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Sample records for acute reference dose

  1. Acute reference doses: theory and practical approaches.

    PubMed

    Moretto, A

    2000-07-01

    The approach of the Joint Meeting on Pesticide Residues to the establishment of the acute reference dose for pesticides is presented and related issues are discussed. Three main points seem relevant when discussing the acute reference dose: (1) what compounds should have an acute reference dose, (2) what toxicological database is required for the establishment of an acute reference dose; (3) what safety factors are to be used. It is concluded that (1) groups of compounds that need an acute reference dose can be identified, whereas general rules for identifying groups not requiring an acute reference dose cannot be easily given; (2) studies from the standard toxicological database can often be used to allocate an acute reference dose and the usefulness of refinements (by requesting specific studies) should be evaluated after intake assessment; general rules on study requirements cannot be easily given; (3) more thought should be given to what safety factors apply in certain circumstances. PMID:10983586

  2. [A new toxicological concept-acute reference dose].

    PubMed

    Liu, Zhiwei; Chen, Bingheng

    2003-01-01

    Acute reference dose (ARfD) is a new concept in toxicology and risk assessment, and mainly used for assessing health effect from short-time exposure to environmental chemicals. The ARfD of a chemical was defined as "an estimate of a substance in food or drinking water, expressed on a body weight basis, that can be ingested over a short period of time, usually during one meal or one day, without appreciable health risk to the consumer on the basis of all the known facts at the time of the evaluation. It is usually expressed in milligrams per kilogram of body weight." ARfD is different from ADI and reference dose. In this review the principles and methods in establishing ARfD were explained. PMID:12731294

  3. [Basic principles for setting acute reference dose, ARfD in Japan].

    PubMed

    Yoshida, Midori; Suzuki, Daisetsu; Matsumoto, Kiyoshi; Shirota, Mariko; Inoue, Kaoru; Takahashi, Miwa; Morita, Takeshi; Ono, Atsushi

    2013-01-01

    Basic principles for simulation of acute reference dose (ARfD) setting were defined based on the work of Solecki et al. (2005). The principles are: (1) Appearance of acute toxicity within 24 h after oral administration. (2) Rationale for setting toxicity that appears or could appear after single oral administration. (3) ARfD setting is assumed to be necessary for all pesticides. (4) ARfD setting is not necessary when the value is at or above the cutoff level. (5) The setting basically applies to the general population. (6) ARfD is set based on the lowest NOAEL among all the available study data concerning endpoints for acute effects. (7) Effects of exposure during critical periods should be considered as endpoints for ARfD setting. (8) The approach for the safety coefficient is the same as that for acceptable daily intake. (9) If available, human data are acceptable as an endpoint for ARfD setting. PMID:24025213

  4. Guidance on setting of acute reference dose (ARfD) for pesticides.

    PubMed

    Solecki, Roland; Davies, Les; Dellarco, Vicki; Dewhurst, Ian; Raaij, Marcel van; Tritscher, Angelika

    2005-11-01

    This paper summarises and extends the work developed over the last decade by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) for acute health risk assessment of agricultural pesticides. The general considerations in setting of acute reference doses (ARfDs) in a step-wise process, as well as specific considerations and guidance regarding selected toxicological endpoints are described in detail. The endpoints selected are based on the practical experience with agricultural pesticides by the JMPR and are not a comprehensive listing of all possible relevant endpoints. Haematotoxicity, immunotoxicity, neurotoxicity, liver and kidney toxicity, endocrine effects as well as developmental effects are taken into account as acute toxic alerts, relevant for the consideration of ARfDs for pesticides. The general biological background and the data available through standard toxicological testing for regulatory purposes, interpretation of the data, conclusions and recommendations for future improvements are described for each relevant endpoint. The paper also considers a single dose study protocol. This type of study is not intended to be included in routine toxicological testing for regulatory purposes, but rather to guide further testing when the current database indicates the necessity for an ARfD but does not allow a reliable derivation of the value. PMID:16040182

  5. Simulation of acute reference dose (ARfD) settings for pesticides in Japan.

    PubMed

    Yoshida, Midori; Suzuki, Daisetsu; Matsumoto, Kiyoshi; Shirota, Mariko; Inoue, Kaoru; Takahashi, Miwa; Morita, Takeshi; Ono, Atsushi

    2013-01-01

    In order to develop guidelines for setting acute reference doses (ARfDs) for pesticides in Japan, we conducted simulations of ARfD settings based on evaluation reports for 201 pesticides assessed by the Food Safety Commission (FSC) in Japan over the last 8 years. Our conceptual principles were based on the concepts written by Solecki et al. (2005) and were adapted for toxicological data required in Japan. Through this process, we were able to set the ARfDs for over 90% of the 201 pesticides tested. The studies that provided the rationale for ARfD setting were primarily reproductive and developmental toxicity studies, acute neurotoxicity studies, and pharmacology studies. For approximately 30% of the pesticides simulated in the present study, it was not necessary to establish ARfDs. Some of the simulated ARfDs resulting from their endpoints may be conservative estimates, because the evaluation reports were written for acceptable daily intake settings. Thus, it was sometimes difficult to distinguish acute toxic alerts from repeated toxicities. We were unable to set an ARfD for 14 pesticides because of insufficient data on acute toxicities. This could be improved by more complete recordkeeping. Furthermore, we categorized the 201 pesticides by mechanism of action or chemical structure. Our simulation indicates that the conceptual framework presented here can be used as a basis for the development of guidelines on ARfD settings for pesticides in Japan. PMID:23535399

  6. The use of safety or uncertainty factors in the setting of acute reference doses.

    PubMed

    Renwick, A G

    2000-07-01

    A 100-fold safety or uncertainty factor has been used for about 40 years to derive safe daily intakes for humans based on animal studies; the 100-fold factor comprises separate 10-fold factors to allow for species differences and inter-individual variability. Each factor has to allow for toxicokinetic and toxicodynamic differences. Sub-dividing the 10-fold factors into kinetic and dynamic defaults, which when multiplied give a product of 10, offers a number of advantages. The main rationale for this sub-division is so that chemical-specific data can be introduced to replace one or more of the default sub-factors, hence contributing to a chemical-related overall factor. However, sub-division of the 10-fold factors has allowed analysis of the appropriateness of the overall 10-fold defaults, and analysis of special situations, such as infants and children. The establishment of an acute reference dose based on animal studies has to allow for both species differences and inter-individual variability; comparison with the factors used for chronic effects suggests that modification of the usual defaults may be appropriate under certain specific circumstances, but that the usual default of 100 remains appropriate for most cases. PMID:10983588

  7. Genetics Home Reference: acute promyelocytic leukemia

    MedlinePlus

    ... acute myeloid leukemia, a cancer of the blood-forming tissue ( bone marrow ). In normal bone marrow, hematopoietic ... 7186-203. Review. Citation on PubMed de Thé H, Chen Z. Acute promyelocytic leukaemia: novel insights into ...

  8. Chemical warfare agents: estimating oral reference doses.

    PubMed

    Opresko, D M; Young, R A; Faust, R A; Talmage, S S; Watson, A P; Ross, R H; Davidson, K A; King, J

    1998-01-01

    Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other

  9. U.S. EPA'S ACUTE REFERENCE EXPOSURE METHODOLOGY FOR ACUTE INHALATION EXPOSURES

    EPA Science Inventory

    The US EPA National Center for Environmental Assessment has developed a methodology to derive acute inhalation toxicity benchmarks, called acute reference exposures (AREs), for noncancer effects. The methodology provides guidance for the derivation of chemical-specific benchmark...

  10. Total dose performance of radiation hardened voltage regulators and references

    NASA Technical Reports Server (NTRS)

    McClure, S.; Gorelick, J.; Pease, R.; Rax, B.; Ladbury, R.

    2001-01-01

    Total dose test of commercially available radiation hardened bipolar voltage regulators and references show reduced sensitivity to dose rate and varying sensitivity to bias under pressure. Behavior of critical parameters in different dose rate and bias conditions is compared and the impact to hardness assurance methodology is discussed.

