than those produced using a 10-mm collimator. However, with the detector stem parallel to the beam axis, the microchambers could be used for TMR measurements for all

  16. High Dose MicroCT Does Not Contribute Toward Improved MicroPET/CT Image Quantitative Accuracy and Can Limit Longitudinal Scanning of Small Animals

    Directory of Open Access Journals (Sweden)

    Wendy A. McDougald

    2017-10-01

    Full Text Available Obtaining accurate quantitative measurements in preclinical Positron Emission Tomography/Computed Tomography (PET/CT imaging is of paramount importance in biomedical research and helps supporting efficient translation of preclinical results to the clinic. The purpose of this study was two-fold: (1 to investigate the effects of different CT acquisition protocols on PET/CT image quality and data quantification; and (2 to evaluate the absorbed dose associated with varying CT parameters.Methods: An air/water quality control CT phantom, tissue equivalent material phantom, an in-house 3D printed phantom and an image quality PET/CT phantom were imaged using a Mediso nanoPET/CT scanner. Collected data was analyzed using PMOD software, VivoQuant software and National Electric Manufactures Association (NEMA software implemented by Mediso. Measured Hounsfield Unit (HU in collected CT images were compared to the known HU values and image noise was quantified. PET recovery coefficients (RC, uniformity and quantitative bias were also measured.Results: Only less than 2 and 1% of CT acquisition protocols yielded water HU values < −80 and air HU values < −840, respectively. Four out of 11 CT protocols resulted in more than 100 mGy absorbed dose. Different CT protocols did not impact PET uniformity and RC, and resulted in <4% overall bias relative to expected radioactive concentration.Conclusion: Preclinical CT protocols with increased exposure times can result in high absorbed doses to the small animals. These should be avoided, as they do not contributed toward improved microPET/CT image quantitative accuracy and could limit longitudinal scanning of small animals.

  17. Expanded complexity of unstable repeat diseases

    OpenAIRE

    Polak, Urszula; McIvor, Elizabeth; Dent, Sharon Y.R.; Wells, Robert D.; Napierala, Marek.

    2012-01-01

    Unstable Repeat Diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly expansion, of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequen...

  18. Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study

    Directory of Open Access Journals (Sweden)

    Minami Seigo

    2012-07-01

    Full Text Available Abstract Background Erlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC. These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients. Methods A phase I dose-finding study (Trial registration: UMIN000002900 was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m2 of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2 orally on days 2–16. Results Twelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48–78 years, stage IV disease (nine cases, adenocarcinoma (seven cases and activating mutation-positives in the epidermal growth factor receptor gene (two cases. Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients. Conclusions Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.

  19. On the measurement of dose in-air for small radiation fields: choice of mini-phantom material.

    Science.gov (United States)

    Hug, Benjamin; Warrener, Kirbie; Liu, Paul; Ralston, Anna; Suchowerska, Natalka; McKenzie, David; Ebert, Martin A

    2015-03-21

    The purpose of this work was to determine the effect of choice of mini-phantom material on the measurement and calculation of in-air output factors (Sc) in small fields. Monte Carlo simulations in conjunction with a theoretical determination of Sc were used to validate previously reported measurements. Options for alternative mini-phantom materials were compared. A 6 MV beam from a Varian Novalis linear accelerator operating in stereotactic (SRS) mode was modelled. Phase-space data were used to determine the theoretical value of Sc. To validate previously reported Sc measurements the data were used to model the fibre-optic detector and brass mini-phantom. The impact of mini-phantom material was investigated by comparing the energy spectra of electrons entering the detector volume as a function of field size, and comparing the simulated Sc-measurement to the theoretical calculation. In order to determine factors leading to changes in Sc with field size, the origins of particles in the beam as incident on the mini-phantom were determined. Sc values derived from simulated measurements using a brass mini-phantom on a fibre-optic detector agreed with the measured Sc to within 0.7%. For simulation of measurement for all other mini-phantom materials, Sc values agreed with the theoretically calculated values to within 0.6%. The dominant processes responsible for a decrease in Sc with field size is occlusion of the focal and primary collimator contributions, while the secondary scatter, from the flattening filter and cone collimators, has minimal effect. The secondary electron spectrum is affected by the choice of mini-phantom material, but is almost independent of field size. For cone-collimated small fields in the Novalis beam (<30 mm), the decrease in Sc with field size is primarily due to collimation of the focal radiation beam and scatter from the primary collimator. A fibre optic detector with either a brass, gold or lead mini-phantom with at least d

  20. Origin and fate of repeats in bacteria.

    Science.gov (United States)

    Achaz, G; Rocha, E P C; Netter, P; Coissac, E

    2002-07-01

    We investigated 53 complete bacterial chromosomes for intrachromosomal repeats. In previous studies on eukaryote chromosomes, we proposed a model for the dynamics of repeats based on the continuous genesis of tandem repeats, followed by an active process of high deletion rate, counteracted by rearrangement events that may prevent the repeats from being deleted. The present study of long repeats in the genomes of Bacteria and Archaea suggests that our model of interspersed repeats dynamics may apply to them. Thus the duplication process might be a consequence of very ancient mechanisms shared by all three domains. Moreover, we show that there is a strong negative correlation between nucleotide composition bias and the repeat density of genomes. We hypothesise that in highly biased genomes, non-duplicated small repeats arise more frequently by random effects and are used as primers for duplication mechanisms, leading to a higher density of large repeats.

  1. Is Intermediate Radiation Dose Escalation With Concurrent Chemotherapy for Stage III Non–Small-Cell Lung Cancer Beneficial? A Multi-Institutional Propensity Score Matched Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, George, E-mail: george.rodrigues@lhsc.on.ca [London Health Sciences Centre, London, Ontario (Canada); Oberije, Cary [MAASTRO Clinic, Maastricht (Netherlands); Senan, Suresh [VU University Medical Center, Amsterdam (Netherlands); Tsujino, Kayoko [Hyogo Cancer Center, Akashi (Japan); Wiersma, Terry [MAASTRO Clinic, Maastricht (Netherlands); Moreno-Jimenez, Marta [Universidad de Navarra, Pamplona (Spain); Kim, Tae Hyun [National Cancer Center, Goyang-si, Gy eonggi (Korea, Republic of); Marks, Lawrence B. [University of North Carolina, Chapel Hill, North Carolina (United States); Rengan, Ramesh [University of Washington, Seattle, Washington (United States); De Petris, Luigi [Karolinska University Hospital, Stockholm (Sweden); Ramella, Sara [Campus Bio-Medico University, Rome (Italy); DeRuyck, Kim [Ghent University, Ghent (Belgium); De Dios, Núria Rodriguez [Universidad Pompeu Fabra, Barcelona (Spain); Warner, Andrew [London Health Sciences Centre, London, Ontario (Canada); Bradley, Jeffrey D. [Washington University School of Medicine, St. Louis, Missouri (United States); Palma, David A. [London Health Sciences Centre, London, Ontario (Canada)

    2015-01-01

    Purpose: The clinical benefits and risks of dose escalation (DE) for stage III non–small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. Methods and Materials: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. Results: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0

  2. Repeat Gamma Knife surgery for vestibular schwannomas

    Science.gov (United States)

    Lonneville, Sarah; Delbrouck, Carine; Renier, Cécile; Devriendt, Daniel; Massager, Nicolas

    2015-01-01

    Background: Gamma Knife (GK) surgery is a recognized treatment option for the management of small to medium-sized vestibular schwannoma (VS) associated with high-tumor control and low morbidity. When a radiosurgical treatment fails to stop tumor growth, repeat GK surgery can be proposed in selected cases. Methods: A series of 27 GK retreatments was performed in 25 patients with VS; 2 patients underwent three procedures. The median time interval between GK treatments was 45 months. The median margin dose used for the first, second, and third GK treatments was 12 Gy, 12 Gy, and 14 Gy, respectively. Six patients (4 patients for the second irradiation and 2 patients for the third irradiation) with partial tumor regrowth were treated only on the growing part of the tumor using a median margin dose of 13 Gy. The median tumor volume was 0.9, 2.3, and 0.7 cc for the first, second, and third treatments, respectively. Stereotactic positron emission tomography (PET) guidance was used for dose planning in 6 cases. Results: Mean follow-up duration was 46 months (range 24–110). At the last follow-up, 85% of schwannomas were controlled. The tumor volume decreased, remained unchanged, or increased after retreatment in 15, 8, and 4 cases, respectively. Four patients had PET during follow-up, and all showed a significant metabolic decrease of the tumor. Hearing was not preserved after retreatment in any patients. New facial or trigeminal palsy did not occur after retreatment. Conclusions: Our results support the long-term efficacy and low morbidity of repeat GK treatment for selected patients with tumor growth after initial treatment. PMID:26500799

  3. Comparison of chest radiography, chest digital tomosynthesis and low dose MDCT to detect small ground-glass opacity nodules: an anthropomorphic chest phantom study

    Energy Technology Data Exchange (ETDEWEB)

    Doo, Kyung Won; Kang, Eun-Young; Yong, Hwan Seok [Korea University Guro Hospital, Korea University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Ham, Soo-Youn [Korea University Anam Hospital, Korea University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Lee, Ki Yeol; Choo, Ji Yung [Korea University Ansan Hospital, Korea University College of Medicine, Department of Radiology, Ansan (Korea, Republic of)

    2014-12-15

    The purpose of this study was to evaluate the diagnostic performance of chest radiography (CXR), chest digital tomosynthesis (DT) and low dose multidetector computed tomography (LDCT) for the detection of small pulmonary ground-glass opacity (GGO) nodules, using an anthropomorphic chest phantom. Artificial pulmonary nodules were placed in a phantom and a total of 40 samples of different nodule settings underwent CXR, DT and LDCT. The images were randomly read by three experienced chest radiologists. Free-response receiver-operating characteristics (FROC) were used. The figures of merit for the FROC curves averaged for the three observers were 0.41, 0.37 and 0.76 for CXR, DT and LDCT, respectively. FROC analyses revealed significantly better performance of LDCT over CXR or DT for the detection of GGO nodules (P < 0.05). The difference in detectability between CXR and DT was not statistically significant (P = 0.73). The diagnostic performance of DT for the detection of pulmonary small GGO nodules was not significantly different from that of CXR, but LDCT performed significantly better than both CXR and DT. DT is not a suitable alternative to CT for small GGO nodule detection, and LDCT remains the method of choice for this purpose. (orig.)

  4. Dose establishing a safety margin reduce local recurrence in subsegmental transarterial chemoembolization for small nodular hepatocellular carcinomas?

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Hyo Jin; Kim, Young Il; Kim, Hyo Cheol; Jae, Hwan Jun; Hur, Sae Beam; Chung, Jin Wook [Dept. of Radiology, Seoul National University Hospital, Seoul(Korea, Republic of)

    2015-10-15

    To test the hypothesis that a safety margin may affect local tumor recurrence (LTR) in subsegmental chemoembolization. In 101 patients with 128 hepatocellular carcinoma (HCC) nodules (1-3 cm in size and ≤ 3 in number), cone-beam CT-assisted subsegmental lipiodol chemoembolization was performed. Immediately thereafter, a non-contrast thin-section CT image was obtained to evaluate the presence or absence of intra-tumoral lipiodol uptake defect and safety margin. The effect of lipiodol uptake defect and safety margin on LTR was evaluated. Univariate and multivariate analyses were performed to indentify determinant factors of LTR. Of the 128 HCC nodules in 101 patients, 49 (38.3%) nodules in 40 patients showed LTR during follow-up period (median, 34.1 months). Cumulative 1- and 2-year LTR rates of nodules with lipiodol uptake defect (n = 27) and those without defect (n = 101) were 58.1% vs. 10.1% and 72.1% vs. 19.5%, respectively (p < 0.001). Among the 101 nodules without a defect, the 1- and 2-year cumulative LTR rates for nodules with complete safety margin (n = 52) and those with incomplete safety margin (n = 49) were 9.8% vs. 12.8% and 18.9% vs. 19.0% (p = 0.912). In multivariate analyses, ascites (p = 0.035), indistinct tumor margin on cone-beam CT (p = 0.039), heterogeneous lipiodol uptake (p = 0.023), and intra-tumoral lipiodol uptake defect (p < 0.001) were determinant factors of higher LTR. In lipiodol chemoembolization, the safety margin in completely lipiodolized nodule without defect will not affect LTR in small nodular HCCs.

  5. The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin.

    Science.gov (United States)

    Shaw, Jiajiu; Media, Joseph; Chen, Ben; Valeriote, Fredrick

    2013-09-01

    UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored. UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin. In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.

  6. Induction chemotherapy with carboplatin-paclitaxel followed by standard radiotherapy with concurrent daily low-dose cisplatin plus weekly paclitaxel for inoperable non-small-cell lung cancer.

    Science.gov (United States)

    Ardizzoni, Andrea; Scolaro, Tindaro; Mereu, Carlo; Cafferata, Mara Argenide; Tixi, Lucia; Bacigalupo, Almalina; Tiseo, Marcello; Monetti, Francesco; Rosso, Riccardo

    2005-02-01

    Both induction chemotherapy and concurrent platinating agents have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study investigated activity and feasibility of a novel chemoradiation regimen, including platinum and paclitaxel, both as induction chemotherapy and concurrently with thoracic radiotherapy. Previously untreated patients with histologically/cytologically proven unresectable stage I-III NSCLC were eligible. Induction chemotherapy consisted of 2 courses of 200 mg/m2 paclitaxel and carboplatin at AUC of 6 mg/mL/min every 3 weeks. From day 43, continuous thoracic irradiation (60 Gy in 30 fractions radiotherapy for 6 weeks) was given concurrently with daily cisplatin at a dose of 5 mg/m2 intravenously and weekly paclitaxel at a dose of 45 mg/m2 for 6 weeks. Fifteen patients were accrued in the first stage of the trial. According to the previous statistical considerations, accrual at the second stage of the study was halted as a result of the achievement an insufficient number of successes. Major toxicity of combined chemoradiation was grade III-IV esophagitis requiring hospitalization for artificial nutrition, which occurred in 58% of patients. Other toxicities included grade II-IV fatigue in 75% of patients and grade I-IV neuromuscular toxicity in 67%. Only 7 patients completed the treatment program as scheduled. Eight patients (53.3%; 95% confidence interval, 26.5-78.7%) had a major response (5 partial response, 3 complete response), 2 patients had disease progression, and 1 was stable at the end of treatment. Four patients died early. With a median follow up of 38 months, the median survival was 12 months. A combined chemoradiation program, including platinum and paclitaxel, appears difficult to deliver at full dose as a result of toxicity, mainly esophagitis. More active and less toxic combined modality treatments need to be developed for inoperable NSCLC.