  11. Single dose dipyrone for acute postoperative pain

    PubMed Central

    Derry, Sheena; Faura, Clara; Edwards, Jayne; McQuay, Henry J; Moore, R Andrew

    2014-01-01

    Background Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. Objectives To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. Search methods The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Selection criteria Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls. Over 70% of participants

  12. Single dose oral diclofenac for acute postoperative pain in adults

    PubMed Central

    Derry, Philip; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), available as a potassium salt (immediate-release) or sodium salt (delayed-release). This review updates an earlier review published in The Cochrane Database of Systematic Reviews (Issue 2, 2004) on ‘Single dose oral diclofenac for postoperative pain’. Objectives To assess single dose oral diclofenac for the treatment of acute postoperative pain. Search methods Cochrane CENTRAL, MEDLINE, EMBASE, Biological Abstracts, the Oxford Pain Relief Database, and reference lists of articles were searched; last search December 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of single dose, oral diclofenac (sodium or potassium) for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed studies for inclusion and quality, and extracted data. The area under the pain relief versus time curve was used to derive the proportion of participants with at least 50% pain relief over 4 to 6 hours, using validated equations. Relative benefit (risk) and number needed to treat to benefit (NNT) were calculated. Information on adverse events, time to remedication, and participants needing additional analgesia was also collected. Main results Fifteen studies (eight additional studies) with 1512 participants more than doubled the information available at each dose. Overall 50% to 60% of participants experienced at least 50% pain relief over 4 to 6 hours at any dose with diclofenac, compared to 10 to 20% with placebo, giving NNTs of about 2.5 for doses of 25 mg to 100 mg (similar to earlier review); no dose response was demonstrated. At 50 mg and 100 mg, NNTs for diclofenac potassium (2.1 (1.8 to 2.4) and 1.9 (1.7 to 2.2)) were significantly lower (better) than for diclofenac sodium (6.7 (4.2 to 17) and 4.5 (3.2 to 7.7)). The median time to use of rescue medication was 2 hours for placebo, 4.3 hours for diclofenac 50 mg and 4.9 hours

  13. Construction of Taiwanese Adult Reference Phantoms for Internal Dose Evaluation.

    PubMed

    Chang, Shu-Jun; Hung, Shih-Yen; Liu, Yan-Lin; Jiang, Shiang-Huei

    2016-01-01

    In the internal dose evaluation, the specific absorbed fraction (SAF) and S-value are calculated from the reference phantom based on Caucasian data. The differences in height and weight between Caucasian and Asian may lead to inaccurate dose estimation. In this study, we developed the Taiwanese reference phantoms. 40 volunteers were recruited. Magnetic resonance images (MRI) were obtained, and the contours of 15 organs were drawn. The Taiwanese reference man (TRM) and Taiwanese reference woman (TRW) were constructed. For the SAF calculation, the differences in the self-absorption SAF (self-SAF) between the TRM, TRW, and Oak Ridge National Laboratory (ORNL) adult phantom were less than 10% when the difference in organ mass was less than 20%. The average SAF from liver to pancreas of TRM was 38% larger than that of the ORNL adult phantom, and the result of TRW was 2.02 times higher than that of the ORNL adult phantom. For the S-value calculation, the ratios of TRW and ORNL adult phantom ranged from 0.91 to 1.57, and the ratios of TRM and ORNL adult phantom ranged from 1.04 to 2.29. The SAF and S-value results were dominantly affected by the height, weight, organ mass, and geometric relationship between organs. By using the TRM and TRW, the accuracy of internal dose evaluation can be increased for radiation protection and nuclear medicine. PMID:27618708

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

    EPA Science Inventory

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

  15. Dose homogeneity specification for reference dosimetry of nonstandard fields

    SciTech Connect

    Chung, Eunah; Soisson, Emilie; Seuntjens, Jan

    2012-01-15

    Purpose: To investigate the sensitivity of the plan-class specific correction factor to dose distributions in composite nonstandard field dosimetry. Methods: A cylindrical water-filled PMMA phantom was constructed at the center of which reference absorbed dose could be measured. Ten different TomoTherapy-based IMRT fields were created on the CT images of the phantom. The dose distribution for each IMRT field was estimated at the position of a radiation detector or ionization chamber. The dose in each IMRT field normalized to that in a reference 10 x 10 cm{sup 2} field was measured using a PTW micro liquid ion chamber. Based on the new dosimetry formalism, a plan-class specific correction factor k{sub Q{sub p{sub c{sub s{sub r,Q}{sup f{sub p}{sub c}{sub s}{sub r},f{sub r}{sub e}{sub f}}}}}} for each field was measured for two Farmer-type chambers, Exradin A12 and NE2571, as well as for a smaller Exradin A1SL chamber. The dependence of the measured correction factor on parameters characterizing dose distribution was analyzed. Results: Uncertainty on the plan-class specific correction factor measurement was in the range of 0.3%-0.5% and 0.3%-0.8% for the Farmer-type chambers and the Exradin A1SL, respectively. When the heterogeneity of the central region of the target volume was less than 5%, the correction factor did not differ from unity by more than 0.7% for the three air-filled ionization chambers. For more heterogeneous dose deliveries, the correction factor differed from unity by up to 2.4% for the Farmer-type chambers. For the Exradin A1SL, the correction factor was closer to unity due to the reduced effect of dose gradients, while it was highly variable in different IMRT fields because of a more significant impact of positioning uncertainties on the response of this chamber. Conclusions: The authors have shown that a plan-class specific correction factor can be specified as a function of plan evaluation parameters especially for Farmer-type chambers. This work

  16. Derivation of a chronic oral reference dose for cobalt.

    PubMed

    Finley, Brent L; Monnot, Andrew D; Paustenbach, Dennis J; Gaffney, Shannon H

    2012-12-01

    Cobalt (Co) is an essential element in humans as a component of vitamin B12. However, at high levels Co exposure has been shown to have detrimental effects. This study was designed to identify a chronic oral reference dose (RfD) for Co. Currently available data indicate that non-cancer health effects associated with Co exposure may include hematological, neurological, immunological, reproductive, cardiovascular, and endocrine responses. This analysis employs the standard US EPA risk assessment methodology for establishing a chronic RfD. In this analysis, the Jaimet and Thode (1955) 10-week, multiple dose human study of thyroid effects (decreased iodine uptake) in children was determined to be the most robust and sensitive study for identifying a potential point of departure dose (POD). A dose of 0.9 mgCo/kg-day was chosen as the POD. Consistent with the US EPA's previous derivation of the perchlorate RfD, which is also based on decreased iodine uptake in humans, we considered several uncertainly factors (UFs), and determined that a factor of 10 for human variability was appropriate, as well as a factor of three for database adequacy. Applying an aggregate uncertainty factor of 30 to the POD yields a chronic oral RfD of 0.03 mg/kg-day. We believe this value would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Co. PMID:22982439

  17. Development of a reference dose for BDE-47, 99, and 209 using benchmark dose methods.

    PubMed

    Li, Lu Xi; Chen, Li; Cao, Dan; Chen, Bing Heng; Zhao, Yan; Meng, Xiang Zhou; Xie, Chang Ming; Zhang, Yun Hui

    2014-09-01

    Eleven recently completed toxicological studies were critically reviewed to identify toxicologically significant endpoints and dose-response information. Dose-response data were compiled and entered into the USEPA's benchmark dose software (BMDS) for calculation of a benchmark dose (BMD) and a benchmark dose low (BMDL). After assessing 91 endpoints across the nine studies, a total of 23 of these endpoints were identified for BMD modeling, and BMDL estimates corresponding to various dose-response models were compiled for these separate endpoints. Thyroid, neurobehavior and reproductive endpoints for BDE-47, -99, -209 were quantitatively evaluated. According to methods and feature of each study, different uncertainty factor (UF) value was decided and subsequently reference doses (RfDs) were proposed. Consistent with USEPA, the lowest BMDLs of 2.10, 81.77, and 1698 µg/kg were used to develop RfDs for BDE-47, -99, and -209, respectively. RfDs for BDE-99 and BDE-209 were comparable to EPA results, and however, RfD of BDE-47 was much lower than that of EPA, which may result from that reproductive/developmental proves to be more sensitive than neurobehavior for BDE-47 and the principal study uses very-low-dose exposure. PMID:25256863

  18. Patient Dose Reference Levels for Interventional Radiology: A National Approach

    SciTech Connect

    Vano, Eliseo Sanchez, R.; Fernandez, J. M.; Gallego, J. J.; Verdu, J. F.; Garay, M. Gonzalez de; Azpiazu, A.; Segarra, A.; Hernandez, M. T.; Canis, M.; Diaz, F.; Moreno, F.; Palmero, J.

    2009-01-15

    A set of patient dose reference levels (RLs) for fluoroscopically guided interventional procedures was obtained in a survey launched by the National Society of Interventional Radiology (IR), involving 10 public hospitals, as recommended by the European Medical Exposures Directive. A sample of 1391 dose values (kerma area product [KAP]) was collected randomly during clinical procedures for seven of the most frequent procedures. Third quartiles of the KAP distributions were used to set the RLs. A regular quality control of the X-ray systems and a calibration of the dose meters were performed during the survey. The fluoroscopy time and total number of digital subtraction angiography images per procedure were also analyzed. The RL values proposed were 12 Gy cm{sup 2} for fistulography (hemodialysis access; sample of 180 cases), 73 Gy cm{sup 2} for lower limb arteriography (685 cases), 89 Gy cm{sup 2} for renal arteriography (55 cases), 80 Gy cm{sup 2} for biliary drainage (205 cases), 289 Gy cm{sup 2} for hepatic chemoembolization (151 cases), 94 Gy cm{sup 2} for iliac stent (70 cases), and 236 Gy cm{sup 2} for uterine embolization (45 cases). The provisional national RL values are lower than those obtained in a similar survey carried out in the United States from 2002 to 2004. These new values could be used to improve the practice of centers consistently working with doses higher than the RLs. This national survey also had a positive impact, as it helped increase the awareness of the members of the National Society of IR on a topic as crucial as patient dose values and programs on radiation protection.

  19. Immediate and Complex Cardiovascular Adaptation to an Acute Alcohol Dose

    PubMed Central

    Buckman, Jennifer F.; Eddie, David; Vaschillo, Evgeny G.; Vaschillo, Bronya; Garcia, Aaron; Bates, Marsha E.

    2016-01-01

    Background The detrimental effects of chronic heavy alcohol use on the cardiovascular system are well established and broadly appreciated. Integrated cardiovascular response to an acute dose of alcohol has been less studied. This study examined the early effects of an acute dose of alcohol on the cardiovascular system, with particular emphasis on system variability and sensitivity. The goal was to begin to understand how acute alcohol disrupts dynamic cardiovascular regulatory processes prior to the development of cardiovascular disease. Methods Healthy participants (N = 72, age 21 to 29) were randomly assigned to an alcohol, placebo, or no-alcohol control beverage condition. Beat-to-beat heart rate (HR) and blood pressure (BP) were assessed during a low-demand cognitive task prior to and following beverage consumption. Between-group differences in neurocardiac response to an alcohol challenge (blood alcohol concentration ~ 0.06 mg/dl) were tested. Results The alcohol beverage group showed higher average HR, lower average stroke volume, lower HR variability and BP variability, and increased vascular tone baroreflex sensitivity after alcohol consumption. No changes were observed in the placebo group, but the control group showed slightly elevated average HR and BP after beverage consumption, possibly due to juice content. At the level of the individual, an active alcohol dose appeared to disrupt the typically tight coupling between cardiovascular processes. Conclusions A dose of alcohol quickly invoked multiple cardiovascular responses, possibly as an adaptive reaction to the acute pharmacological challenge. Future studies should assess how exposure to alcohol acutely disrupts or dissociates typically integrated neurocardiac functions. PMID:26614647

  20. Genetics Home Reference: core binding factor acute myeloid leukemia

    MedlinePlus

    ... acute myeloid leukemia core binding factor acute myeloid leukemia Enable Javascript to view the expand/collapse boxes. ... Close All Description Core binding factor acute myeloid leukemia (CBF-AML) is one form of a cancer ...

  1. Establishment of dose reference levels for nuclear medicine in Greece.

    PubMed

    Vogiatzi, S; Kipouros, P; Chobis, M

    2011-09-01

    Greek Atomic Energy Commission's Department of Licensing and Inspections conducted a national survey for the establishment of nuclear medicine (NM) dose reference levels (DRLs) for adult patients, in Greece. The administered activities (AAs) (MBq) were collected from 120 NM departments (88 % of total), during on-site inspections for licensing purposes. Factors influencing the image quality were also investigated. The established national DRLs represent the AA value corresponding to the 75th percentile of the AA frequency distributions. In their majority, national DRLs and average AAs are comparable with the ones published in the international literature. In the light of new technologies, there might be potential for reducing the higher values of AAs, in co-operation with the nuclear medicine experts. PMID:21765158

  2. Genetics Home Reference: cytogenetically normal acute myeloid leukemia

    MedlinePlus

    ... one form of a cancer of the blood-forming tissue (bone marrow) called acute myeloid leukemia. In ... 1 link) PubMed Sources for This Page Döhner H. Implication of the molecular characterization of acute myeloid ...

  3. Pediatric reference ranges for acute kidney injury biomarkers

    PubMed Central

    Nehus, Edward; Haffner, Christopher; Ma, Qing; Devarajan, Prasad

    2015-01-01

    Background Novel urinary biomarkers are useful for the prediction of acute kidney injury (AKI). Most promising are the urine markers NGAL, IL-18, KIM-1, and LFABP. Each of these has shown considerable promise diagnosing AKI earlier than serum creatinine (Scr) using disease controls. We set out to determine reference levels of these markers in a healthy pediatric population. Methods Urine was collected from 368 healthy children and assayed for NGAL, IL-18, KIM-1, and LFABP using commercially available kits or assay materials. Analysis of biomarkers by linear regression and according to age groups (3–<5 years; 5–<10; 10–<15; 15–<18) was performed to determine if biomarker levels differed with age and gender. Results Median values were: NGAL (6.6 ng/ml; IQR 2.8–17), IL-18 (21.6 pg/ml; IQR 13.6–32.9), KIM-1 (410 pg/ml; IQR 226–703), LFABP (3.4 ng/ml; IQR 1.6–6.0). Significant gender differences were found with NGAL and IL-18 and significant age differences were found with all markers. 95th percentile values for each marker varied with age and gender greater than median values. Conclusions This is the largest pediatric reference range study for the urinary measurement of NGAL, IL-18, KIM-1, and LFABP and highlights age and gender differences in these markers. This information is essential for rational interpretation of studies and clinical trials utilizing these emerging AKI biomarkers. PMID:25348707

  4. The Acute Gastrointestinal Syndrome in High-Dose Irradiated Mice

    PubMed Central

    Booth, Catherine; Tudor, Gregory; Tudor, Julie; Katz, Barry P; MacVittie, Thomas

    2012-01-01

    The most detailed reports of the response of the gastrointestinal system to high dose acute radiation have focused mainly on understanding the histopathology. However, to enable medical countermeasure assessment under the animal rule criteria, it is necessary to have a robust model in which the relationship between radiation dose and intestinal radiation syndrome incidence, timing and severity are established and correlated with histopathology. Although many mortality studies have been published, they have used a variety of mouse strains, ages, radiation sources and husbandry conditions, all of which influence the dose response. Further, it is clear that the level of bone marrow irradiation and supportive care can influence endpoints. In order to create robust baseline data we have generated dose response data in adult male mice, maintained under identical conditions, and exposed to either total or partial-body irradiation. Partial-body irradiation includes both extensive (40%) and minimal (5%) bone marrow sparing models, the latter designed to correlate with an established primate model and allow assessment of effects of any medical countermeasure on all three major radiation syndromes (intestinal, bone marrow and lung) in the surviving mice. Lethal dose (LD30, LD50 and LD70) data are described in the various models, along with the impact of enteric flora and response to supportive care. Correlation with diarrhea severity and histopathology are also described. This data can be used to aid the design of good laboratory practice (GLP) compliant Animal Rule studies that are reflective of the conditions following accidental radiation exposure. PMID:23091876

  5. Linking Doses with Clinical Scores of Hematopoietic Acute Radiation Syndrome.

    PubMed

    Hu, Shaowen

    2016-10-01

    In radiation accidents, determining the radiation dose the victim received is a key step for medical decision making and patient prognosis. To reconstruct and evaluate the absorbed dose, researchers have developed many physical devices and biological techniques during the last decades. However, using the physical parameter "absorbed dose" alone is not sufficient to predict the clinical development of the various organs injured in an individual patient. In operational situations for radiation accidents, medical responders need more urgently to classify the severity of the radiation injury based on the signs and symptoms of the patient. In this work, the author uses a unified hematopoietic model to describe dose-dependent dynamics of granulocytes, lymphocytes, and platelets, and the corresponding clinical grading of hematopoietic acute radiation syndrome. This approach not only visualizes the time course of the patient's probable outcome in the form of graphs but also indirectly gives information of the remaining stem and progenitor cells, which are responsible for the autologous recovery of the hematopoietic system. Because critical information on the patient's clinical evolution can be provided within a short time after exposure and only peripheral cell counts are required for the simulation, these modeling tools will be useful to assess radiation exposure and injury in human-involved radiation accident/incident scenarios. PMID:27575346

  6. Toxicological dose assessment and acute health effect criteria

    SciTech Connect

    Stalker, A.C.; White, B.