  7. Optimization of dose and fractionation of endobronchial brachytherapy with or without external radiation in the palliative management of non-small cell lung cancer: A prospective randomized study

    Directory of Open Access Journals (Sweden)

    Mallick I

    2006-01-01

    Full Text Available Aims: Endobronchial brachytherapy (EBBT is an established modality for the palliation in advanced non-small cell lung cancer. We compared three different schedules using EBBT with or without external radiation (XRT in this setting. Materials and Methods: Forty-five patients were randomized to three treatment arms. Arm A received XRT to a dose of 30 Gy/ 10 fr/ 2 weeks and two sessions of EBBT 8 Gy each. Arm B received the same XRT and a single session of EBBT 10 Gy at 1 cm. Arm C received only a single fraction of brachytherapy to a dose of 15 Gy at 1 cm without XRT. Symptomatic response rates, duration of symptom palliation, obstruction scores, quality of life outcomes and complications were assessed and compared. Results: The overall symptomatic response rates were 91% for dyspnea, 84% for cough, 94% for hemoptysis and 83% for obstructive pneumonia. There was no significant difference between the arms. The median time to symptom relapse was 4-8 months for all symptoms and the median time to symptom progression was 6-11 months. The results were comparable between groups except for hemoptysis, where a shorter palliation was seen in Arm C that achieved statistical significance ( P < 0.01. Quality of life showed significant improvement, with maximum benefit in Arm A. Complication rates were low. Only one patient died of fatal hemoptysis. Conclusion: EBBT is thus a safe and effective palliative tool in advanced non-small cell lung cancer, either alone or in conjunction with XRT. The difference between the treatment arms were not statistically significant in most categories, but patients treated with XRT and two endobronchial sessions of 8 Gy had the most consistent benefit in terms of all the parameters studied.

  8. Which Is the Optimal Biologically Effective Dose of Stereotactic Body Radiotherapy for Stage I Non-Small-Cell Lung Cancer? A Meta-Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Jian; Yang Fujun [Department of Radiation Oncology, Cancer Hospital, Tianjin Medical University, Tianjin (China); Department of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Shandong' s Key Laboratory of Radiation Oncology, Jinan (China); Li Baosheng, E-mail: baoshli@yahoo.com [Department of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Shandong' s Key Laboratory of Radiation Oncology, Jinan (China); Li Hongsheng [Department of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Shandong' s Key Laboratory of Radiation Oncology, Jinan (China); Liu Jing [School of Public Health, Shandong University, Jinan (China); Huang Wei; Wang Dongqing; Yi Yan; Wang Juan [Department of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Shandong' s Key Laboratory of Radiation Oncology, Jinan (China)

    2011-11-15

    Purpose: To assess the relationship between biologically effective dose (BED) and efficacy of stereotactic body radiation therapy (SBRT) and to explore the optimal BED range for Stage I non-small-cell lung cancer (NSCLC). Methods and Materials: Eligible studies were identified on Medline, Embase, the Cochrane Library, and the proceedings of annual meetings through June 2010. According to the quartile of included studies, BED was divided into four dose groups: low (<83.2 Gy), medium (83.2-106 Gy), medium to high (106-146 Gy), high (>146 Gy). To obtain pooled estimates of overall survival (OS), cancer-specific survival (CSS), and local control rate (LCR), data were combined in a random effect model. Pooled estimates were corrected for the percentage of small tumors (<3 cm). Results: Thirty-four observational studies with a total of 2,587 patients were included in the meta-analysis. Corrected pooled estimates of 2- or 3-year OS in the medium BED (76.1%, 63.5%) or the medium to high BED (68.3%, 63.2%) groups were higher than in the low (62.3%, 51.9%) or high groups (55.9%, 49.5%), respectively (p {<=} 0.004). Corrected 3-year CSS in the medium (79.5%), medium to high (80.6%), and high groups (90.0%) were higher than in the low group (70.1%, p = 0.016, 0.018, 0.001, respectively). Conclusion: The OS for the medium or medium to high BED groups were higher than those for the low or high BED group for SBRT in Stage I NSCLC. The medium or medium to high BED (range, 83.2-146 Gy) for SBRT may currently be more beneficial and reasonable in Stage I NSCLC.

  9. Study of 201 Non-Small Cell Lung Cancer Patients Given Stereotactic Ablative Radiation Therapy Shows Local Control Dependence on Dose Calculation Algorithm

    Energy Technology Data Exchange (ETDEWEB)

    Latifi, Kujtim, E-mail: Kujtim.Latifi@Moffitt.org [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida (United States); Oliver, Jasmine [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida (United States); Department of Physics, University of South Florida, Tampa, Florida (United States); Baker, Ryan [University of South Florida School of Medicine, Tampa, Florida (United States); Dilling, Thomas J.; Stevens, Craig W. [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida (United States); Kim, Jongphil; Yue, Binglin [Department of Biostatics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida (United States); DeMarco, MaryLou; Zhang, Geoffrey G.; Moros, Eduardo G.; Feygelman, Vladimir [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida (United States)

    2014-04-01

    Purpose: Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). Methods and Materials: Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. Results: Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99{sub GITV} = 7.4 Gy, ΔD99{sub PTV} = 10.4 Gy, ΔV90{sub GITV} = 13.7%, ΔV90{sub PTV} = 37.6%, ΔD95{sub PTV} = 9.8 Gy, and ΔD{sub ISO} = 3.4 Gy. GITV = gross internal tumor volume. Conclusions: Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible

  10. Clinical Outcomes of Biological Effective Dose-Based Fractionated Stereotactic Radiation Therapy for Metastatic Brain Tumors From Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Matsuyama, Tomohiko, E-mail: matsutomo_llp@yahoo.co.jp [Department of Radiation Oncology, Kumamoto University, Kumamoto (Japan); Kogo, Kasei [Kumamoto Radiosurgery Clinic, Kumamoto (Japan); Oya, Natsuo [Department of Radiation Oncology, Kumamoto University, Kumamoto (Japan)

    2013-03-15

    Purpose: To evaluate the efficacy and toxicity of fractionated stereotactic radiation therapy (FSRT) based on biological effective dose (BED), a novel approach to deliver a fixed BED irrespective of dose fractionation, for brain metastases from non-small cell lung cancer (NSCLC). Methods and Materials: Between March 2005 and March 2009 we treated 299 patients with 1 to 5 lesions from NSCLC (573 total brain metastases) with FSRT using Novalis. The dose fractionation schedules were individually determined to deliver a peripheral BED10 (α/β ratio = 10) of approximately 80 Gy{sub 10}. The median number of fractions was 3 (range, 2-10), the median peripheral BED10 was 83.2 Gy (range, 19.1-89.6 Gy). Patients were followed up with magnetic resonance imaging (MRI) studies performed at 1- to 2-month intervals. The local tumor control rate and overall local progression-free and intracranial relapse-free survival were calculated by the Kaplan-Meier method. Results: Local control rates for all 573 lesions at 6 and 12 months were 96.3% and 94.5%, respectively. By multivariate analysis the tumor diameter was the only factor predictive of the local control rate (P=.001). The median overall survival, local progression-free survival, and intracranial relapse-free survival were 17.1, 14.9, and 4.4 months, respectively. The overall survival, local progression-free survival, and intracranial relapse-free survival rates at 6 and 12 months were 78.5% and 63.3%, 74.3% and 57.8%, and 41.0% and 21.8%, respectively. Six patients (2%) manifested progressive radiation injury to the brain even during therapy with corticosteroids; they underwent hyperbaric oxygen therapy, and follow-up MRI showed improvement. Conclusions: This study showed that BED-based FSRT for brain metastases from NSCLC is a promising strategy that may yield excellent outcomes with acceptable toxicity. Criteria must be established to determine the optimal dose fractionation for individual patients.

  11. SOT1, a pentatricopeptide repeat protein with a small MutS-related domain, is required for correct processing of plastid 23S-4.5S rRNA precursors in Arabidopsis thaliana.

    Science.gov (United States)

    Wu, Wenjuan; Liu, Sheng; Ruwe, Hannes; Zhang, Delin; Melonek, Joanna; Zhu, Yajuan; Hu, Xupeng; Gusewski, Sandra; Yin, Ping; Small, Ian D; Howell, Katharine A; Huang, Jirong

    2016-03-01

    Ribosomal RNA processing is essential for plastid ribosome biogenesis, but is still poorly understood in higher plants. Here, we show that SUPPRESSOR OF THYLAKOID FORMATION1 (SOT1), a plastid-localized pentatricopeptide repeat (PPR) protein with a small MutS-related domain, is required for maturation of the 23S-4.5S rRNA dicistron. Loss of SOT1 function leads to slower chloroplast development, suppression of leaf variegation, and abnormal 23S and 4.5S processing. Predictions based on the PPR motif sequences identified the 5' end of the 23S-4.5S rRNA dicistronic precursor as a putative SOT1 binding site. This was confirmed by electrophoretic mobility shift assay, and by loss of the abundant small RNA 'footprint' associated with this site in sot1 mutants. We found that more than half of the 23S-4.5S rRNA dicistrons in sot1 mutants contain eroded and/or unprocessed 5' and 3' ends, and that the endonucleolytic cleavage product normally released from the 5' end of the precursor is absent in a sot1 null mutant. We postulate that SOT1 binding protects the 5' extremity of the 23S-4.5S rRNA dicistron from exonucleolytic attack, and favours formation of the RNA structure that allows endonucleolytic processing of its 5' and 3' ends. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  12. Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).

    Science.gov (United States)

    Getlik, Matthäus; Smil, David; Zepeda-Velázquez, Carlos; Bolshan, Yuri; Poda, Gennady; Wu, Hong; Dong, Aiping; Kuznetsova, Ekaterina; Marcellus, Richard; Senisterra, Guillermo; Dombrovski, Ludmila; Hajian, Taraneh; Kiyota, Taira; Schapira, Matthieu; Arrowsmith, Cheryl H; Brown, Peter J; Vedadi, Masoud; Al-Awar, Rima

    2016-03-24

    WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

  13. Repeat-until-success quantum repeaters

    Science.gov (United States)

    Bruschi, David Edward; Barlow, Thomas M.; Razavi, Mohsen; Beige, Almut

    2014-09-01

    We propose a repeat-until-success protocol to improve the performance of probabilistic quantum repeaters. Conventionally, these rely on passive static linear-optics elements and photodetectors to perform Bell-state measurements (BSMs) with a maximum success rate of 50%. This is a strong impediment for entanglement swapping between distant quantum memories. Every time a BSM fails, entanglement needs to be redistributed between the corresponding memories in the repeater link. The key ingredients of our scheme are repeatable BSMs. Under ideal conditions, these turn probabilistic quantum repeaters into deterministic ones. Under realistic conditions, our protocol too might fail. However, using additional threshold detectors now allows us to improve the entanglement generation rate by almost orders of magnitude, at a nominal distance of 1000 km, compared to schemes that rely on conventional BSMs. This improvement is sufficient to make the performance of our scheme comparable to the expected performance of some deterministic quantum repeaters.

  14. [Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment].

    Science.gov (United States)

    Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi

    2008-12-01

    In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

  15. Repeat Gamma Knife Radiosurgery for Trigeminal Neuralgia

    Energy Technology Data Exchange (ETDEWEB)

    Aubuchon, Adam C., E-mail: acaubuchon@gmail.com [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Chan, Michael D. [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Lovato, James F. [Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Balamucki, Christopher J. [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States); Ellis, Thomas L.; Tatter, Stephen B. [Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, NC (United States); McMullen, Kevin P.; Munley, Michael T.; Deguzman, Allan F.; Ekstrand, Kenneth E.; Bourland, J. Daniel; Shaw, Edward G. [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States)

    2011-11-15

    Purpose: Repeat gamma knife stereotactic radiosurgery (GKRS) for recurrent or persistent trigeminal neuralgia induces an additional response but at the expense of an increased incidence of facial numbness. The present series summarized the results of a repeat treatment series at Wake Forest University Baptist Medical Center, including a multivariate analysis of the data to identify the prognostic factors for treatment success and toxicity. Methods and Materials: Between January 1999 and December 2007, 37 patients underwent a second GKRS application because of treatment failure after a first GKRS treatment. The mean initial dose in the series was 87.3 Gy (range, 80-90). The mean retreatment dose was 84.4 Gy (range, 60-90). The dosimetric variables recorded included the dorsal root entry zone dose, pons surface dose, and dose to the distal nerve. Results: Of the 37 patients, 81% achieved a >50% pain relief response to repeat GKRS, and 57% experienced some form of trigeminal dysfunction after repeat GKRS. Two patients (5%) experienced clinically significant toxicity: one with bothersome numbness and one with corneal dryness requiring tarsorraphy. A dorsal root entry zone dose at repeat treatment of >26.6 Gy predicted for treatment success (61% vs. 32%, p = .0716). A cumulative dorsal root entry zone dose of >84.3 Gy (72% vs. 44%, p = .091) and a cumulative pons surface dose of >108.5 Gy (78% vs. 44%, p = .018) predicted for post-GKRS numbness. The presence of any post-GKRS numbness predicted for a >50% decrease in pain intensity (100% vs. 60%, p = .0015). Conclusion: Repeat GKRS is a viable treatment option for recurrent trigeminal neuralgia, although the patient assumes a greater risk of nerve dysfunction to achieve maximal pain relief.

  16. Measurement-based quantum repeaters

    CERN Document Server

    Zwerger, M; Briegel, H J

    2012-01-01

    We introduce measurement-based quantum repeaters, where small-scale measurement-based quantum processors are used to perform entanglement purification and entanglement swapping in a long-range quantum communication protocol. In the scheme, pre-prepared entangled states stored at intermediate repeater stations are coupled with incoming photons by simple Bell-measurements, without the need of performing additional quantum gates or measurements. We show how to construct the required resource states, and how to minimize their size. We analyze the performance of the scheme under noise and imperfections, with focus on small-scale implementations involving entangled states of few qubits. We find measurement-based purification protocols with significantly improved noise thresholds. Furthermore we show that already resource states of small size suffice to significantly increase the maximal communication distance. We also discuss possible advantages of our scheme for different set-ups.