    1992-01-01

    The use of hazardous materials requires the means of assessing doses from postulated accidental exposures to the hazardous materials. Hazardous materials include radiological and toxicological substances. Health effects are often divided into either acute (short term exposure) or chronic (long-term-exposure)-categories. Dose assessments and health effects are used in Hazard Classification, Safety Analysis Reports and Unreviewed Safety Question Determinations. The use of hazardous substances requires a means of assessing the potential health effects from exposure. Two types of toxicological data exist. The first is measured effects from human exposure, either accidentally or studies. The second consists of data from toxicity and lethality studies on mammals, often mice or rats. Because the data for human exposure is severely limited, an approach is needed that uses basic toxicity and lethality data from animal studies to estimate acute health effects in humans. The approach chosen is the one suggested jointly by the EPA, FEMA, and DOT in their Technical Guidance for Hazards Analysis'', December 1987.

  7. Toxicological dose assessment and acute health effect criteria

    SciTech Connect

    Stalker, A.C.; White, B.

    1992-09-01

    The use of hazardous materials requires the means of assessing doses from postulated accidental exposures to the hazardous materials. Hazardous materials include radiological and toxicological substances. Health effects are often divided into either acute (short term exposure) or chronic (long-term-exposure)-categories. Dose assessments and health effects are used in Hazard Classification, Safety Analysis Reports and Unreviewed Safety Question Determinations. The use of hazardous substances requires a means of assessing the potential health effects from exposure. Two types of toxicological data exist. The first is measured effects from human exposure, either accidentally or studies. The second consists of data from toxicity and lethality studies on mammals, often mice or rats. Because the data for human exposure is severely limited, an approach is needed that uses basic toxicity and lethality data from animal studies to estimate acute health effects in humans. The approach chosen is the one suggested jointly by the EPA, FEMA, and DOT in their ``Technical Guidance for Hazards Analysis``, December 1987.

  8. HADOC: a computer code for calculation of external and inhalation doses from acute radionuclide releases

    SciTech Connect

    Strenge, D.L.; Peloquin, R.A.

    1981-04-01

    The computer code HADOC (Hanford Acute Dose Calculations) is described and instructions for its use are presented. The code calculates external dose from air submersion and inhalation doses following acute radionuclide releases. Atmospheric dispersion is calculated using the Hanford model with options to determine maximum conditions. Building wake effects and terrain variation may also be considered. Doses are calculated using dose conversion factor supplied in a data library. Doses are reported for one and fifty year dose commitment periods for the maximum individual and the regional population (within 50 miles). The fractional contribution to dose by radionuclide and exposure mode are also printed if requested.

  9. Single dose oral ibuprofen for acute postoperative pain in adults

    PubMed Central

    Derry, Christopher J; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background This review updates a 1999 Cochrane review showing that ibuprofen at various doses was effective in postoperative pain in single dose studies designed to demonstrate analgesic efficacy. New studies have since been published. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory (NSAID) analgesics both by prescription and as an over-the-counter medicine. Ibuprofen is used for acute and chronic painful conditions. Objectives To assess analgesic efficacy of ibuprofen in single oral doses for moderate and severe postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered ibuprofen (any formulation) in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Seventy-two studies compared ibuprofen and placebo (9186 participants). Studies were predominantly of high reporting quality, and the bulk of the information concerned ibuprofen 200 mg and 400 mg. For at least 50% pain relief compared with placebo the NNT for ibuprofen 200 mg (2690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6475 participants) it was 2.5 (2.4 to 2.6). The proportion with at least 50% pain relief was 46% with 200 mg and 54% with 400 mg. Remedication within 6 hours was less

  10. Genetics Home Reference: familial acute myeloid leukemia with mutated CEBPA

    MedlinePlus

    ... N. A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation. Genes Chromosomes Cancer. 2010 Mar; ...

  11. Single dose oral analgesics for acute postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; McQuay, Henry J; Wiffen, Philip J

    2014-01-01

    Background Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. Objectives To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. Methods We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. Main results The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken. There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130

  12. Establishment of Reference Doses for residues of allergenic foods: report of the VITAL Expert Panel.

    PubMed

    Taylor, Steve L; Baumert, Joseph L; Kruizinga, Astrid G; Remington, Benjamin C; Crevel, Rene W R; Brooke-Taylor, Simon; Allen, Katrina J; Houben, Geert

    2014-01-01

    In 2011, an expert panel was assembled to establish appropriate Reference Doses for allergenic food residues as a part of the VITAL (Voluntary Incidental Trace Allergen Labeling) program of The Allergen Bureau of Australia & New Zealand (ABA). These Reference Doses would guide advisory labeling decisions for use on food labels. Individual NOAELs and LOAELs were obtained from clinical challenges of food-allergic subjects. Statistical dose-distribution models (log-normal, log-logistic, Weibull) were applied to the individual NOAELs and LOAELs for each allergenic food. The Reference Doses, in terms of mg of total protein from the allergenic food, were based upon either the ED01 (for peanut, cow's milk), the 95% lower confidence interval of the ED05 (for wheat, soybean, cashew, shrimp, sesame seed, mustard, and lupine), or both (egg, hazelnut) using all appropriate statistical dose-distribution models. Reference Doses were established for 11 allergenic foods ranging from 0.03 mg for egg protein to 10mg for shrimp protein. Reference Doses were not established for fish or celery due to poor model fits with existing data. Reference Doses were not established for other tree nuts beyond hazelnut and cashew because of the absence of data on NOAELs and LOAELs from individual subjects. PMID:24184597

  13. A case of acute psychosis in a patient following exposure to a single high dose of styrene.

    PubMed

    Moon, Eunsoo; Suh, Hwagyu; Lee, Byung Dae; Park, Je Min; Lee, Young Min; Jeong, Hee Jeong

    2015-09-01

    We report a case of acute psychotic symptoms following exposure to a single high dose of styrene monomer. The 24-year-old male patient showed psychotic and cognitive symptoms immediately after exposure. His psychotic symptoms included auditory hallucinations and delusions of reference. Brain magnetic resonance imaging, electroencephalography, and laboratory examinations were performed to evaluate any other causes. The clinical, neuroimaging, and laboratory review in this case suggested that the suddenly developed psychotic symptoms that led to chronic deterioration were caused by the single exposure to styrene monomer. This is the first recent report in which acute psychotic symptoms developed from a single high dose of styrene suffocation compared with previous findings showing symptoms because of long-term low-dose exposure. PMID:26184570

  14. Absorbed dose to water reference dosimetry using solid phantoms in the context of absorbed-dose protocols

    SciTech Connect

    Seuntjens, Jan; Olivares, Marina; Evans, Michael; Podgorsak, Ervin

    2005-09-15

    For reasons of phantom material reproducibility, the absorbed dose protocols of the American Association of Physicists in Medicine (AAPM) (TG-51) and the International Atomic Energy Agency (IAEA) (TRS-398) have made the use of liquid water as a phantom material for reference dosimetry mandatory. In this work we provide a formal framework for the measurement of absorbed dose to water using ionization chambers calibrated in terms of absorbed dose to water but irradiated in solid phantoms. Such a framework is useful when there is a desire to put dose measurements using solid phantoms on an absolute basis. Putting solid phantom measurements on an absolute basis has distinct advantages in verification measurements and quality assurance. We introduce a phantom dose conversion factor that converts a measurement made in a solid phantom and analyzed using an absorbed dose calibration protocol into absorbed dose to water under reference conditions. We provide techniques to measure and calculate the dose transfer from solid phantom to water. For an Exradin A12 ionization chamber, we measured and calculated the phantom dose conversion factor for six Solid Water{sup TM} phantoms and for a single Lucite phantom for photon energies between {sup 60}Co and 18 MV photons. For Solid Water{sup TM} of certified grade, the difference between measured and calculated factors varied between 0.0% and 0.7% with the average dose conversion factor being low by 0.4% compared with the calculation whereas for Lucite, the agreement was within 0.2% for the one phantom examined. The composition of commercial plastic phantoms and their homogeneity may not always be reproducible and consistent with assumed composition. By comparing measured and calculated phantom conversion factors, our work provides methods to verify the consistency of a given plastic for the purpose of clinical reference dosimetry.

  15. Translating reference doses into allergen management practice: challenges for stakeholders.

    PubMed

    Crevel, René W R; Baumert, Joseph L; Luccioli, Stefano; Baka, Athanasia; Hattersley, Sue; Hourihane, Jonathan O'B; Ronsmans, Stefan; Timmermans, Frans; Ward, Rachel; Chung, Yong-joo

    2014-05-01

    Risk assessment describes the impact of a particular hazard as a function of dose and exposure. It forms the foundation of risk management and contributes to the overall decision-making process, but is not its endpoint. This paper outlines a risk analysis framework to underpin decision-making in the area of allergen cross-contact. Specifically, it identifies challenges relevant to each component of the risk analysis: risk assessment (data gaps and output interpretation); risk management (clear and realistic objectives); and risk communication (clear articulation of risk and benefit). Translation of the outputs from risk assessment models into risk management measures must be informed by a clear understanding of the model outputs and their limitations. This will lead to feasible and achievable risk management objectives, grounded in a level of risk accepted by the different stakeholders, thereby avoiding potential unintended detrimental consequences. Clear, consistent and trustworthy communications actively involving all stakeholders underpin these objectives. The conclusions, integrating the perspectives of different stakeholders, offer a vision where clear, science-based benchmarks form the basis of allergen management and labelling, cutting through the current confusion and uncertainty. Finally, the paper recognises that the proposed framework must be adaptable to new and emerging evidence. PMID:24491260

  16. National reference doses for common radiographic, fluoroscopic and dental X-ray examinations in the UK.

    PubMed

    Hart, D; Hillier, M C; Wall, B F

    2009-01-01

    The National Patient Dose Database (NPDD) is maintained by the Radiation Protection Division of the Health Protection Agency. The latest review of the database analysed the data collected from 316 hospitals over a 5-year period to the end of 2005. The information supplied amounted to a total of 23 000 entrance surface dose measurements and 57 000 dose-area product measurements for single radiographs, and 208 000 dose-area product measurements along with 187 000 fluoroscopy times for diagnostic examinations or interventional procedures. In addition, patient dose data for dental X-ray examinations were included for the first time in the series of 5-yearly reviews. This article presents a summary of a key output from the NPDD - national reference doses. These are based on the third quartile values of the dose distributions for 30 types of diagnostic X-ray examination and 8 types of interventional procedure on adults, and for 4 types of X-ray examination on children. The reference doses are approximately 16% lower than the corresponding values in the previous (2000) review, and are typically less than half the values of the original UK national reference doses that were derived from a survey in the mid-1980s. This commentary suggests that two of the national reference doses from the 2000 review be retained as diagnostic reference levels because the older sample size was larger than for the 2005 review. No clear evidence could be found for the use of digital imaging equipment having a significant effect on dose. PMID:18852213

  17. Measurement and comparison of skin dose using OneDose MOSFET and Mobile MOSFET for patients with acute lymphoblastic leukemia

    PubMed Central

    Mattar, Essam H.; Hammad, Lina F.; Al-Mohammed, Huda I.

    2011-01-01

    Summary Background Total body irradiation is a protocol used to treat acute lymphoblastic leukemia in patients prior to bone marrow transplant. It is involved in the treatment of the whole body using a large radiation field with extended source-skin distance. Therefore measuring and monitoring the skin dose during the treatment is important. Two kinds of metal oxide semiconductor field effect transistor (OneDose MOSFET and mobile MOSEFT) dosimeter are used during the treatment delivery to measure the skin dose to specific points and compare it with the target prescribed dose. The objective of this study was to compare the variation of skin dose in patients with acute lymphatic leukemia (ALL) treated with total body irradiation (TBI) using OneDose MOSFET detectors and Mobile MOSFET, and then compare both results with the target prescribed dose. Material/Methods The measurements involved 32 patient’s (16 males, 16 females), aged between 14–30 years, with an average age of 22.41 years. One-Dose MOSFET and Mobile MOSFET dosimetry were performed at 10 different anatomical sites on every patient. Results The results showed there was no variation between skin dose measured with OneDose MOSFET and Mobile MOSFET in all patients. Furthermore, the results showed for every anatomical site selected there was no significant difference in the dose delivered using either OneDose MOSFET detector or Mobile MOSFET as compared to the prescribed dose. Conclusions The study concludes that One-Dose MOSFET detectors and Mobile MOSFET both give a direct read-out immediately after the treatment; therefore both detectors are suitable options when measuring skin dose for total body irradiation treatment. PMID:21709641

  18. Acute dosing and p53-deficiency promote cellular sensitivity to DNA methylating agents.

    PubMed

    Chapman, Katherine E; Doak, Shareen H; Jenkins, Gareth J S

    2015-04-01

    Risk assessment of human exposure to chemicals is crucial for understanding whether such agents can cause cancer. The current emphasis on avoidance of animal testing has placed greater importance on in vitro tests for the identification of genotoxicants. Selection of an appropriate in vitro dosing regime is imperative in determining the genotoxic effects of test chemicals. Here, the issue of dosing approaches was addressed by comparing acute and chronic dosing, uniquely using low-dose experiments. Acute 24 h exposures were compared with equivalent dosing every 24 h over 5-day, fractionated treatment periods. The in vitro micronucleus assay was used to measure clastogenicity induced by methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU) in human lymphoblastoid cell line, TK6. Quantitative real-time (qRT) PCR was used to measure mRNA level induction of DNA repair enzymes. Lowest observed genotoxic effect levels (LOGELs) for MMS were obtained at 0.7 µg/ml for the acute study and 1.0 µg/ml for the chronic study. For acute MNU dosing, a LOGEL was observed at 0.46 µg/ml, yet genotoxicity was completely removed following the chronic study. Interestingly, acute MNU dosing demonstrated a statistically significant decrease at 0.009 µg/ml. Levels of selected DNA repair enzymes did not change significantly following doses tested. However, p53 deficiency (using the TK6-isogenic cell line, NH32) increased sensitivity to MMS during chronic dosing, causing this LOGEL to equate to the acute treatment LOGEL. In the context of the present data for 2 alkylating agents, chronic dosing could be a valuable in vitro supplement to acute dosing and could contribute to reduction of unnecessary in vivo follow-up tests. PMID:25595616

  19. Single dose oral piroxicam for acute postoperative pain

    PubMed Central

    Moore, R Andrew; Edwards, Jayne; Loke, Yoon; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 2, 2000. Piroxicam is a non-steroidal anti-inflammatory drug (NSAID) with analgesic properties, and is used mainly for treating rheumatic disorders. Some drugs have been directly compared against each other within a trial setting to determine their relative efficacies, whereas other have not. It is possible, however, to compare analgesics indirectly by examining the effectiveness of each drug against placebo when used in similar clinical situations. Objectives To determine the analgesic efficacy and adverse effects of single-dose piroxicam compared with placebo in moderate to severe postoperative pain. To compare the effects of piroxicam with other analgesics. Search methods Published studies were identified from systematic searching of MEDLINE, Biological Abstracts, EMBASE, CENTRAL and the Oxford Pain Relief Database in December 2007. Additional studies were identified from the reference lists of retrieved reports. Selection criteria The following inclusion criteria were used: full journal publication, randomised placebo controlled trial, double-blind design, adult participants, postoperative pain of moderate to severe intensity at the baseline assessment, postoperative administration of oral or intramuscular piroxicam. Data collection and analysis Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of participants obtaining at least 50% pain relief. This was used to calculate estimates of relative benefit and number-needed-to-treat-to-benefit (NNT) for one participant to obtain at least 50% pain relief. Information was collected on adverse effects and estimates of relative risk and number-needed-to-treat-to-harm (NNH) were calculated. Main results In this update no further studies were found. The original search identified three studies (141 participants) which compared oral piroxicam 20 mg with placebo and

  20. Organ doses for reference adult male and female undergoing computed tomography estimated by Monte Carlo simulations

    SciTech Connect

    Lee, Choonsik; Kim, Kwang Pyo; Long, Daniel; Fisher, Ryan; Tien, Chris; Simon, Steven L.; Bouville, Andre; Bolch, Wesley E.