  17. Accelerated high-dose radiotherapy alone or combined with either concomitant or sequential chemotherapy; treatments of choice in patients with Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Pieters Bradley R

    2007-07-01

    Full Text Available Abstract Background Results of high-dose chemo-radiotherapy (CRT, using the treatment schedules of EORTC study 08972/22973 or radiotherapy (RT alone were analyzed among all patients (pts with Non Small Cell Lung Cancer (NSCLC treated with curative intent in our department from 1995–2004. Material Included are 131 pts with medically inoperable or with irresectable NSCLC (TNM stage I:15 pts, IIB:15 pts, IIIA:57 pts, IIIB:43 pts, X:1 pt. Treatment Group I: Concomitant CRT: 66 Gy/2.75 Gy/24 fractions (fx/33 days combined with daily administration of cisplatin 6 mg/m2: 56 pts (standard. Group II: Sequential CRT: two courses of a 21-day schedule of chemotherapy (gemcitabin 1250 mg/m2 d1, cisplatin 75 mg/m2 d2 followed by 66 Gy/2.75 Gy/24 fx/33 days without daily cisplatin: 26 pts. Group III: RT: 66 Gy/2.75 Gy/24 fx/33 days or 60 Gy/3 Gy/20 fx/26 days: 49 pts. Results The 1, 2, and 5 year actuarial overall survival (OS were 46%, 24%, and 15%, respectively. At multivariate analysis the only factor with a significantly positive influence on OS was treatment with chemo-radiation (P = 0.024 (1-, 2-, and 5-yr OS 56%, 30% and 22% respectively. The incidence of local recurrence was 36%, the incidence of distant metastases 46%. Late complications grade 3 were seen in 21 pts and grade 4 in 4 patients. One patient had a lethal complication (oesophageal. For 32 patients insufficient data were available to assess late complications. Conclusion In this study we were able to reproduce the results of EORTC trial 08972/22973 in a non-selected patient population outside of the setting of a randomised trial. Radiotherapy (66 Gy/24 fx/33 days combined with either concomitant daily low dose cisplatin or with two neo-adjuvant courses of gemcitabin and cisplatin are effective treatments for patients with locally advanced Non-Small Cell Lung Cancer. The concomitant schedule is also suitable for elderly people with co-morbidity.

  18. Highly sensitive LC-MS/MS methods for the determination of seven human CYP450 activities using small oral doses of probe-drugs in human.

    Science.gov (United States)

    Grangeon, Alexia; Gravel, Sophie; Gaudette, Fleur; Turgeon, Jacques; Michaud, Veronique

    2017-01-01

    Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively. Serial plasma and urine samples were collected over an 8h period. The probe-drugs and their respective metabolites were measured in both human plasma and urine, except for omeprazole (plasma only) and chlorzoxazone (urine only). Samples were analyzed by high performance liquid chromatography with heated electrospray ionization tandem mass spectrometry (HPLC-HESI-MS/MS) using a Phenomenex Luna PFP (2) analytical column (3μm PFP(2) 150×3mm) for chromatographic separation. Optimal detection was achieved based on 3 different analytical methods; (1) isocratic elution with a mobile phase consisting of acetonitrile and water both fortified with 0.01% formic acid for the analysis of bupropion, tolbutamide, chlorzoxazone and their respective metabolites; (2) isocratic elution with a mobile phase composed of acetonitrile and ammonium formate (pH 3; 10mM) for omeprazole, dextromethorphan, midazolam and their metabolites; (3) for caffeine and paraxanthine, gradient elution using acetonitrile and 0.01% formic acid in water was used. All calibration functions were linear for all probe drugs and metabolites in both matrices over wide analytical ranges. The main advantages of our methods are the use of specific probe drugs available in most countries, the administration of small doses of probe drugs, small

  19. Active Detection of Small Quantities of Shielded Highly-Enriched Uranium Using Low-Dose 60-keV Neutron Interrogation

    Energy Technology Data Exchange (ETDEWEB)

    Kerr, P; Rowland, M; Dietrich, D; Stoeffl, W; Wheeler, B; Nakae, L; Howard, D; Hagmann, C; Newby, J; Porter, R

    2006-08-16

    Active interrogation with low-energy neutrons provides a search technique for shielded highly-enriched uranium. We describe the technique and show initial results using a low-dose 60 keV neutron beam. This technique produces a clear induced fission signal in the presence of small quantities of {sup 235}U. The technique has been validated with low-Z and high-Z shielding materials. The technique uses a forward-directed beam of 60 keV neutrons to induce fission in {sup 235}U. The induced fission produces fast neutrons which are then detected as the signature for {sup 235}U. The beam of neutrons is generated with a 1.93 MeV proton beam impinging on a natural lithium target. The proton beam is produced by a radio-frequency quadrupole (RFQ) LINAC. The 60 keV neutron beam is forward directed because the {sup 7}Li(p,n) reaction is just at threshold for the proton energy of 1.93 MeV.

  20. The early predictive value of a decrease of metabolic tumor volume in repeated {sup 18}F-FDG PET/CT for recurrence of locally advanced non-small cell lung cancer with concurrent radiochemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Wei, E-mail: weihuang@mcw.com [Department of Radiation Oncology (Chest Section), Shandong' s Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250117 (China); Liu, Bo; Fan, Min [Department of Internal Medicine Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Zhou, Tao [Department of Radiation Oncology (Chest Section), Shandong' s Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250117 (China); Fu, Zheng [PET/CT center, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan (China); Zhang, Zicheng; Li, Hongsheng [Department of Radiation Oncology (Chest Section), Shandong' s Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250117 (China); Li, Baosheng, E-mail: alvinbird@163.com [Department of Radiation Oncology (Chest Section), Shandong' s Key Laboratory of Radiation Oncology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250117 (China)

    2015-03-15

    Highlights: •The patients underwent the second FDG PET during the early stage of concurrent chemoradiotherapy (CCRT). •To our knowledge, this could be the first study showing that the repeated FDG PET during the early stage of CCRT has added value by being a prognostic factor for recurrence of the locally advanced NSCLC patients. •This is a result of continuous research. •The decrease of MTV was the only significant risk factor for recurrence. -- Abstract: Purpose: The aim of this study is to investigate the value of [{sup 18}F] fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F FDG PET/CT) to predict recurrence of patients with locally advanced non-small cell lung cancer (NSCLC) during the early stage of concurrent chemoradiotherapy (CCRT). Methods: A total of 53 stage III NSCLC patients without diabetics or undergoing surgery were enrolled in the prospective study. Those patients were evaluated by FDG PET before and following 40 Gy radiotherapy (RT) with a concurrent cisplatin-based heterogeneous chemotherapy regimen. Semiquantitative assessment was used to determine maximum and mean SUVs (SUVmax/SUVmean) and metabolic tumor volume (MTV) of the primary tumor. The prognostic significance of PET/CT parameters and other clinical variables was assessed using Cox regression analyses. The cutoffs of PET/CT parameters which have been determined by the previous study were used to separate the groups with Kaplan–Meier curves. Results: Recurrence rates at 1- and 2-years were 18.9% (10/53) and 50.9% (27/53) for all patients, respectively. Cox regression analysis showed that the only prognostic factor for recurrence was a decrease of MTV. Using the cutoff of 29.7%, a decrease of MTV can separate the patients into 2 groups with Kaplan–Meier curve successfully. Conclusion: The prospective study has reinforced the early predictive value of MTV in repeated {sup 18}F-FDG PET/CT for recurrence in a subgroup of locally advanced NSCLC who

  1. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

  2. Long-term outcome of phase I/II prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer.

    Science.gov (United States)

    Chang, Joe Y; Zhang, Wencheng; Komaki, Ritsuko; Choi, Noah C; Chan, Shen; Gomez, Daniel; O'Reilly, Michael; Jeter, Melenda; Gillin, Michael; Zhu, Xiaorong; Zhang, Xiaodong; Mohan, Radhe; Swisher, Stephen; Hahn, Stephen; Cox, James D

    2017-02-01

    The aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). From June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time was 83.1months (95% CI: 69.2-97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%). According to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Improving repeatability by improving quality

    Energy Technology Data Exchange (ETDEWEB)

    Ronen, Shuki; Ackers, Mark; Schlumberger, Geco-Prakla; Brink, Mundy

    1998-12-31

    Time lapse (4-D) seismic is a promising tool for reservoir characterization and monitoring. The method is apparently simple: to acquire data repeatedly over the same reservoir, process and interpret the data sets, then changes between the data sets indicate changes in the reservoir. A problem with time lapse seismic data is that reservoirs are a relatively small part of the earth and important reservoir changes may cause very small differences to the time lapse data. The challenge is to acquire and process economical time lapse data such that reservoir changes can be detected above the noise of varying acquisition and environment. 7 refs., 9 figs.

  4. 注射用右旋雷贝拉唑钠大鼠13周重复给药毒性研究%Study on Repeated Dose Toxicity of Dexrabeprazole Sodium Injection in Rats for 13 Weeks

    Institute of Scientific and Technical Information of China (English)

    戴晓莉; 戴学栋; 郭峰; 胡建庭; 马玉奎

    2016-01-01

    taken the blood at ifrst and last injection for toxicokinetics. Results The rats in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 apperanced shortness of breath, unsteady gait, prone motionless and other symptoms. The levels of RBC,HGB,HCT in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 were significantly lower than those in vehicle control group at 13 weeks (P<0.05). The change of these parameters regained to normal at 4 weeks after withdrawal. The amount of small follicular in the thyroid gland increased at 13 weeks, and failed to fully recover at 4 weeks after the withdrawal.Conclusion Repeated administration of dexrabeprazole Sodium injection (80, 20 mg·kg-1) for 13 weeks could lead to abnormal indicators related erythrocyte and pathological lesions of thyroid in rats.

  5. The early predictive value of a decrease of metabolic tumor volume in repeated (18)F-FDG PET/CT for recurrence of locally advanced non-small cell lung cancer with concurrent radiochemotherapy.

    Science.gov (United States)

    Huang, Wei; Liu, Bo; Fan, Min; Zhou, Tao; Fu, Zheng; Zhang, Zicheng; Li, Hongsheng; Li, Baosheng

    2015-03-01

    The aim of this study is to investigate the value of [(18)F] fluorodeoxyglucose positron emission tomography/computed tomography ((18)F FDG PET/CT) to predict recurrence of patients with locally advanced non-small cell lung cancer (NSCLC) during the early stage of concurrent chemoradiotherapy (CCRT). A total of 53 stage III NSCLC patients without diabetics or undergoing surgery were enrolled in the prospective study. Those patients were evaluated by FDG PET before and following 40Gy radiotherapy (RT) with a concurrent cisplatin-based heterogeneous chemotherapy regimen. Semiquantitative assessment was used to determine maximum and mean SUVs (SUVmax/SUVmean) and metabolic tumor volume (MTV) of the primary tumor. The prognostic significance of PET/CT parameters and other clinical variables was assessed using Cox regression analyses. The cutoffs of PET/CT parameters which have been determined by the previous study were used to separate the groups with Kaplan-Meier curves. Recurrence rates at 1- and 2-years were 18.9% (10/53) and 50.9% (27/53) for all patients, respectively. Cox regression analysis showed that the only prognostic factor for recurrence was a decrease of MTV. Using the cutoff of 29.7%, a decrease of MTV can separate the patients into 2 groups with Kaplan-Meier curve successfully. The prospective study has reinforced the early predictive value of MTV in repeated (18)F-FDG PET/CT for recurrence in a subgroup of locally advanced NSCLC who underwent CCRT. A decrease of MTV in (18)F-FDG uptake by the primary tumor correlates with higher LRFS. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Bladder dose accumulation based on a biomechanical deformable image registration algorithm in volumetric modulated arc therapy for prostate cancer

    DEFF Research Database (Denmark)

    Andersen, E S; Muren, L P; Sørensen, T S

    2012-01-01

    ) to improve the accuracy of bladder dose assessment. For each of nine prostate cancer patients, the initial treatment plan was re-calculated on eight to nine repeat computed tomography (CT) scans. The planned bladder dose–volume histogram (DVH) parameters were compared to corresponding parameters derived from...... DIR-based accumulations and DVH summation were small and well within 1 Gy. For the investigated treatment scenario, DIR- based bladder dose accumulation did not result in substantial improvement of dose estimation as compared to the straightforward DVH summation. Large variations were found...... in individual patients between the doses from the initial treatment plan and the accumulated bladder doses. Hence, the use of repeat imaging has a potential for improved accuracy in treatment dose reporting....

  7. Hypoxic Repeat Sprint Training Improves Rugby Player's Repeated Sprint but Not Endurance Performance.

    Science.gov (United States)

    Hamlin, Michael J; Olsen, Peter D; Marshall, Helen C; Lizamore, Catherine A; Elliot, Catherine A

    2017-01-01

    This study aims to investigate the performance changes in 19 well-trained male rugby players after repeat-sprint training (six sessions of four sets of 5 × 5 s sprints with 25 s and 5 min of active recovery between reps and sets, respectively) in either normobaric hypoxia (HYP; n = 9; FIO2 = 14.5%) or normobaric normoxia (NORM; n = 10; FIO2 = 20.9%). Three weeks after the intervention, 2 additional repeat-sprint training sessions in hypoxia (FIO2 = 14.5%) was investigated in both groups to gauge the efficacy of using "top-up" sessions for previously hypoxic-trained subjects and whether a small hypoxic dose would be beneficial for the previously normoxic-trained group. Repeated sprint (8 × 20 m) and Yo-Yo Intermittent Recovery Level 1 (YYIR1) performances were tested twice at baseline (Pre 1 and Pre 2) and weekly after (Post 1-3) the initial intervention (intervention 1) and again weekly after the second "top-up" intervention (Post 4-5). After each training set, heart rate, oxygen saturation, and rate of perceived exertion were recorded. Compared to baseline (mean of Pre 1 and Pre 2), both the hypoxic and normoxic groups similarly lowered fatigue over the 8 sprints 1 week after the intervention (Post 1: -1.8 ± 1.6%, -1.5 ± 1.4%, mean change ± 90% CI in HYP and NORM groups, respectively). However, from Post 2 onwards, only the hypoxic group maintained the performance improvement compared to baseline (Post 2: -2.1 ± 1.8%, Post 3: -2.3 ± 1.7%, Post 4: -1.9 ± 1.8%, and Post 5: -1.2 ± 1.7%). Compared to the normoxic group, the hypoxic group was likely to have substantially less fatigue at Post 3-5 (-2.0 ± 2.4%, -2.2 ± 2.4%, -1.6 ± 2.4% Post 3, Post 4, Post 5, respectively). YYIR1 performances improved throughout the recovery period in both groups (13-37% compared to baseline) with unclear differences found between groups. The addition of two sessions of "top-up" training after intervention 1, had little effect on either group. Repeat-sprint training in

  8. Hypoxic Repeat Sprint Training Improves Rugby Player's Repeated Sprint but Not Endurance Performance

    Science.gov (United States)

    Hamlin, Michael J.; Olsen, Peter D.; Marshall, Helen C.; Lizamore, Catherine A.; Elliot, Catherine A.