    2011-03-15

    Purpose: To develop a computed tomography (CT) organ dose estimation method designed to readily provide organ doses in a reference adult male and female for different scan ranges to investigate the degree to which existing commercial programs can reasonably match organ doses defined in these more anatomically realistic adult hybrid phantomsMethods: The x-ray fan beam in the SOMATOM Sensation 16 multidetector CT scanner was simulated within the Monte Carlo radiation transport code MCNPX2.6. The simulated CT scanner model was validated through comparison with experimentally measured lateral free-in-air dose profiles and computed tomography dose index (CTDI) values. The reference adult male and female hybrid phantoms were coupled with the established CT scanner model following arm removal to simulate clinical head and other body region scans. A set of organ dose matrices were calculated for a series of consecutive axial scans ranging from the top of the head to the bottom of the phantoms with a beam thickness of 10 mm and the tube potentials of 80, 100, and 120 kVp. The organ doses for head, chest, and abdomen/pelvis examinations were calculated based on the organ dose matrices and compared to those obtained from two commercial programs, CT-EXPO and CTDOSIMETRY. Organ dose calculations were repeated for an adult stylized phantom by using the same simulation method used for the adult hybrid phantom. Results: Comparisons of both lateral free-in-air dose profiles and CTDI values through experimental measurement with the Monte Carlo simulations showed good agreement to within 9%. Organ doses for head, chest, and abdomen/pelvis scans reported in the commercial programs exceeded those from the Monte Carlo calculations in both the hybrid and stylized phantoms in this study, sometimes by orders of magnitude. Conclusions: The organ dose estimation method and dose matrices established in this study readily provides organ doses for a reference adult male and female for different

  1. Organ doses for reference adult male and female undergoing computed tomography estimated by Monte Carlo simulations

    PubMed Central

    Lee, Choonsik; Kim, Kwang Pyo; Long, Daniel; Fisher, Ryan; Tien, Chris; Simon, Steven L.; Bouville, Andre; Bolch, Wesley E.

    2011-01-01

    Purpose: To develop a computed tomography (CT) organ dose estimation method designed to readily provide organ doses in a reference adult male and female for different scan ranges to investigate the degree to which existing commercial programs can reasonably match organ doses defined in these more anatomically realistic adult hybrid phantoms Methods: The x-ray fan beam in the SOMATOM Sensation 16 multidetector CT scanner was simulated within the Monte Carlo radiation transport code MCNPX2.6. The simulated CT scanner model was validated through comparison with experimentally measured lateral free-in-air dose profiles and computed tomography dose index (CTDI) values. The reference adult male and female hybrid phantoms were coupled with the established CT scanner model following arm removal to simulate clinical head and other body region scans. A set of organ dose matrices were calculated for a series of consecutive axial scans ranging from the top of the head to the bottom of the phantoms with a beam thickness of 10 mm and the tube potentials of 80, 100, and 120 kVp. The organ doses for head, chest, and abdomen∕pelvis examinations were calculated based on the organ dose matrices and compared to those obtained from two commercial programs, CT-EXPO and CTDOSIMETRY. Organ dose calculations were repeated for an adult stylized phantom by using the same simulation method used for the adult hybrid phantom. Results: Comparisons of both lateral free-in-air dose profiles and CTDI values through experimental measurement with the Monte Carlo simulations showed good agreement to within 9%. Organ doses for head, chest, and abdomen∕pelvis scans reported in the commercial programs exceeded those from the Monte Carlo calculations in both the hybrid and stylized phantoms in this study, sometimes by orders of magnitude. Conclusions: The organ dose estimation method and dose matrices established in this study readily provides organ doses for a reference adult male and female for

  2. Diagnostic reference levels and patient doses in computed tomography examinations in Greece.

    PubMed

    Simantirakis, G; Hourdakis, C J; Economides, S; Kaisas, I; Kalathaki, M; Koukorava, C; Manousaridis, G; Pafilis, C; Tritakis, P; Vogiatzi, S; Kamenopoulou, V; Dimitriou, P

    2015-02-01

    The purpose of this study is to present a national survey that was performed in Greece for the establishment of national Dose Reference Levels (DRLs) for seven common adult Computed Tomography (CT) examinations. Volumetric computed tomography dose index and dose-length product values were collected from the post-data page of 65 'modern' systems that incorporate tube current modulation. Moreover, phantom dose measurements on 26 'older' systems were performed. Finally, the effective dose to the patient from a typical acquisition during these examinations was estimated. The suggested national DRLs are generally comparable with respective published values from similar European studies, with the exception of sinuses CT, which presents significantly higher values. This fact, along with the large variation of the systems' dose values that were observed even for scanners of the same type, indicates a need for further patient protection optimisation without compromising the clinical outcome. PMID:24891405

  3. USE OF LETHALITY DATA DURING CATEGORICAL REGRESSION MODELING OF ACUTE REFERENCE EXPOSURES

    EPA Science Inventory

    Categorical regression is being considered by the U.S. EPA as an additional tool for derivation of acute reference exposures (AREs) to be used for human health risk assessment for exposure to inhaled chemicals. Categorical regression is used to calculate probability-response fun...

  4. Acute generalized weakness in patients referred to Amirkola Children’s Hospital from 2005 to 2010

    PubMed Central

    Salehiomran, Mohammad Reza; Naserkhaki, Somayeh; Hajiahmadi, Mahmoud

    2012-01-01

    Background: Diseases that cause acute flaccid paralysis (AFP) often progress rapidly, thus may cause life threatening complications, therefore, their diagnosis and cure are important. This study was carried out to investigate the causes of acute generalized weakness in children referred to Amirkola Children’s Hospital, in Babol, Iran. Methods: In this case series, the epidemiological causes of the disease and clinical features of 15 cases with acute generalized weakness from April 2005 to September 2010 were evaluated. The data were collected and analyzed. Results: The mean age of cases was 4.7±3.5 years. The male/female ratio was 2. Twenty cases had Guillain-Barre syndrome, two with myositis and one with periodic hyperkalemic paralysis. Conclusion: Guillain-Barre syndrome is the most common cause of AFP in children admitted due to acute generalized weakness in Amirkola Children’s Hospital. PMID:24358438

  5. Quantitative Evaluation and Selection of Reference Genes for Quantitative RT-PCR in Mouse Acute Pancreatitis

    PubMed Central

    Yan, Zhaoping; Gao, Jinhang; Lv, Xiuhe; Yang, Wenjuan; Wen, Shilei; Tong, Huan; Tang, Chengwei

    2016-01-01

    The analysis of differences in gene expression is dependent on normalization using reference genes. However, the expression of many of these reference genes, as evaluated by quantitative RT-PCR, is upregulated in acute pancreatitis, so they cannot be used as the standard for gene expression in this condition. For this reason, we sought to identify a stable reference gene, or a suitable combination, for expression analysis in acute pancreatitis. The expression stability of 10 reference genes (ACTB, GAPDH, 18sRNA, TUBB, B2M, HPRT1, UBC, YWHAZ, EF-1α, and RPL-13A) was analyzed using geNorm, NormFinder, and BestKeeper software and evaluated according to variations in the raw Ct values. These reference genes were evaluated using a comprehensive method, which ranked the expression stability of these genes as follows (from most stable to least stable): RPL-13A, YWHAZ > HPRT1 > GAPDH > UBC > EF-1α > 18sRNA > B2M > TUBB > ACTB. RPL-13A was the most suitable reference gene, and the combination of RPL-13A and YWHAZ was the most stable group of reference genes in our experiments. The expression levels of ACTB, TUBB, and B2M were found to be significantly upregulated during acute pancreatitis, whereas the expression level of 18sRNA was downregulated. Thus, we recommend the use of RPL-13A or a combination of RPL-13A and YWHAZ for normalization in qRT-PCR analyses of gene expression in mouse models of acute pancreatitis. PMID:27069927

  6. Calculates External and Inhalation Doses from Acute Radionuclide Releases on the Hanford Site.

    1984-03-02

    HADOC (Hanford Acute Dose Calculations) calculates external and inhalation doses resulting from postulated accidental radionuclide releases on the Hanford site. It generates doses to an individual at a specified location and to the population in the region near the Hanford site for specified organs. Doses reported include the maximally exposed individual's dose (by organ and exposure mode) and the total population dose (by organ and exposure mode) in the sector having the highest population exposuremore » factor. The first year and fifty-year dose commitments are reported. Optional reports giving the fractional contribution to total dose by radionuclide for each organ and dose commitment period for a maximally exposed individual and the population may be printed.« less

  7. Organ doses for reference pediatric and adolescent patients undergoing computed tomography estimated by Monte Carlo simulation

    SciTech Connect

    Lee, Choonsik; Kim, Kwang Pyo; Long, Daniel J.; Bolch, Wesley E.