    2017-01-01

    This study aims to investigate the performance changes in 19 well-trained male rugby players after repeat-sprint training (six sessions of four sets of 5 × 5 s sprints with 25 s and 5 min of active recovery between reps and sets, respectively) in either normobaric hypoxia (HYP; n = 9; FIO2 = 14.5%) or normobaric normoxia (NORM; n = 10; FIO2 = 20.9%). Three weeks after the intervention, 2 additional repeat-sprint training sessions in hypoxia (FIO2 = 14.5%) was investigated in both groups to gauge the efficacy of using “top-up” sessions for previously hypoxic-trained subjects and whether a small hypoxic dose would be beneficial for the previously normoxic-trained group. Repeated sprint (8 × 20 m) and Yo-Yo Intermittent Recovery Level 1 (YYIR1) performances were tested twice at baseline (Pre 1 and Pre 2) and weekly after (Post 1–3) the initial intervention (intervention 1) and again weekly after the second “top-up” intervention (Post 4–5). After each training set, heart rate, oxygen saturation, and rate of perceived exertion were recorded. Compared to baseline (mean of Pre 1 and Pre 2), both the hypoxic and normoxic groups similarly lowered fatigue over the 8 sprints 1 week after the intervention (Post 1: −1.8 ± 1.6%, −1.5 ± 1.4%, mean change ± 90% CI in HYP and NORM groups, respectively). However, from Post 2 onwards, only the hypoxic group maintained the performance improvement compared to baseline (Post 2: −2.1 ± 1.8%, Post 3: −2.3 ± 1.7%, Post 4: −1.9 ± 1.8%, and Post 5: −1.2 ± 1.7%). Compared to the normoxic group, the hypoxic group was likely to have substantially less fatigue at Post 3–5 (−2.0 ± 2.4%, −2.2 ± 2.4%, −1.6 ± 2.4% Post 3, Post 4, Post 5, respectively). YYIR1 performances improved throughout the recovery period in both groups (13–37% compared to baseline) with unclear differences found between groups. The addition of two sessions of “top-up” training after intervention 1, had little effect on either

  9. Quantum repeated games revisited

    CERN Document Server

    Frackiewicz, Piotr

    2011-01-01

    We present a scheme for playing quantum repeated 2x2 games based on the Marinatto and Weber's approach to quantum games. As a potential application, we study twice repeated Prisoner's Dilemma game. We show that results not available in classical game can be obtained when the game is played in the quantum way. Before we present our idea, we comment on the previous scheme of playing quantum repeated games.

  10. Development of Real-Time Measurement of Effective Dose for High Dose Rate Neutron Fields

    CERN Document Server

    Braby, L A; Reece, W D

    2003-01-01

    Studies of the effects of low doses of ionizing radiation require sources of radiation which are well characterized in terms of the dose and the quality of the radiation. One of the best measures of the quality of neutron irradiation is the dose mean lineal energy. At very low dose rates this can be determined by measuring individual energy deposition events, and calculating the dose mean of the event size. However, at the dose rates that are normally required for biology experiments, the individual events can not be separated by radiation detectors. However, the total energy deposited in a specified time interval can be measured. This total energy has a random variation which depends on the size of the individual events, so the dose mean lineal energy can be calculated from the variance of repeated measurements of the energy deposited in a fixed time. We have developed a specialized charge integration circuit for the measurement of the charge produced in a small ion chamber in typical neutron irradiation exp...

  11. Dose Calculations for Lung Inhomogeneity in High-Energy Photon Beams and Small Beamlets: A Comparison between XiO and TiGRT Treatment Planning Systems and MCNPX Monte Carlo Code

    Directory of Open Access Journals (Sweden)

    Asghar Mesbahi

    2015-09-01

    Full Text Available Introduction Radiotherapy with small fields is used widely in newly developed techniques. Additionally, dose calculation accuracy of treatment planning systems in small fields plays a crucial role in treatment outcome. In the present study, dose calculation accuracy of two commercial treatment planning systems was evaluated against Monte Carlo method. Materials and Methods Siemens Once or linear accelerator was simulated, using MCNPX Monte Carlo code, according to manufacturer’s instructions. Three analytical algorithms for dose calculation including full scatter convolution (FSC in TiGRT, along with convolution and superposition in XiO system were evaluated for a small solid liver tumor. This solid tumor with a diameter of 1.8 cm was evaluated in a thorax phantom, and calculations were performed for different field sizes (1×1, 2×2, 3×3 and4×4 cm2. The results obtained in these treatment planning systems were compared with calculations by MC method (regarded as the most reliable method. Results For FSC and convolution algorithm, comparison with MC calculations indicated dose overestimations of up to 120%and 25% inside the lung and tumor, respectively in 1×1 cm2field size, using an 18 MV photon beam. Regarding superposition, a close agreement was seen with MC simulation in all studied field sizes. Conclusion The obtained results showed that FSC and convolution algorithm significantly overestimated doses of the lung and solid tumor; therefore, significant errors could arise in treatment plans of lung region, thus affecting the treatment outcomes. Therefore, use of MC-based methods and super position is recommended for lung treatments, using small fields and beamlets.

  12. 小剂量米索前列醇片在晚期妊娠引产中的应用效果%Appling effect of small dose misoprostol tablet in induced labor of late pregnancy

    Institute of Scientific and Technical Information of China (English)

    杨水艳; 王迎迎

    2014-01-01

    Objective To explore the efficacy and safety of small dose of misoprostol tablet to the induced labor for late pregnancy. Methods 100 pregnant women ( pregnancy≥38 weeks,and cervical ripeness score 2-6 points) with single birth and first gestation were divided into the misoprostol group (n=50) and the oxytocin group (n=50).The misoprostol group was given misoprostol 25μg (1/8 tablet) placed in the posterior fornix of vagina,after 6 hours,it was not in labor,pa-tients could be repeatedly administered 1 time.and a day the most ≤50 μ g;the oxytocin group was given 0.5% or 1%oxytocin for continue intravenous infusion,6-8 h/d,up to a maximum of 72 h. Induction effect,the time of from the first dose to labor,total labor time,the rate of cesarean section of the two groups were compared. Results The induction suc-cess rate in the misoprostol group was higher than that in the oxytocin group (P<0.05).The effective rate of induction of in the misoprostol group [labor beforecervical score 2-4 points (including 4 points)] (89.3%) was higher than that of the oxytocin group (32%) (P<0.05).The time of from the first dose to labor in the misoprostol group was obviously shorter than that in the oxytocin group (P<0.01).Cesarean section rate in the misoprostol group was significantly lower than that of the oxytocin group (P<0.01). Conclusion The effect of a small dose of misoprostol (25μg every time) with vaginal administration for promoting cervical ripening in late pregnancy women is sure,it is easy to be accepted by puerperae with little side effect,and it is worthy of clinical promotion,especially it is superior for patients having vaginal delivery conditions with immature cervical conditions.%目的:探讨小剂量米索前列醇片对晚期妊娠引产的有效性及安全性。方法100例妊娠≥38周宫颈评分2~6分的单胎头位初产妇分成米索组与缩宫素组,每组各50例。米索组应用米索前列醇25μg (1/8片),置于阴道后穹隆,6 h

  13. Phase II Study of Accelerated High-Dose Radiotherapy With Concurrent Chemotherapy for Patients With Limited Small-Cell Lung Cancer: Radiation Therapy Oncology Group Protocol 0239

    Energy Technology Data Exchange (ETDEWEB)

    Komaki, Ritsuko, E-mail: rkomaki@mdanderson.org [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Paulus, Rebecca [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Ettinger, David S. [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (United States); Videtic, Gregory M.M. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Bradley, Jeffrey D. [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Glisson, Bonnie S. [Department of Thoracic/Head and Neck Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Langer, Corey J. [Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Sause, William T. [Radiation Center, LDS Hospital, Salt Lake City, Utah (United States); Curran, Walter J. [Department of Radiation Oncology, Jefferson Medical College, Philadelphia, Pennsylvania (United States); Choy, Hak [Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas (United States)

    2012-07-15

    Purpose: To investigate whether high-dose thoracic radiation given twice daily during cisplatin-etoposide chemotherapy for limited small-cell lung cancer (LSCLC) improves survival, acute esophagitis, and local control rates relative to findings from Intergroup trial 0096 (47%, 27%, and 64%). Patients and Methods: Patients were accrued over a 3-year period from 22 US and Canadian institutions. Patients with LSCLC and good performance status were given thoracic radiation to 61.2 Gy over 5 weeks (daily 1.8-Gy fractions on days 1-22, then twice-daily 1.8-Gy fractions on days 23-33). Cisplatin (60 mg/m{sup 2} IV) was given on day 1 and etoposide (120 mg/m{sup 2} IV) on days 1-3 and days 22-24, followed by 2 cycles of cisplatin plus etoposide alone. Patients who achieved complete response were offered prophylactic cranial irradiation. Endpoints included overall and progression-free survival; severe esophagitis (Common Toxicity Criteria v 2.0) and treatment-related fatalities; response (Response Evaluation Criteria in Solid Tumors); and local control. Results: Seventy-two patients were accrued from June 2003 through May 2006; 71 were evaluable (median age 63 years; 52% female; 58% Zubrod 0). Median survival time was 19 months; at 2 years, the overall survival rate was 36.6% (95% confidence interval [CI] 25.6%-47.7%), and progression-free survival 19.7% (95% CI 11.4%-29.6%). Thirteen patients (18%) experienced severe acute esophagitis, and 2 (3%) died of treatment-related causes; 41% achieved complete response, 39% partial response, 10% stable disease, and 6% progressive disease. The local control rate was 73%. Forty-three patients (61%) received prophylactic cranial irradiation. Conclusions: The overall survival rate did not reach the projected goal; however, rates of esophagitis were lower, and local control higher, than projected. This treatment strategy is now one of three arms of a prospective trial of chemoradiation for LSCLC (Radiation Therapy Oncology Group 0538

  14. Measurement of the ambient gamma dose equivalent and kerma from the small 252Cf source at 1 meter and the small 60Co source at 2 meters

    Energy Technology Data Exchange (ETDEWEB)

    Carl, W. F. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-07-30

    NASA Langley Research Center requested a measurement and determination of the ambient gamma dose equivalent rate and kerma at 100 cm from the 252Cf source and determination of the ambient gamma dose equivalent rate and kerma at 200 cm from the 60Co source for the Radiation Budget Instrument Experiment (Rad-X). An Exradin A6 ion chamber with Shonka air-equivalent plastic walls in combination with a Supermax electrometer were used to measure the exposure rate and free-in-air kerma rate of the two sources at the requested distances. The measured gamma exposure, kerma, and dose equivalent rates are tabulated.

  15. Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

    Science.gov (United States)

    Krug, L M; Grant, S C; Miller, V A; Ng, K K; Kris, M G

    1999-10-01

    In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

  16. Reconfigurable multiport EPON repeater

    Science.gov (United States)

    Oishi, Masayuki; Inohara, Ryo; Agata, Akira; Horiuchi, Yukio

    2009-11-01

    An extended reach EPON repeater is one of the solutions to effectively expand FTTH service areas. In this paper, we propose a reconfigurable multi-port EPON repeater for effective accommodation of multiple ODNs with a single OLT line card. The proposed repeater, which has multi-ports in both OLT and ODN sides, consists of TRs, BTRs with the CDR function and a reconfigurable electrical matrix switch, can accommodate multiple ODNs to a single OLT line card by controlling the connection of the matrix switch. Although conventional EPON repeaters require full OLT line cards to accommodate subscribers from the initial installation stage, the proposed repeater can dramatically reduce the number of required line cards especially when the number of subscribers is less than a half of the maximum registerable users per OLT. Numerical calculation results show that the extended reach EPON system with the proposed EPON repeater can save 17.5% of the initial installation cost compared with a conventional repeater, and can be less expensive than conventional systems up to the maximum subscribers especially when the percentage of ODNs in lightly-populated areas is higher.

  17. Revisiting the TALE repeat.

    Science.gov (United States)

    Deng, Dong; Yan, Chuangye; Wu, Jianping; Pan, Xiaojing; Yan, Nieng

    2014-04-01

    Transcription activator-like (TAL) effectors specifically bind to double stranded (ds) DNA through a central domain of tandem repeats. Each TAL effector (TALE) repeat comprises 33-35 amino acids and recognizes one specific DNA base through a highly variable residue at a fixed position in the repeat. Structural studies have revealed the molecular basis of DNA recognition by TALE repeats. Examination of the overall structure reveals that the basic building block of TALE protein, namely a helical hairpin, is one-helix shifted from the previously defined TALE motif. Here we wish to suggest a structure-based re-demarcation of the TALE repeat which starts with the residues that bind to the DNA backbone phosphate and concludes with the base-recognition hyper-variable residue. This new numbering system is consistent with the α-solenoid superfamily to which TALE belongs, and reflects the structural integrity of TAL effectors. In addition, it confers integral number of TALE repeats that matches the number of bound DNA bases. We then present fifteen crystal structures of engineered dHax3 variants in complex with target DNA molecules, which elucidate the structural basis for the recognition of bases adenine (A) and guanine (G) by reported or uncharacterized TALE codes. Finally, we analyzed the sequence-structure correlation of the amino acid residues within a TALE repeat. The structural analyses reported here may advance the mechanistic understanding of TALE proteins and facilitate the design of TALEN with improved affinity and specificity.

  18. Star repeaters for fiber optic links.

    Science.gov (United States)

    McMahon, D H; Gravel, R L

    1977-02-01

    A star repeater combines the functions of a passive star coupler and a signal regenerating amplifier. By more effectively utilizing the light power radiated by a light emitting diode, the star repeater can, when used with small diameter channels, couple as much power to all receivers of a multiterminal link as would be coupled to the single receiver of a simple point-to-point link.

  19. Absorbed Dose Distributions in Small Copper Wire Insulation due to Multiple-Sided Irradiations by 0.4 MeV Electrons

    DEFF Research Database (Denmark)

    Miller, Arne; McLaughlin, W. L.; Pedersen, Walther Batsberg

    1979-01-01

    When scanned electron beams are used to crosslink polymeric insulation of wire and cable, an important goal is to achieve optimum uniformity of absorbed dose distributions. Accurate measurements of dose distributions in a plastic dosimeter simulating a typical insulating material (polyethylene....... and insulation thicknesses between 0.4 and 0.8 mm. The plastic dosimeter simulating polyethylene insulations was a thin radiochromic polyvinyl butyral film wrapped several times around the copper wire, such that when unwrapped and analyzed optically on a scanning microspectrophotometer, high-resolution radial...

  20. Dose per unit area - a study of elicitation of nickel allergy

    DEFF Research Database (Denmark)

    Fischer, Louise Arup; Menné, Torkil; Johansen, Jeanne Duus

    2007-01-01

    with a patch test and a repeated open application test (ROAT). Nickel was applied on small and large areas. The varying parameters were area, total dose and dose per unit area. RESULTS: In the patch test, at a low concentration [15 microg nickel (microg Ni)/cm(2)], there were significantly higher scores...... concentrations, even though the same dose per unit area is applied.......BACKGROUND: Experimental sensitization depends upon the amount of allergen per unit skin area and is largely independent of the area size. OBJECTIVES: This study aimed at testing if this also applies for elicitation of nickel allergy. PATIENTS/METHODS: 20 nickel allergic individuals were tested...

  1. Recursive quantum repeater networks

    CERN Document Server

    Van Meter, Rodney; Horsman, Clare

    2011-01-01

    Internet-scale quantum repeater networks will be heterogeneous in physical technology, repeater functionality, and management. The classical control necessary to use the network will therefore face similar issues as Internet data transmission. Many scalability and management problems that arose during the development of the Internet might have been solved in a more uniform fashion, improving flexibility and reducing redundant engineering effort. Quantum repeater network development is currently at the stage where we risk similar duplication when separate systems are combined. We propose a unifying framework that can be used with all existing repeater designs. We introduce the notion of a Quantum Recursive Network Architecture, developed from the emerging classical concept of 'recursive networks', extending recursive mechanisms from a focus on data forwarding to a more general distributed computing request framework. Recursion abstracts independent transit networks as single relay nodes, unifies software layer...

  2. The 28S-18S rDNA intergenic spacer from Crithidia fasciculata: repeated sequences, length heterogeneity, putative processing sites and potential interactions between U3 small nucleolar RNA and the ribosomal RNA precursor.

    Science.gov (United States)

    Schnare, M N; Collings, J C; Spencer, D F; Gray, M W

    2000-09-15

    In Crithidia fasciculata, the ribosomal RNA (rRNA) gene repeats range in size from approximately 11 to 12 kb. This length heterogeneity is localized to a region of the intergenic spacer (IGS) that contains tandemly repeated copies of a 19mer sequence. The IGS also contains four copies of an approximately 55 nt repeat that has an internal inverted repeat and is also present in the IGS of Leishmania species. We have mapped the C.fasciculata transcription initiation site as well as two other reverse transcriptase stop sites that may be analogous to the A0 and A' pre-rRNA processing sites within the 5' external transcribed spacer (ETS) of other eukaryotes. Features that could influence processing at these sites include two stretches of conserved primary sequence and three secondary structure elements present in the 5' ETS. We also characterized the C.fasciculata U3 snoRNA, which has the potential for base-pairing with pre-rRNA sequences. Finally, we demonstrate that biosynthesis of large subunit rRNA in both C. fasciculata and Trypanosoma brucei involves 3'-terminal addition of three A residues that are not present in the corresponding DNA sequences.

  3. Thermal transfer and apparent-dose distributions in poorly bleached mortar samples: Results from single grains and small aliquots of quartz

    DEFF Research Database (Denmark)

    Jain, M.; Thomsen, Kristina Jørkov; Bøtter-Jensen, L.

    2004-01-01

    and inner wall plaster from a building built in 1964. These samples are found to be both poorly bleached and weakly sensitive (only 0.3% of grains giving a detectable dose response). We study thermal transfer in single grains of quartz, investigate the grain-size dependence of bleaching in the size range 90...

  4. Supplementation of a low dose of DHA or DHA plus AA does not prevent peripartum depressive symptoms in a small population based sample

    NARCIS (Netherlands)

    Doornbos, B.; van Goor, S. A.; Dijck-Brouwer, D. A. J.; Schaafsma, A.; Korf, J.; Muskiet, F. A. J.

    2009-01-01

    Background: The decrease of maternal docosahexaenoic (DHA) status during pregnancy has been associated with postpartum depression, especially in women with a low intake of DHA. Since the DHA intake in the Netherlands is low, we investigated whether supplementation of low doses of DHA or DHA plus ara

  5. Radiation dose for thoracic and coronary step-and-shoot CT using a 128-slice dual-source machine in infants and small children with congenital heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Paul, Jean-Francois; Rohnean, Adela; Elfassy, Eric; Sigal-Cinqualbre, Anne [Radiology-Centre Chirurgical Marie Lannelongue, Plessis-Robinson (France)

    2011-02-15

    For coronary artery visualization, retrospective ECG-gated acquisition by dual-source computed tomography (DSCT) was superior to spiral non-ECG-gated acquisition in a paediatric population of congenital heart disease (CHD) patients. However, retrospective cardiac CT is associated with substantial radiation doses to the patient. Recently, DSCT with end-systolic reconstruction was found to be robust for imaging the coronary arteries in patients with high heart rates. To evaluate step-and-shoot DSCT with end-systolic reconstruction for evaluating the heart, coronary arteries and other thoracic structures in young children with CHD. All neonates and children younger than 6 years of age who were referred to our institution for CHD evaluation between September and October 2009 were included in the study. ECG-gated DSCT was performed in sequential prospective mode centred on the systolic phase identified by ECG analysis. To assess the radiation dose, we recorded the dose-length product (DLP) in mGy.cm and the effective dose in mSv estimated from the DLP. Overall image quality was evaluated using a 5-grade scoring system and was assessed by looking at cardiac and vascular structures. The image quality for the proximal and middle segments of the right and left coronary arteries was also evaluated using a 5-grade scale. Images of diagnostic quality (grade {>=} 3) were obtained in all 30 children with a mean image quality grade of 4.7 {+-} 0.6 (range, 3-5). Mean DLP was 5.7 {+-} 4.8 mGy*cm (range, 1-22 mGy cm) and mean effective radiation dose was 0.26 {+-} 0.16 mSv (range, 0.05-0.8 mSv). Prospective ECG-gated thoracic DSCT at end-systole usually provides adequate thoracic and coronary artery image quality in neonates, infants and young children with CHD, independent of heart rate. This new method is associated with lower radiation doses compared to previous literature (mean effective dose, 0.26 mSv). (orig.)

  6. Repeated fecal microbiota transplantation in a child with ulcerative colitis.

    Science.gov (United States)

    Shimizu, Hirotaka; Arai, Katsuhiro; Abe, Jun; Nakabayashi, Kazuhiko; Yoshioka, Takako; Hosoi, Kenji; Kuroda, Makoto

    2016-08-01

    We report the case of an 11-year-old girl with ulcerative colitis refractory to conventional therapy, who was subsequently treated successfully with repeated fecal microbiota transplantation (FMT). The patient was steroid dependent despite several infliximab treatments, and colectomy was proposed to improve quality of life. After repeated FMT, she was able to maintain remission with on minimal dose of steroid. Although her fecal microbiota was dysbiotic before FMT, it was restored to a similar pattern as the donor after repeated FMT.

  7. Digital repeat analysis; setup and operation.

    Science.gov (United States)

    Nol, J; Isouard, G; Mirecki, J

    2006-06-01

    Since the emergence of digital imaging, there have been questions about the necessity of continuing reject analysis programs in imaging departments to evaluate performance and quality. As a marketing strategy, most suppliers of digital technology focus on the supremacy of the technology and its ability to reduce the number of repeats, resulting in less radiation doses given to patients and increased productivity in the department. On the other hand, quality assurance radiographers and radiologists believe that repeats are mainly related to positioning skills, and repeat analysis is the main tool to plan training needs to up-skill radiographers. A comparative study between conventional and digital imaging was undertaken to compare outcomes and evaluate the need for reject analysis. However, digital technology still being at its early development stages, setting a credible reject analysis program became the major task of the study. It took the department, with the help of the suppliers of the computed radiography reader and the picture archiving and communication system, over 2 years of software enhancement to build a reliable digital repeat analysis system. The results were supportive of both philosophies; the number of repeats as a result of exposure factors was reduced dramatically; however, the percentage of repeats as a result of positioning skills was slightly on the increase for the simple reason that some rejects in the conventional system qualifying for both exposure and positioning errors were classified as exposure error. The ability of digitally adjusting dark or light images reclassified some of those images as positioning errors.

  8. Cholinesterase inhibition and depression of the photic after discharge of flash evoked potentials following acute or repeated exposures to a mixture of carbaryl and propoxur.

    Science.gov (United States)

    Mwanza, Jean-Claude; Lyke, Danielle F; Hertzberg, Richard C; Haber, Lynne; Kohrman-Vincent, Melissa; Li, Ruosha; Pan, Yi; Lyles, Robert H; Simmons, Jane Ellen; Macmillan, Denise K; Zehr, R Dan; Swank, Adam E; Herr, David W

    2012-06-01

    Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration of the photic after discharge (PhAD) of flash evoked potentials (FEPs). In the current studies, we compared the effects of acute or repeated exposure to a mixture of carbaryl and propoxur (1:1.45 ratio; propoxur:carbaryl) on the duration of the PhAD and brain ChE activity in Long Evans rats. Animals were exposed (po) either to a single dose (0, 3, 10, 45 or 75 mg/kg), or 14 daily dosages (0, 3, 10, 30, 45 mg/kg), of the mixture. Acute and repeated treatment with 3mg/kg (or greater) of the mixture produced dose-related inhibition of brain ChE activity. Compared to controls, the PhAD duration decreased after acute administration of 75 mg/kg or repeated treatment with 30 mg/kg of the mixture. The linear relationship between the percent of control brain ChE activity and the PhAD duration was similar for both exposure paradigms. Dose-response models for the acute and repeated exposure data did not differ for brain ChE activity or the duration of the PhAD. Repeated treatment with the mixture resulted in slightly less (13-22%) erythrocyte ChE inhibition than acute exposure. Both acute and repeated treatment resulted in dose-additive results for the PhAD duration and less than dose-additive responses (6-16%) for brain ChE activity for the middle range of dosages. Acute treatment resulted in greater than dose-additive erythrocyte ChE inhibition (15-18%) at the highest dosages. In contrast, repeated treatment resulted in less than dose-additive erythrocyte ChE inhibition (16-22%) at the middle dosages. Brain and plasma levels of propoxur and carbaryl did not differ between the acute and repeated dosing paradigms. In summary, a physiological measure of central nervous system function and brain ChE activity had similar responses after acute or repeated treatment with the carbamate mixture, and brain ChE showed only small deviations from dose-additivity. Erythrocyte ChE activity had

  9. The Pentapeptide Repeat Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Vetting,M.; Hegde, S.; Fajardo, J.; Fiser, A.; Roderick, S.; Takiff, H.; Blanchard, J.

    2006-01-01

    The Pentapeptide Repeat Protein (PRP) family has over 500 members in the prokaryotic and eukaryotic kingdoms. These proteins are composed of, or contain domains composed of, tandemly repeated amino acid sequences with a consensus sequence of [S, T,A, V][D, N][L, F]-[S, T,R][G]. The biochemical function of the vast majority of PRP family members is unknown. The three-dimensional structure of the first member of the PRP family was determined for the fluoroquinolone resistance protein (MfpA) from Mycobacterium tuberculosis. The structure revealed that the pentapeptide repeats encode the folding of a novel right-handed quadrilateral {beta}-helix. MfpA binds to DNA gyrase and inhibits its activity. The rod-shaped, dimeric protein exhibits remarkable size, shape and electrostatic similarity to DNA.

  10. Repeating the Past

    Science.gov (United States)

    Moore, John W.

    1998-05-01

    As part of the celebration of the Journal 's 75th year, we are scanning each Journal issue from 25, 50, and 74 years ago. Many of the ideas and practices described are so similar to present-day "innovations" that George Santayana's adage (1) "Those who cannot remember the past are condemned to repeat it" comes to mind. But perhaps "condemned" is too strong - sometimes it may be valuable to repeat something that was done long ago. One example comes from the earliest days of the Division of Chemical Education and of the Journal.

  11. Metabolic Health in Short Children Born Small for Gestational Age Treated With Growth Hormone and Gonadotropin-Releasing Hormone Analog : Results of a Randomized, Dose-Response Trial

    NARCIS (Netherlands)

    van der Steen, Manouk; Lem, Annemieke J.; van der Kaay, Danielle C. M.; Bakker-van Waarde, Willie M.; van der Hulst, Flip J. P. C. M.; Neijens, Floor S.; Noordam, Cees; Odink, Roelof J.; Oostdijk, Wilma; Schroor, Eelco J.; Westerlaken, Ciska; Hokken-Koelega, Anita C. S.

    2015-01-01

    Context: Previously we showed that pubertal children born small for gestational age (SGA) with a poor adult height (AH) expectation can benefit from treatment with GH1 mg/m(2) per day (similar to 0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with a double GH

  12. All-optical repeater.

    Science.gov (United States)

    Silberberg, Y

    1986-06-01

    An all-optical device containing saturable gain, saturable loss, and unsaturable loss is shown to transform weak, distorted optical pulses into uniform standard-shape pulses. The proposed device performs thresholding, amplification, and pulse shaping as required from an optical repeater. It is shown that such a device could be realized by existing semiconductor technology.

  13. Bidirectional Manchester repeater

    Science.gov (United States)

    Ferguson, J.

    1980-01-01

    Bidirectional Manchester repeater is inserted at periodic intervals along single bidirectional twisted pair transmission line to detect, amplify, and transmit bidirectional Manchester 11 code signals. Requiring only 18 TTL 7400 series IC's, some line receivers and drivers, and handful of passive components, circuit is simple and relatively inexpensive to build.