    2012-04-15

    Purpose: To establish an organ dose database for pediatric and adolescent reference individuals undergoing computed tomography (CT) examinations by using Monte Carlo simulation. The data will permit rapid estimates of organ and effective doses for patients of different age, gender, examination type, and CT scanner model. Methods: The Monte Carlo simulation model of a Siemens Sensation 16 CT scanner previously published was employed as a base CT scanner model. A set of absorbed doses for 33 organs/tissues normalized to the product of 100 mAs and CTDI{sub vol} (mGy/100 mAs mGy) was established by coupling the CT scanner model with age-dependent reference pediatric hybrid phantoms. A series of single axial scans from the top of head to the feet of the phantoms was performed at a slice thickness of 10 mm, and at tube potentials of 80, 100, and 120 kVp. Using the established CTDI{sub vol}- and 100 mAs-normalized dose matrix, organ doses for different pediatric phantoms undergoing head, chest, abdomen-pelvis, and chest-abdomen-pelvis (CAP) scans with the Siemens Sensation 16 scanner were estimated and analyzed. The results were then compared with the values obtained from three independent published methods: CT-Expo software, organ dose for abdominal CT scan derived empirically from patient abdominal circumference, and effective dose per dose-length product (DLP). Results: Organ and effective doses were calculated and normalized to 100 mAs and CTDI{sub vol} for different CT examinations. At the same technical setting, dose to the organs, which were entirely included in the CT beam coverage, were higher by from 40 to 80% for newborn phantoms compared to those of 15-year phantoms. An increase of tube potential from 80 to 120 kVp resulted in 2.5-2.9-fold greater brain dose for head scans. The results from this study were compared with three different published studies and/or techniques. First, organ doses were compared to those given by CT-Expo which revealed dose

  8. PROPOSED ORAL REFERENCE DOSE (RFD) FOR BARIUM AND COMPOUNDS (Final Report) 2004

    EPA Science Inventory

    This document is the final report for the 2004 external peer review of the Proposed Oral Reference Dose (RfD) for Barium and Compounds, prepared by the U.S. Environmental Protection Agency (EPA), National Center for Environmental Assessment (NCEA), for the Integrated Risk Informa...

  9. Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

    PubMed Central

    Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

    2012-01-01

    BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

  10. Single dose oral naproxen and naproxen sodium for acute postoperative pain (Review)

    PubMed Central

    Mason, L; Edwards, JE; Moore, RA; McQuay, HJ

    2014-01-01

    Background Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. Objectives To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. Selection criteria Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. Data collection and analysis Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. Main results Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500

  11. Air kerma and absorbed dose standards for reference dosimetry in brachytherapy

    PubMed Central

    2014-01-01

    This article reviews recent developments in primary standards for the calibration of brachytherapy sources, with an emphasis on the currently most common photon-emitting radionuclides. The introduction discusses the need for reference dosimetry in brachytherapy in general. The following section focuses on the three main quantities, i.e. reference air kerma rate, air kerma strength and absorbed dose rate to water, which are currently used for the specification of brachytherapy photon sources and which can be realized with primary standards from first principles. An overview of different air kerma and absorbed dose standards, which have been independently developed by various national metrology institutes over the past two decades, is given in the next two sections. Other dosimetry techniques for brachytherapy will also be discussed. The review closes with an outlook on a possible transition from air kerma to absorbed dose to water-based calibrations for brachytherapy sources in the future. PMID:24814696

  12. Dose Assessment in Computed Tomography Examination and Establishment of Local Diagnostic Reference Levels in Mazandaran, Iran

    PubMed Central

    Janbabanezhad Toori, A.; Shabestani-Monfared, A.; Deevband, M.R.; Abdi, R.; Nabahati, M.

    2015-01-01

    Background Medical X-rays are the largest man-made source of public exposure to ionizing radiation. While the benefits of Computed Tomography (CT) are well known in accurate diagnosis, those benefits are not risk-free. CT is a device with higher patient dose in comparison with other conventional radiation procedures. Objective This study is aimed at evaluating radiation dose to patients from Computed Tomography (CT) examination in Mazandaran hospitals and defining diagnostic reference level (DRL). Methods Patient-related data on CT protocol for four common CT examinations including brain, sinus, chest and abdomen & pelvic were collected. In each center, Computed Tomography Dose Index (CTDI) measurements were performed using pencil ionization chamber and CT dosimetry phantom according to AAPM report No. 96 for those techniques. Then, Weighted Computed Tomography Dose Index (CTDIW), Volume Computed Tomography Dose Index (CTDI vol) and Dose Length Product (DLP) were calculated. Results The CTDIw for brain, sinus, chest and abdomen & pelvic ranged (15.6-73), (3.8-25. 8), (4.5-16.3) and (7-16.3), respectively. Values of DLP had a range of (197.4-981), (41.8-184), (131-342.3) and (283.6-486) for brain, sinus, chest and abdomen & pelvic, respectively. The 3rd quartile of CTDIW, derived from dose distribution for each examination is the proposed quantity for DRL. The DRLs of brain, sinus, chest and abdomen & pelvic are measured 59.5, 17, 7.8 and 11 mGy, respectively. Conclusion Results of this study demonstrated large scales of dose for the same examination among different centers. For all examinations, our values were lower than international reference doses. PMID:26688796

  13. Factors affecting quality for beta dose rate measurements using ISO 6980 series I reference sources

    SciTech Connect

    Burns, R.E. Jr.; O`Brien, J.M. Jr.

    1993-12-31

    Atlan-Tech, Inc. has performed several calibrations of ISO 6980 Series 1 reference beta sources over the past two to three years. There were many problems encountered in attempting to compare the results of these calibrations with those from other laboratories, indicating the need for more standardization in the methodology employed for the measurement of the absorbed dose rate from ISO 6980 Series 1 reference beta sources. This document describes some of the problems encountered in attempting to intercompare results of beta dose-rate measurements. It proposes some solutions in an attempt to open a dialogue among facilities using reference beta standards for the purpose of promoting better measurement quality assurance through data intercomparison.

  14. The influence of acute kidney injury on antimicrobial dosing in critically ill patients: are dose reductions always necessary?

    PubMed

    Blot, Stijn; Lipman, Jeffrey; Roberts, Darren M; Roberts, Jason A

    2014-05-01

    Optimal dosing of antimicrobial therapy is pivotal to increase the likelihood of survival in critically ill patients with sepsis. Drug exposure that maximizes bacterial killing, minimizes the development of antimicrobial resistance, and avoids concentration-related toxicities should be considered the target of therapy. However, antimicrobial dosing is problematic as pathophysiological factors inherent to sepsis that alter may result in reduced concentrations. Alternatively, sepsis may evolve to multiple-organ dysfunction including acute kidney injury (AKI). In this case, decreased clearance of renally cleared drugs is possible, which may lead to increased concentrations that may cause drug toxicities. Consequently, when dosing antibiotics in septic patients with AKI, one should consider factors that may lead to underdosing and overdosing. Drug-specific pharmacokinetic and pharmacodynamic data may be helpful to guide dosing in these circumstances. Yet, because of the high interpatient variability in pharmacokinetics of antibiotics during sepsis, this issue remains a significant challenge. PMID:24602849