  14. High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center

    Energy Technology Data Exchange (ETDEWEB)

    Bush, David A., E-mail: dbush@llu.edu [Department of Radiation Oncology, Loma Linda University Medical Center, Loma Linda, California (United States); Cheek, Gregory [Department of Pulmonary Medicine, Loma Linda University Medical Center, Loma Linda, California (United States); Zaheer, Salman; Wallen, Jason [Department of Thoracic Surgery, Loma Linda University Medical Center, Loma Linda, California (United States); Mirshahidi, Hamid [Department of Medical Oncology, Loma Linda University Medical Center, Loma Linda, California (United States); Katerelos, Ari; Grove, Roger; Slater, Jerry D. [Department of Radiation Oncology, Loma Linda University Medical Center, Loma Linda, California (United States)

    2013-08-01

    Purpose: We update our previous reports on the use of hypofractionated proton beam radiation therapy for early-stage lung cancer patients. Methods and Materials: Eligible subjects had biopsy-proven non-small cell carcinoma of the lung and were medically inoperable or refused surgery. Clinical workup required staging of T1 or T2, N0, M0. Subjects received hypofractionated proton beam therapy to the primary tumor only. The dose delivered was sequentially escalated from 51 to 60 Gy, then to 70 Gy in 10 fractions over 2 weeks. Endpoints included toxicity, pulmonary function, overall survival (OS), disease-specific survival (DSS), and local control (LC). Results: One hundred eleven subjects were analyzed for treatment outcomes. The patient population had the following average characteristics; age 73.2 years, tumor size 3.6 cm, and 1.33 L forced expiratory volume in 1 second. The entire group showed improved OS with increasing dose level (51, 60, and 70 Gy) with a 4-year OS of 18%, 32%, and 51%, respectively (P=.006). Peripheral T1 tumors exhibited LC of 96%, DSS of 88%, and OS of 60% at 4 years. Patients with T2 tumors showed a trend toward improved LC and survival with the 70-Gy dose level. On multivariate analysis, larger tumor size was strongly associated with increased local recurrence and decreased survival. Central versus peripheral location did not correlate with any outcome measures. Clinical radiation pneumonitis was not found to be a significant complication, and no patient required steroid therapy after treatment for radiation pneumonitis. Pulmonary function was well maintained 1 year after treatment. Conclusions: High-dose hypofractionated proton therapy achieves excellent outcomes for lung carcinomas that are peripherally or centrally located. The 70-Gy regimen has been adopted as standard therapy for T1 tumors at our institution. Larger T2 tumors show a trend toward improved outcomes with higher doses, suggesting that better results could be seen with

  15. Costly renegotiation in repeated Bertand games

    DEFF Research Database (Denmark)

    Andersson, Ola; Wengström, Erik Roland

    2010-01-01

    This paper extends the concept of weak renegotiation-proof equilibrium (WRP) to allow for costly renegotiation and shows that even small renegotiation costs can have dramatic effects on the set of equilibria. More specifically, the paper analyzes the infinitely repeated Bertrand game. It is shown...

  16. Costly renegotiation in repeated Bertand games

    DEFF Research Database (Denmark)

    Andersson, Ola; Wengström, Erik Roland

    2010-01-01

    This paper extends the concept of weak renegotiation-proof equilibrium (WRP) to allow for costly renegotiation and shows that even small renegotiation costs can have dramatic effects on the set of equilibria. More specifically, the paper analyzes the infinitely repeated Bertrand game. It is shown...

  17. Efficacy and safety of small dose of amiodarone in treatment of arrhythmia%小剂量胺碘酮在心律失常治疗中的疗效及安全性

    Institute of Scientific and Technical Information of China (English)

    冯杰

    2015-01-01

    目的:探讨小剂量胺碘酮在心律失常治疗中的疗效和安全性。方法将该院2013年10月—2014年9月医治的54例心律失常患者随机分为常规组与观察组。两组患者在常规治疗基础上分别使用普鲁帕酮与小剂量的胺碘酮进行治疗。比较两组患者不同药物治疗后总有效率和不良反应情况。结果在治疗后,观察组、对照组总有效率分别为88.89%(24/27)、59.26%(16/27),观察组疗效优于对照组(P<0.05);观察组不良反应情况明显低于对照组(P<0.05)。结论使用小剂量胺碘酮治疗室性心律失常,治疗效果明显,安全、有效,值得推广。%Objective To investigate the efficacy and safety of small dose of amiodarone in treatment of arrhythmia. Methods 54 patients with arrhythmia were divided into control group and observation group randomly. Two groups of patients were given propafenone and small dose of amiodarone on the basis of conventional treatment. the clinical efficacy and adverse reactions of propafenone situation with a small dose of amiodarone. Results after treatment, the observation group, the control group total effectiveness respectively is 88.89% (24/27), 59.26% (16/27), the effect of observation group is better than control group (P <0.05); the adverse reactions observed was significantly lower than control group (P < 0.05). Conclusion the use of small dose amiodarone in therapeutic room, arrhythmia, obvious curative effect, safety, effective, worthy of promotion.

  18. High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age.

    OpenAIRE

    Dijk, M. van; Mulder, P.; Houdijk, M.; Mulder, J.; Noordam, K.; Odink, R.J.; Rongen-Westerlaken, C; P. Voorhoeve; Waelkens, J; Stokvis-Brantsma, J.; Hokken-Koelega, A C

    2006-01-01

    CONTEXT: Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. OBJECTIVE: The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. PATIENTS: Thirty-six prepubertal short SGA children were the subjects of this study. Intervention: Subjects received 1 (group A) ...

  19. Safety of Repeated Yttrium-90 Radioembolization

    Energy Technology Data Exchange (ETDEWEB)

    Lam, Marnix G. E. H.; Louie, John D. [Stanford University School of Medicine, Division of Interventional Radiology (United States); Iagaru, Andrei H.; Goris, Michael L. [Stanford University School of Medicine, Division of Nuclear Medicine (United States); Sze, Daniel Y., E-mail: dansze@stanford.edu [Stanford University School of Medicine, Division of Interventional Radiology (United States)

    2013-10-15

    Purpose: Repeated radioembolization (RE) treatments carry theoretically higher risk of radiation-induced hepatic injury because of the liver's cumulative memory of previous exposure. We performed a retrospective safety analysis on patients who underwent repeated RE. Methods: From 2004 to 2011, a total of 247 patients were treated by RE. Eight patients (5 men, 3 women, age range 51-71 years) underwent repeated treatment of a targeted territory, all with resin microspheres (SIR-Spheres; Sirtex, Lane Cove, Australia). Adverse events were graded during a standardized follow-up. In addition, the correlation between the occurrence of RE-induced liver disease (REILD) and multiple variables was investigated in univariate and multivariate analyses in all 247 patients who received RE. Results: Two patients died shortly after the second treatment (at 84 and 107 days) with signs and symptoms of REILD. Both patients underwent whole liver treatment twice (cumulative doses 3.08 and 2.66 GBq). The other 6 patients demonstrated only minor toxicities after receiving cumulative doses ranging from 2.41 to 3.88 GBq. All patients experienced objective tumor responses. In the whole population, multifactorial analysis identified three risk factors associated with REILD: repeated RE (p = 0.036), baseline serum total bilirubin (p = 0.048), and baseline serum aspartate aminotransferase (p = 0.043). Repeated RE proved to be the only independent risk factor for REILD in multivariate analysis (odds ratio 9.6; p = 0.002). Additionally, the administered activity per target volume (in GBq/L) was found to be an independent risk factor for REILD, but only in whole liver treatments (p = 0.033). Conclusion: The risk of REILD appears to be elevated for repeated RE. Objective tumor responses were observed, but establishment of safety limits will require improvement in dosimetric measurement and prediction.

  20. Quality of Life (QOL) Analysis of a Randomized Radiation Dose Escalation Non-Small Cell Lung Cancer (NSCLC) Study: Radiation Therapy Oncology Group (RTOG) Trial 0617

    Science.gov (United States)

    Movsas, Benjamin; Hu, Chen; Sloan, Jeffrey; Bradley, Jeffrey; Komaki, Ritsuko; Masters, Gregory; Kavadi, Vivek; Narayan, Samir; Michalski, Jeff; Johnson, Douglas W.; Koprowski, Christopher; Curran, Walter J.; Garces, Yolanda I.; Gaur, Rakesh; Wynn, Raymond B.; Schallenkamp, John; Gelblum, Daphna Y.; MacRae, Robert M; Paulus, Rebecca; Choy, Hak

    2015-01-01

    Importance A recent randomized radiation dose escalation trial in unresectable stage III NSCLC showed a lower survival in the high-dose arm (74Gy vs. 60Gy) with concurrent chemotherapy. Quality of life (QOL), an important secondary endpoint, is presented here. Objective The primary QOL hypothesis predicted a clinically meaningful decline (CMD) in QOL via the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) in the high-dose RT-arm at 3 months. Design RTOG 0617 was a randomized phase III study (conducted from Nov 2007 to Nov 2011) in stage III NSCLC using a 2×2 factorial design and stratified by histology, PET staging, performance status and radiation technique (3D-conformal RT [3DCRT] vs. intensity-modulated radiation [IMRT]). Setting 185 institutions in the USA and Canada. Participants Of 424 eligible stage III NSCLC patients randomized, 360 (85%) consented to QOL, of whom 313 (88%) completed baseline QOL assessments. Intervention for Clinical Trials 74Gy vs. 60Gy with concurrent and consolidation carboplatin/paclitaxel +/− cetuximab. Main Outcomes and Measures QOL was collected prospectively via FACT-Trial Outcome Index (FACT-TOI), equaling Physical-Well-Being (PWB) + Functional-Well-Being (FWB) + Lung Cancer Subscale (LCS). Data are presented at baseline & 3 and 12 months via minimal clinically meaningful changes of >=2 points for PWB, FWB or LCS or >=5 points for TOI. Results Patient demographics and baseline QOL scores were comparable between the 74Gy and 60Gy arms. Two-hundred-nineteen (72%) of living patients who completed QOL at baseline did so at 3 months and 137 (57%) of living patients did so at 12 months. Significantly more patients on 74Gy arm had clinically meaningful decline in FACT-LCS at 3 months than on the 60Gy arm (45% vs. 30%, p=0.02). At 12 months, fewer patients who received IMRT (vs 3DCRT) had clinically meaningful decline in FACT-LCS (21% vs 46%, p=0.003). Baseline FACT-TOI was associated with overall survival in

  1. Calcium kinetics with microgram stable isotope doses and saliva sampling

    Science.gov (United States)

    Smith, S. M.; Wastney, M. E.; Nyquist, L. E.; Shih, C. Y.; Wiesmann, H.; Nillen, J. L.; Lane, H. W.

    1996-01-01

    Studies of calcium kinetics require administration of tracer doses of calcium and subsequent repeated sampling of biological fluids. This study was designed to develop techniques that would allow estimation of calcium kinetics by using small (micrograms) doses of isotopes instead of the more common large (mg) doses to minimize tracer perturbation of the system and reduce cost, and to explore the use of saliva sampling as an alternative to blood sampling. Subjects received an oral dose (133 micrograms) of 43Ca and an i.v. dose (7.7 micrograms) of 46Ca. Isotopic enrichment in blood, urine, saliva and feces was well above thermal ionization mass spectrometry measurement precision up to 170 h after dosing. Fractional calcium absorptions determined from isotopic ratios in blood, urine and saliva were similar. Compartmental modeling revealed that kinetic parameters determined from serum or saliva data were similar, decreasing the necessity for blood samples. It is concluded from these results that calcium kinetics can be assessed with micrograms doses of stable isotopes, thereby reducing tracer costs and with saliva samples, thereby reducing the amount of blood needed.

  2. Copy number of tandem direct repeats within the inverted repeats of Marek's disease virus DNA.

    Science.gov (United States)

    Kanamori, A; Nakajima, K; Ikuta, K; Ueda, S; Kato, S; Hirai, K

    1986-12-01

    We previously reported that DNA of the oncogenic strain BC-1 of Marek's disease virus serotype 1 (MDV1) contains three units of tandem direct repeats with 132 base pair (bp) repeats within the inverted repeats of the long regions of the MDV1 genome, whereas the attenuated, nononcogenic viral DNA contains multiple units of tandem direct repeats (Maotani et al., 1986). In the present study, the difference in the copy numbers of 132 bp repeats of oncogenic and nononcogenic MDV1 DNAs in other strains of MDV1 was investigated by Southern blot hybridization. The main copy numbers in different oncogenic MDV1 strains differed: those of BC-1, JM and highly oncogenic Md5 were 3, 5 to 12 and 2, respectively. The viral DNA population with two units of repeats was small, but detectable, in cells infected with either the oncogenic BC-1 or JM strain. The MDV1 DNA in various MD cell lines contained either two units or both two and three units of repeats. The significance of the copy number of repeats in oncogenicity of MDV1 is discussed.

  3. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial

    OpenAIRE

    Sas, Theo; Waal, Wouter; Houdijk, M.; Jansen, Maarten; Reeser, M.; Mulder, Paul; Hokken-Koelega, Anita

    1999-01-01

    textabstractThe growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy ...

  4. Dynamic combinatorial libraries of artificial repeat proteins.

    Science.gov (United States)

    Eisenberg, Margarita; Shumacher, Inbal; Cohen-Luria, Rivka; Ashkenasy, Gonen

    2013-06-15

    Repeat proteins are found in almost all cellular systems, where they are involved in diverse molecular recognition processes. Recent studies have suggested that de novo designed repeat proteins may serve as universal binders, and might potentially be used as practical alternative to antibodies. We describe here a novel chemical methodology for producing small libraries of repeat proteins, and screening in parallel the ligand binding of library members. The first stage of this research involved the total synthesis of a consensus-based three-repeat tetratricopeptide (TPR) protein (~14 kDa), via sequential attachment of the respective peptides. Despite the effectiveness of the synthesis and ligation steps, this method was found to be too demanding for the production of proteins containing variable number of repeats. Additionally, the analysis of binding of the individual proteins was time consuming. Therefore, we designed and prepared novel dynamic combinatorial libraries (DCLs), and show that their equilibration can facilitate the formation of TPR proteins containing up to eight repeating units. Interestingly, equilibration of the library building blocks in the presence of the biologically relevant ligands, Hsp90 and Hsp70, induced their oligomerization into forming more of the proteins with large recognition surfaces. We suggest that this work presents a novel simple and rapid tool for the simultaneous screening of protein mixtures with variable binding surfaces, and for identifying new binders for ligands of interest.

  5. 小剂量间歇补铁法治疗小儿缺铁性贫血疗效观察%Small dose of iron supplements of treatment for the children with iron deficiency anemia

    Institute of Scientific and Technical Information of China (English)

    庞清华; 吴勇

    2015-01-01

    Objective To study the curative and side effects of small dose of iron supplements on the inter-mittent treatment for children with iron deficiency anemia ( IDA) .Methods 133 children with IDA were divided into two groups, respectively given A group(small doses of intermittent iron supplements) and B group(regular daily dose iron supplement as control group).After two months′treatment, serum ferritin(SF) and hemoglobin(Hb) were de-tected and adverse reactions were observed in the two groups .Results SF and Hb were same after treatment .They were significantly elevated in both groups ( P0.05).The adverse reaction rate of B group was obviously higher than that of A group (P<0.01). Conclusion Small dose of iron supplements of intermittent treatment for the children with IDA is effective and has lower side effects .%目的:研究小剂量间歇补铁法治疗小儿缺铁性贫血( IDA)的临床疗效及副作用。方法将133例缺铁性贫血患儿半随机分为间歇治疗组( A组)和常规治疗组( B组),分别给予小剂量间歇补铁及常规剂量每日补铁治疗,2个月后复查患儿的血清铁蛋白(SF)和血红蛋白(Hb),同时观察并记录患儿不良反应。结果治疗前两组比较SF和Hb基本相同,差异无统计学意义( P>0.05),治疗前后比较两组的SF及Hb均显著增加,差异有统计学意义( P<0.01)。常规治疗组不良反应发生率明显大于间歇治疗组,差异有统计学意义( P<0.01)。结论小剂量间歇补铁法能有效治疗IDA,且药物副作用少、依从性好。

  6. Duct Leakage Repeatability Testing

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Iain [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sherman, Max [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2014-01-01

    Duct leakage often needs to be measured to demonstrate compliance with requirements or to determine energy or Indoor Air Quality (IAQ) impacts. Testing is often done using standards such as ASTM E1554 (ASTM 2013) or California Title 24 (California Energy Commission 2013 & 2013b), but there are several choices of methods available within the accepted standards. Determining which method to use or not use requires an evaluation of those methods in the context of the particular needs. Three factors that are important considerations are the cost of the measurement, the accuracy of the measurement and the repeatability of the measurement. The purpose of this report is to evaluate the repeatability of the three most significant measurement techniques using data from the literature and recently obtained field data. We will also briefly discuss the first two factors. The main question to be answered by this study is to determine if differences in the repeatability of these tests methods is sufficient to indicate that any of these methods is so poor that it should be excluded from consideration as an allowed procedure in codes and standards.

  7. Peroxidised dietary lipids impair intestinal function and morphology of the small intestine villi of nursery pigs in a dose-dependent manner.

    Science.gov (United States)

    Rosero, David S; Odle, Jack; Moeser, Adam J; Boyd, R Dean; van Heugten, Eric

    2015-12-28

    The objective of this study was to investigate the effect of increasing degrees of lipid peroxidation on structure and function of the small intestine of nursery pigs. A total of 216 pigs (mean body weight was 6·5 kg) were randomly allotted within weight blocks and sex and fed one of five experimental diets for 35 d (eleven pens per treatment with three to four pigs per pen). Treatments included a control diet without added lipid, and diets supplemented with 6 % soyabean oil that was exposed to heat (80°C) and constant oxygen flow (1 litre/min) for 0, 6, 9 and 12 d. Increasing lipid peroxidation linearly reduced feed intake (Pdigestibility of gross energy (P=0·001) and fat (PAbsorption of mannitol (linear, P=0·097) and d-xylose (linear, P=0·089), measured in serum 2 h post gavage with a solution containing 0·2 g/ml of d-xylose and 0·3 g/ml of mannitol, tended to decrease progressively as the peroxidation level increased. Increasing peroxidation also resulted in increased villi height (linear, Plipid peroxidation progressively diminished animal performance and modified the function and morphology of the small intestine of nursery pigs. Detrimental effects were related with the disruption of redox environment of the intestinal mucosa.

  8. A Phase I Study of Light Dose for Photodynamic Therapy (PDT) Using 2-[1-hexyloxyethyl]-2 devinyl Pyropheophorbide-a (HPPH) for Treatment of Non-small Cell Carcinoma in situ or Non-small Cell Microinvasive Bronchogenic Carcinoma. A Dose Ranging Study

    Science.gov (United States)

    Dhillon, Samjot Singh; Demmy, Todd L.; Yendamuri, Sai; Loewen, Gregory; Nwogu, Chukwumere; Cooper, Michele; Henderson, Barbara W.

    2015-01-01

    Introduction We report a phase I trial of photodynamic therapy (PDT) of carcinoma-insitu (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used PS porfimer sodium (Photofrin®). Methods The objectives of this study were 1) to determine the maximally tolerated light dose at a fixed PS dose and 2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was done at one and six months, respectively. Results The rate of pathological complete response (CR) was 82.4% (14/17 evaluable lesions; 14 patients) at one-month and 72.7% (8/11 lesions; 8 patients) at 6 months. Only 4 patients developed mild skin erythema. One of the three patients in 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress due to mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The third sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose not exceed 125J/cm2. Conclusions PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies. PMID:26718878

  9. Comparison of the repeated dose toxicity of isomers of dinitrotoluene.

    Science.gov (United States)

    Lent, Emily May; Crouse, Lee C B; Quinn, Michael J; Wallace, Shannon M

    2012-03-01

    Dinitrotoluene (DNT) is a nitroaromatic explosive used in propellant mixtures and in the production of plastics. Isomers of DNT were administered daily via oral gavage to male Sprague-Dawley rats for 14 days to determine the subacute toxicity of individual isomers of DNT. The 3,5-DNT isomer was the most toxic isomer, inducing weight loss and mortality within 3 days. Cyanosis and anemia were observed for all isomers. Exposure to 2,4-, 2,6-, and 3,5-DNT resulted in decreased testes mass and degenerative histopathological changes. Increased splenic mass was observed for 2,4-, 2,6-, and 2,5-DNT. Extramedullary hematopoiesis of the spleen was noted for all isomers, while lymphoid hyperplasia of the spleen was noted for all isomers except 2,5-DNT. Increased liver mass was observed for 2,3-DNT and 3,4-DNT. Hepatocellular lesions were observed for 2,6-DNT and 2,4-DNT. Neurotoxic effects were noted for 3,4-DNT, 2,4-DNT, and 3,5-DNT.

  10. Antithrombotic effect of repeated doses of the ethanolic extract of ...

    African Journals Online (AJOL)

    2013-05-22

    May 22, 2013 ... botic drugs for the prevention and treatment of arterial and venous ... 7), antidiabetic (8, 9) and anticancer effects (10, 11), and also to possesses .... Another possible explanation for non-adherence of the thrombi to the vessel ...

  11. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  12. The Effects of Repeated Low-Dose Sarin Exposure

    Science.gov (United States)

    2006-01-01

    and slight enzyme that breaks down the cholinergic neurotransmitter ataxia . It has been observed in rats and mice that (NT) acetylcholine (ACh). The...minutes) Latency to the first movement (see)_ Total # of rears (C) Total # of grooming episodes (C) Arousal: (R) (choose one) I. Very low (little or...description: (D) (choose one) 1. No movement 2. Normal 3. Impairment a. Uncoordinated movement ( ataxia ) b. Walking on toes c. Splayed hind limbs d

  13. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  14. 小剂量咪达唑仑用于剖宫产术中的临床观察%Clinical Observation of Small-dose of Midazolam for Cesarean Section

    Institute of Scientific and Technical Information of China (English)

    谷文萍

    2012-01-01

    目的:观察小剂量咪达唑仑复合芬太尼用于剖宫产手术时产妇抗焦虑、抗应激、抑制内脏牵拉反应的效果.方法:选择我院美国麻醉师协会Ⅰ级的22~35岁产妇100例,按用药情况均分为A、B组.A组切皮前给予咪达唑仑0.03 mg·kg-1静脉注射;B组切皮前给予咪达唑仑0.03 mg·kg-1静脉注射,2 min后芬太尼0.75 μg·kg-1静脉注射.观察2组产妇血压(BP)、心率(HR)等临床指标.结果:与麻醉前比较,2组产妇用药后抗焦虑作用效果显著(P<0.05);A组用药后BP、HR、血氧饱和度(SpO2)、呼吸频率(RR)无显著变化(P>0.05);B组用药后BP、HR、SpO2、RR均有所下降,与A组同一时间点比较差异有统计学意义(P<0.05).2组术中的牵拉反应、镇静状态、术后24h遗忘率均相似(P>0.05).2组产妇均未见明显不良反应发生.结论:小剂量咪达唑仑复合芬太尼在剖宫产术中有满意的镇静、抗焦虑、术后遗忘及抗内脏牵拉反应效果,但单用小剂量咪达唑仑对产妇呼吸、循环影响较小.%OBJECTIVE: To observe the clinical efficacy of small doses of midazolam and small doses of midazolam combined with fentanyl for anxiety, stress and visceral traction reaction of delivery woman undergoing cesarean section. METHODS: 100 ASA I delivery women aged 22~35 years old were divided into group A and B according to the situation of drug use. Group A and B received given intravenous bolus injection of 0.03 nig-kg-1 midazolam before skin incision, and group B was additionally given intravenous bolus injection of 0.75 ng-kg-1 fentanyl after 2 minutes. RESULTS: After treatment, there were significant anxio-lytic effects in both 2 groups. Specifically, there was no significant change in group A about BP, HR, SpO2 and RR, while those were decreased in group B, compared with group A at the same time point (P0.05). There was no significant ADR found. CONCLUSION: Small doses of midazolam and small doses of midazolam

  15. Safety and Palliative Efficacy of Single-Dose 8-Gy Reirradiation for Painful Local Failure in Patients With Stage IV Non-Small Cell Lung Cancer Previously Treated With Radical Chemoradiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Topkan, Erkan, E-mail: docdretopkan@gmail.com [Baskent Department of Radiation Oncology, University Adana Medical Faculty, Adana (Turkey); Yildirim, Berna Akkus; Guler, Ozan Cem; Parlak, Cem [Baskent Department of Radiation Oncology, University Adana Medical Faculty, Adana (Turkey); Pehlivan, Berrin [Koc University, School of Medicine, Department of Radiation Oncology, Istanbul, and American Hospital, University of Texas MD Anderson Radiation Treatment Center, Istanbul (Turkey); Selek, Ugur [Medstar Hospital, Department of Radiation Oncology, Antalya (Turkey)

    2015-03-15

    Purpose: To investigate the safety and efficacy of single-dose 8-Gy palliative chest reirradiation (CRI) in metastatic non-small cell lung cancer (M-NSCLC) patients with painful thoracic failures (TF) within the previous radiation portal. Patients and Methods: We retrospectively analyzed the clinical data of 78 M-NSCLC patients who received single-dose 8-Gy CRI for painful TF after concurrent chemoradiation therapy to a total radiation dose of 52 to 66 Gy between 2007 and 2012. Primary endpoints included significant pain relief (SPR) defined as a ≥2 point decrement in the Visual Analogue Scale for Pain inventory (VAS-P), time to pain relief, and duration of pain control. Secondary objectives were survival and prognostic factors. Results: Treatment was well tolerated, with only 5.1% grade 3 pneumonitis and 1.3% grade 2 esophagitis. Pre-CRI median and post-CRI minimum VAS-P were 7 and 3 (P<.001), respectively. SPR was noted in 67 (85.9%) patients, and only 3 (3.9%) scored progressive pain. Median time to lowest VAS-P and duration of pain control were 27 days and 6.1 months, respectively. Median overall survival (OS) was 7.7 months, and the 1-year OS rate was 26.5%. On multivariate analyses, lower Eastern Cooperative Oncology group score (1-2; P<.001), absence of anemia (P=.001), and fewer metastatic sites (1-2; P<.001) were found to be associated with longer OS. Conclusions: Single-dose 8-Gy CRI provides safe, effective, and durable pain palliation for TF in radically irradiated M-NSCLC patients. Because of its convenience, lower cost, and higher comfort, the present protocol can be considered an appropriate option for patients with limited life spans.

  16. Reliability of PET/CT shape and heterogeneity features in functional and morphological components of Non-Small Cell Lung Cancer tumors: a repeatability analysis in a prospective multi-center cohort

    CERN Document Server

    Desseroit, Marie-Charlotte; Weber, Wolfgang; Siegel, Barry A; Rest, Catherine Cheze Le; Visvikis, Dimitris; Hatt, Mathieu

    2016-01-01

    Purpose: The main purpose of this study was to assess the reliability of shape and heterogeneity features in both Positron Emission Tomography (PET) and low-dose Computed Tomography (CT) components of PET/CT. A secondary objective was to investigate the impact of image quantization.Material and methods: A Health Insurance Portability and Accountability Act -compliant secondary analysis of deidentified prospectively acquired PET/CT test-retest datasets of 74 patients from multi-center Merck and ACRIN trials was performed. Metabolically active volumes were automatically delineated on PET with Fuzzy Locally Adaptive Bayesian algorithm. 3DSlicerTM was used to semi-automatically delineate the anatomical volumes on low-dose CT components. Two quantization methods were considered: a quantization into a set number of bins (quantizationB) and an alternative quantization with bins of fixed width (quantizationW). Four shape descriptors, ten first-order metrics and 26 textural features were computed. Bland-Altman analysi...

  17. Artificial leucine rich repeats as new scaffolds for protein design.

    Science.gov (United States)

    Baabur-Cohen, Hemda; Dayalan, Subashini; Shumacher, Inbal; Cohen-Luria, Rivka; Ashkenasy, Gonen

    2011-04-15

    The leucine rich repeat (LRR) motif that participates in many biomolecular recognition events in cells was suggested as a general scaffold for producing artificial receptors. We describe here the design and first total chemical synthesis of small LRR proteins, and their structural analysis. When evaluating the tertiary structure as a function of different number of repeating units (1-3), we were able to find that the 3-repeats sequence, containing 90 amino acids, folds into the expected structure.

  18. CBF and CMRo/sub 2/ during craniotomy for small supratentorial cerebral tumours in enflurane anaesthesia. A dose-response study

    Energy Technology Data Exchange (ETDEWEB)

    Madsen, J.B.; Cold, G.E.; Eriksen, H.O.; Eskesen, V.; Blatt-Lyon, B.

    1986-01-01

    In 14 patients with supratentorial cerebral tumors with midline shift less than or equal to 10 mm, cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRo/sub 2/) were measured twice on the contralateral side of the craniotomy, using a modification of the Kety and Schmidt method. For induction of anaesthesia, thiopental, fentanyl and pancuronium were used. The anaesthesia was maintained with enflurane 1% in nitrous oxide 67%. Moderate hypocapnia to a level averaging 4.3 kPa was achieved. The patients were divided into two groups. In group 1 (n=7), 1% enflurane was used throughout the anaesthesia, and CBF and CMRo/sub 2/ measured about 70 min after induction averaged 30.1 ml 100 g/sup -1/ min/sub -1/ and 1.98 ml O/sub 2/ 100 g/sup -1/ min/sup -1/, respectively. During the second CBF study 1 h later, CBF and CMRo/sub 2/ were unchanged (P>0.05). In group 2 (n=7), the inspiratory enflurane concentration was increased from 1 to 2% after the first CBF measurement. In this group a significant decrease in CMRo/sub 2/ was observed, while CBF was unchanged. In six patients EEG was recorded simultaneously with the CBF measurements. In patients subjected to increasing enflurane concentration (Group 2), a suppression in the EEG activity was observed without spike waves. It is concluded that enflurane induces a dose-related decrease in CMRo/sub 2/ and suppression in the EEG activity, whereas CBF was unchanged.

  19. 30 Gy or 34 Gy? Comparing 2 Single-Fraction SBRT Dose Schedules for Stage I Medically Inoperable Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Videtic, Gregory M.M., E-mail: videtig@ccf.org; Stephans, Kevin L.; Woody, Neil M.; Reddy, Chandana A.; Zhuang, Tingliang; Magnelli, Anthony; Djemil, Toufik

    2014-09-01

    Purpose: To review outcomes of 2 single-fraction lung stereotactic body radiation therapy (SBRT) schedules used for medically inoperable early stage lung cancer. Methods and Materials: Patients in our institution have been treated on and off protocols using single-fraction SBRT (30 Gy and 34 Gy, respectively). All patients had node-negative lung cancer measuring ≤5 cm and lying ≥2 cm beyond the trachea-bronchial tree and were treated on a Novalis/BrainLAB system with the ExactTrac positioning system for daily image guidance. Results: For the interval from 2009 to 2012, 80 patients with 82 lesions were treated with single-fraction lung SBRT. Fifty-five patients (69%) and 25 patients (31%) received 30 Gy and 34 Gy, respectively. In a comparison of 30 Gy and 34 Gy cohorts, patient and tumor characteristics were balanced and median follow-up in months was 18.7 and 17.8, respectively. The average heterogeneity-corrected mean doses to the target were 33.75 Gy and 37.94 Gy for the 30-Gy and 34-Gy prescriptions, respectively. Comparing 30-Gy and 34-Gy cohorts, 92.7% and 84.0% of patients, respectively, experienced no toxicity (P was not significant), and had neither grade 3 nor higher toxicities. For the 30-Gy and 34-Gy patients, rates of 1-year local failure, overall survival, and lung cancer-specific mortality were 2.0% versus 13.8%, 75.0% versus 64.0%, and 2. 1% versus 16.0%, respectively (P values for differences were not significant). Conclusions: This is the largest single-fraction lung SBRT series yet reported. and it confirms the safety, efficacy, and minimal toxicity of this schedule for inoperable early stage lung cancer.

  20. 低分割放疗治疗老年非小细胞肺癌的临床观察%Clinical observation of elderly non-small-cell lung cancer patients treated by hypofractionated high-dose radiotherapy

    Institute of Scientific and Technical Information of China (English)

    李小龙; 党亚正; 卫伟; 陆婉玲; 赵宏亮; 陆宙; 胡飚; 杨婷

    2013-01-01

    目的:探讨老年非小细胞肺癌低分割放疗的临床疗效.方法:收集接受胸部放疗的老年肺癌35例,单次分割剂量2.5Gy,总剂量50Gy.TNM分期Ⅱ、Ⅲ、Ⅳ期各6、18、11例.结果:随访6-24个月,随访率100%.放射性食管炎发生率22.9%、2级以上放射性肺炎发生率8.6%.近期疗效:CR 11.4%、PR 51.4%、SD 28.6%、PD 8.6%;1年生存率57.1%,2年生存率17.1%.结论:低分割放疗对老年肺癌患者近期疗效确切,放疗毒副反应可以耐受.%Objective:To investigate the clinical efficacy of hypofractionated high -dose radiotherapy for elderly non - small - cell lung cancer. Methods: To analyze 53 cases of lung cancer received chest radiation therapy with dose fractionation 2.5Gy/d,5f/w,total dose 50Gy. TNM staging Ⅱ , Ⅲ and Ⅳ were respectively,6,18 and 11 cases. Results:Followed up for 6-24 months,follow - up rate was 100%. Radiation esophagitis incidence was 22. 9%. The radiation pneumonia rate was 8. 6% . Short term efficacy: CR 11. 4% , PR 51. 4% , SD 28. 6% , PD 8. 6% . 1 - year survival rate was 57. 1% ,2 - year survival rate was 17. 1%. Conclusion: Curative effect of non - small cell lung cancer patients treated by three - dimensional conformal hypofractionated high - dose radiotherapy is definitely, radiation side effects can be tolerated.

  1. Repeatability of Cryogenic Multilayer Insulation

    Science.gov (United States)

    Johnson, W. L.; Vanderlaan, M.; Wood, J. J.; Rhys, N. O.; Guo, W.; Van Sciver, S.; Chato, D. J.

    2017-01-01

    Due to the variety of requirements across aerospace platforms, and one off projects, the repeatability of cryogenic multilayer insulation has never been fully established. The objective of this test program is to provide a more basic understanding of the thermal performance repeatability of MLI systems that are applicable to large scale tanks. There are several different types of repeatability that can be accounted for: these include repeatability between multiple identical blankets, repeatability of installation of the same blanket, and repeatability of a test apparatus. The focus of the work in this report is on the first two types of repeatability. Statistically, repeatability can mean many different things. In simplest form, it refers to the range of performance that a population exhibits and the average of the population. However, as more and more identical components are made (i.e. the population of concern grows), the simple range morphs into a standard deviation from an average performance. Initial repeatability testing on MLI blankets has been completed at Florida State University. Repeatability of five GRC provided coupons with 25 layers was shown to be +/- 8.4 whereas repeatability of repeatedly installing a single coupon was shown to be +/- 8.0. A second group of 10 coupons have been fabricated by Yetispace and tested by Florida State University, through the first 4 tests, the repeatability has been shown to be +/- 16. Based on detailed statistical analysis, the data has been shown to be statistically significant.

  2. Evaluating dose response from flexible dose clinical trials

    Directory of Open Access Journals (Sweden)

    Baron David

    2008-01-01

    Full Text Available Abstract Background The true dose effect in flexible-dose clinical trials may be obscured and even reversed because dose and outcome are related. Methods To evaluate dose effect in response on primary efficacy scales from 2 randomized, double-blind, flexible-dose trials of patients with bipolar mania who received olanzapine (N = 234, 5–20 mg/day, or patients with schizophrenia who received olanzapine (N = 172, 10–20 mg/day, we used marginal structural models, inverse probability of treatment weighting (MSM, IPTW methodology. Dose profiles for mean changes from baseline were evaluated using weighted MSM with a repeated measures model. To adjust for selection bias due to non-random dose assignment and dropouts, patient-specific time-dependent weights were determined as products of (i stable weights based on inverse probability of receiving the sequence of dose assignments that was actually received by a patient up to given time multiplied by (ii stable weights based on inverse probability of patient remaining on treatment by that time. Results were compared with those by unweighted analyses. Results While the observed difference in efficacy scores for dose groups for the unweighted analysis strongly favored lower doses, the weighted analyses showed no strong dose effects and, in some cases, reversed the apparent "negative dose effect." Conclusion While naïve comparison of groups by last or modal dose in a flexible-dose trial may result in severely biased efficacy analyses, the MSM with IPTW estimators approach may be a valuable method of removing these biases and evaluating potential dose effect, which may prove useful for planning confirmatory trials.

  3. Clinical effect of small dose of iodine-131 combined with methimazole in the treatment of hyperthyroidism and its effect on patients with bone turnover markers and bone mineral density

    Institute of Scientific and Technical Information of China (English)

    Tie-Yong Qian; Yi-Fing Chen; Wei-Feng Yao; Hui Wan

    2016-01-01

    Objective:To investigate the clinical effect of small dose of iodine-131 combined with methimazole in the treatment of hyperthyroidism and its effect on patients with bone turnover markers and bone mineral density.Methods:A total of 156 patients with hyperthyroidism who were treated in Wuxi No.2 People's Hospital from January 2013 to January 2014 were selected as research subjects. All of the patients were randomly assigned into observation group (n=78) and control group (n=78). All of the patients in the two groups were treated with methimazole orally, and the observation group was received small dose of iodine-131 on the basis of methimazole. The course of treatment is one year, and follow-up visit was done in 3, 6 and 12 months after treatment. Before and after treatment, the function of thyroid (FT3, FT4, TSH, TT3, TT4), bone turnover markers (CT, BGP, ALP, PINP,β-CTX), and bone mineral density (L2-4 lumbar, radius, hip, and the whole body) of two groups were observed and analyzed. The clinical effect, one-year recurrence rate and incidence of adverse reactions of two groups were compared.Results: Before treatment, there were no statistical differences between the two groups. After treatment, the levels of FT3, FT4, TT3, TT4, CT, BGP, ALP, PINP andβ-CTX of two groups were decreased, along with the treatment time extension decreased more significantly, and the levels of observation group at each time point were lower than the control group at the same period. The levels of TSH of two groups were increased, along with the treatment time extension increased more significantly, and the levels of observation group at each time point were higher than the control group at the same period. The bone mineral density of the two groups were higher than before treatment, and the observation group was higher than the control group. The total effective rate of the observation group was higher than the control group, and the one-year recurrence rate was lower than the

  4. 小剂量地西泮联合莫沙比利治疗功能性消化不良效果分析%Effect Analysis on Functional Dyspepsia Patients by Small Doses of Diazepam Combined with Mosapride

    Institute of Scientific and Technical Information of China (English)

    赵彩云

    2015-01-01

    Objective To investigate the application value evaluation for functional dyspepsia patients by small doses of diazepam combined with mosapride. Methods One hundred and seventy-two functional dyspepsia patients who were treated in the depart-ment of gastroenterology of the hospital of traditional Chinese medicine in jiashan county of jiaxing city in zhejiang province hospi-tal from April 2010 to April 2012 were divided into the control group and the observation group by random number table. The control group were only given mosapride,the observation group were given small doses of diazepam combined with mosapride. Then clinical efficacy and adverse reactions rate were compared. Results The total efficiency rate of the observation group were statisti-cally higher than that of the control group (95.35%vs86.05%,P0.05). Conclusion The clinical efficacy of functional dyspepsia patients by small doses of diazepam combined with mosapride is sure,it is superior to mosapride alone,it has the characteristics of safe and reliable and less adverse reactions.%目的:探究功能性消化不良患者运用小剂量地西泮联合莫沙必利治疗的临床效果。方法应用随机数字表法将该院消化科2012年6月—2014年6月间治疗的172例功能性消化不良患者分为对照组和观察组,对照组给予口服莫沙必利进行治疗,观察组在此基础上给予小剂量地西泮进行治疗,比较两组患者的临床治疗效果和不良反应的发应率。结果观察组的临床治疗效果明显优于对照组,差异有统计学意义(95.35%vs86.05%,P0.05)。结论对于消化性功能不良患者运用小剂量地西泮联合莫沙必利进行治疗的临床效果较为显著,优于单用莫沙必利治疗者,具有安全高效和不良反应少等特点。

  5. The curative effect of small dose Tolterodine in the treatment of primary nocturnal enuresis%小剂量托特罗定治疗小儿遗尿症的临床疗效

    Institute of Scientific and Technical Information of China (English)

    宫小勇; 杜红; 薛亚辉; 郑伟; 孙小敏

    2013-01-01

    Objective To explore the curative effect of small dose Tolterodine to treat primary nocturnal enuresis . Meth-odS From June 2008 to May 2012 , 125 cases diagnosed as primary nocturnal enuresis were randomized into the control group and treatment group . The treatment group took small dose tolterodine tartrate tablets orally for 3 months. Night enuresis times was taken as index to evaluate the curative effect . 5 weeks after the treatment, the curative effect was evaluated . Results The number of primary nocturnal enuresis cases dropped from 69 to 17 in the treatment group , and dropped from 56 to 52 in the control group . There was significant difference between the two groups ( P< 0. 005) . Conclusion Small dose of tolterodine is safe and effective in the treatment of primary nocturnal enuresis .%目的 探讨小剂量托特罗定治疗小儿遗尿症的疗效.方法2008年6月至2012年5月,对125例被诊断为小儿遗尿症的患儿进行随机对照研究,设置空白对照组、治疗组(口服小剂量托特罗定).以夜间遗尿次数作为主要疗效指标.治疗3个月、停药1月后的下1周进行疗效评价.结果治疗后治疗组遗尿≥2次/周的人数由69例下降为17例,对照组由56例下降为52例.治疗组下降率(75.36%)明显高于对照组(7.14%)(P<0.005),无严重副反应.结论 小剂量托特罗定用于治疗小儿遗尿症有较好疗效和安全性.

  6. Effect of small dose of amisulpride in the treatment of senile depression%小剂量氨磺必利辅助治疗老年抑郁症的疗效分析

    Institute of Scientific and Technical Information of China (English)

    刘春仙; 彭华; 张新风

    2015-01-01

    目的 探讨小剂量氨磺必利对老年抑郁症患者的疗效及安全性. 方法 将95例老年抑郁症患者随机分成研究组(使用艾司西酞普兰合并小剂量氨磺必利治疗)和对照组(单用艾司西酞普兰治疗),疗程6周.采用汉密尔顿抑郁量表(HAMD)进行疗效评定,采用治疗中出现的症状量表(TESS)进行安全性评定. 结果 研究组总有效率为84.8%,对照组为67.3%,2组疗效比较,差异有统计学意义(P<0.05);2组间药物不良反应的发生率差异无统计学意义(P>0.05). 结论 小剂量氨磺必利联合艾司西酞普兰治疗老年抑郁症的疗效良好且安全.%Objective To explore the efficacy and safety of small dose of misulpride in the treatment of senile depression.Methods Ninety-six elderly patients with depression were randomly divided into research group (treated with escitalopram combined with small dose of amisulpride) and control group (treated with escitalopram only),and the treatment course was 6 weeks.Efficacy and safety were assessed with HAMD and TESS respectively before and after treatment.Results The efficacy of research group was significantly higher than that of control group (P<0.05).There was no significant difference in the incidence of side effects between two groups(P>0.05).Conclusions It is a safe and effective treatment to use escitalopram combined with small dose amisulpride in elderly patients with depresssion.

  7. Higher Biologically Effective Dose of Radiotherapy Is Associated With Improved Outcomes for Locally Advanced Non-Small Cell Lung Carcinoma Treated With Chemoradiation: An Analysis of the Radiation Therapy Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Machtay, Mitchell, E-mail: Mitchell.machtay@uhhospitals.org [University Hospitals/Case Western Reserve University, Cleveland, OH (United States); Bae, Kyounghwa [Radiation Therapy Oncology Group (RTOG) Department of Statistics, Philadelphia, PA (United States); Movsas, Benjamin [Henry Ford Hospital, Detroit, MI (United States); Paulus, Rebecca [Radiation Therapy Oncology Group (RTOG) Department of Statistics, Philadelphia, PA (United States); Gore, Elizabeth M. [Medical College of Wisconsin, Milwaukee, WI (United States); Komaki, Ritsuko [M.D. Anderson Cancer Center, Houston, TX (United States); Albain, Kathy [Loyola University Chicago Stritch School of Medicine, Maywood, IL (United States); Sause, William T. [LDS Hospital, Salt Lake City, UT (United States); Curran, Walter J. [Emory University, Atlanta, GA (United States)

    2012-01-01

    Purpose: Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity. Methods and Materials: This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) receive