  15. Maintaining the Constant Exposure Condition for an Acute Caenorhabditis elegans Mortality Test Using Passive Dosing

    PubMed Central

    Kwon, Hyuck-Chul; Roh, Ji-Yeon; Lim, Dongyoung; Choi, Jinhee

    2011-01-01

    Objectives Maintaining the constant exposure to hydrophobic organic compouds in acute toxicity tests is one of the most difficult issues in the evaluation of their toxicity and corresponding risks. Passive dosing is an emerging tool to keep constant aqueous concentration because of the overwhelming mass loaded in the dosing phase. The primary objectives of this study were to develop the constant exposure condition for an acute mortality test and to compare the performance of the passive dosing method with the conventional spiking with co-solvent. Methods A custom cut polydimethylsiloxane (PDMS) tubing loaded with benzyl butyl phthalate (BBP) was placed in each well of a 24-well plate containing assay medium. The rate of the release of BBP from PDMS was evaluated by measuring the change in the concentration of BBP in the assay medium. The efficiency of maintaining constant exposure condition was also evaluated using a simple two-compartment mass transport model employing a film-diffusion theory. An acute mortality test using 10 C. elegans in each well was conducted for the evaluation of the validity of passive dosing and the comparative evaluation of the passive dosing method and the conventional spiking method. Results Free concentration in the assay medium reached 95% steady state value within 2.2 hours without test organisms, indicating that this passive dosing method is useful for an acute toxicity test in 24 hours. The measured concentration after the mortality test agreed well with the estimated values from partitioning between PDMS and the assay medium. However, the difference between the nominal and the free concentration became larger as the spiked concentration approached water solubility, indicating the instability of the conventional spiking with a co-solvent. Conclusions The results in this study support that passive dosing provides a stable exposure condition for an acute toxicity test. Thus, it is likely that more reliable toxicity assessment can be

  16. Re-evaluation of the reference dose for methylmercury and assessment of current exposure levels

    SciTech Connect

    Stern, A.H. )

    1993-06-01

    Methylmercury (Me-Hg) is widely distributed through freshwater and saltwater food chains and human consumption of fish and shellfish has lead to widespread exposure. Both the US EPA Reference Dose (0.3 [mu]g/kg/day) and the FAO/WHO Permissible Tolerable Weekly Intake (3.3 [mu]g/kg/week) are currently based on the prevention of paraesthesia in adult and older children. However, Me-Hg exposure in utero is known to result in a range of developmental neurologic effects including clinical CNS symptoms and delayed onset of walking. Based on a critical review of development toxicity data from human and animal studies, it is concluded that current guidelines for the prevention of paraesthesia are not adequate to address developmental effects. A dose of 0.07 [mu]g/kg/day is suggested as the best estimate of a potential reference dose for developmental effects. Data on nationwide fish consumption rates and Me-Hg levels in fish/seafood weighted by proportion of the catch intended for human consumption are analyzed in a Monte Carlo simulation to derive a probability distribution of background Me-Hg exposure. While various uncertainties in the toxicologic and exposure data limit the precision with which health risk can be estimated, this analysis suggests that at current levels of Me-Hg exposure, a significant fraction of women of childbearing age have exposures above this suggested reference dose.

  17. Estimating the population dose from nuclear medicine examinations towards establishing diagnostic reference levels

    PubMed Central

    Niksirat, Fatemeh; Monfared, Ali Shabestani; Deevband, Mohammad Reza; Amiri, Mehrangiz; Gholami, Amir

    2016-01-01

    Purpose of the Study: This study conducted a review on nuclear medicine (NM) services in Mazandaran Province with a view to establish adult diagnostic reference levels (DRLs) and provide updated data on population radiation exposure resulting from diagnostic NM procedures. Materials and Methods: The data were collected from all centers in all cities of Mazandaran Province in the North of Iran from March 2014 to February 2015. The 75th percentile of the distribution and the average administered activity (AAA) were calculated and the average effective dose per examination, collective effective dose to the population and annual effective dose per capita were estimated using dose conversion factors. The gathered data were analyzed via SPSS (version 18) software using descriptive statistics. Results: Based on the data of this study, the collective effective dose was 95.628 manSv, leading to a mean effective dose of 0.03 mSv per capita. It was also observed that the myocardial perfusion was the most common procedure (50%). The 75th percentile of the distribution of administered activity (AA) represents the DRL. The AAA and the 75th percentile of the distribution of AA are slightly higher than DRL of most European countries. Conclusions: Myocardial perfusion is responsible for most of the collective effective dose and it is better to establish national DRLs for myocardial perfusion and review some DRL values through the participation of NM specialists in the future. PMID:26917891

  18. Evaluation of dose conversion coefficients for external exposure using Taiwanese reference man and woman.

    PubMed

    Chang, S J; Hung, S Y; Liu, Y L; Jiang, S H; Wu, J

    2015-11-01

    Reference man has been widely used for external and internal dose evaluation of radiation protection. The parameters of the mathematical model of organs suggested by the International Commission of Radiological Protection (ICRP) are adopted from the average data of Caucasians. However, the organ masses of Asians are significantly different from the data of Caucasians, leading to potentially dosimetric errors. In this study, a total of 40 volunteers whose heights and weights corresponded to the statistical average of Taiwanese adults were recruited. Magnetic resonance imaging was performed, and T2-weighted images were acquired. The Taiwanese reference man and woman were constructed according to the measured organ masses. The dose conversion coefficients (DCFs) for anterior-posterior (AP), posterior-anterior (PA), right lateral (RLAT) and left lateral (LLAT) irradiation geometries were simulated. For the Taiwanese reference man, the average differences of the DCFs compared with the results of ICRP-74 were 7.6, 5.1 and 11.1 % for 0.1, 1 and 10 MeV photons irradiated in the AP direction. The maximum difference reached 51.7 % for the testes irradiated by 10 MeV photons. The size of the trunk, the volume and the geometric position of organs can cause a significant impact on the DCFs for external exposure of radiation. The constructed Taiwanese reference man and woman can be used in radiation protection to increase the accuracy of dose evaluation for the Taiwanese population. PMID:25944957

  19. Neutron activation analysis for reference determination of the implantation dose of cobalt ions

    SciTech Connect

    Garten, R.P.H.; Bubert, H.; Palmetshofer, L.

    1992-05-15

    The authors prepared depth profilling reference materials by cobalt ion implantation at an ion energy of 300 keV into n-type silicon. The implanted Co dose was then determined by instrumental neutron activation analysis (INAA) giving an analytical dynamic range of almost 5 decades and uncertainty of 1.5%. This form of analysis allows sources of error (beam spreading, misalignment) to be corrected. 70 refs., 3 tabs.

  20. Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling.

    PubMed

    Thompson, Chad M; Gaylor, David W; Tachovsky, J Andrew; Perry, Camarie; Carakostas, Michael C; Haws, Laurie C

    2013-12-01

    Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. PMID:22936336

  1. Organ dose conversion coefficients for pediatric reference computational phantoms in external photon radiation fields

    NASA Astrophysics Data System (ADS)

    Chang, Lienard A.

    In the event of a radiological accident or attack, it is important to estimate the organ doses to those exposed. In general, it is difficult to measure organ dose directly in the field and therefore dose conversion coefficients (DCC) are needed to convert measurable values such as air kerma to organ dose. Previous work on these coefficients has been conducted mainly for adults with a focus on radiation protection workers. Hence, there is a large gap in the literature for pediatric values. This study coupled a Monte Carlo N-Particle eXtended (MCNPX) code with International Council of Radiological Protection (ICRP)-adopted University of Florida and National Cancer Institute pediatric reference phantoms to calculate a comprehensive list of dose conversion coefficients (mGy/mGy) to convert air-kerma to organ dose. Parameters included ten phantoms (newborn, 1-year, 5-year, 10-year, 15-year old male and female), 28 organs over 33 energies between 0.01 and 20 MeV in six (6) irradiation geometries relevant to a child who might be exposed to a radiological release: anterior-posterior (AP), posterior-anterior (PA), right-lateral (RLAT), left-lateral (LLAT), rotational (ROT), and isotropic (ISO). Dose conversion coefficients to the red bone marrow over 36 skeletal sites were also calculated. It was hypothesized that the pediatric organ dose conversion coefficients would follow similar trends to the published adult values as dictated by human anatomy, but be of a higher magnitude. It was found that while the pediatric coefficients did yield similar patterns to that of the adult coefficients, depending on the organ and irradiation geometry, the pediatric values could be lower or higher than that of the adult coefficients.

  2. COMPARING BEHAVIORAL DOSE-EFFECT CURVES FOR HUMANS AND LABORATORY ANIMALS ACUTELY EXPOSED TO TOLUENE.

    EPA Science Inventory

    The utility of laboratory animal data in toxicology depends upon the ability to generalize the results quantitatively to humans. To compare the acute behavioral effects of inhaled toluene in humans to those in animals, dose-effect curves were fitted by meta-analysis of published...

  3. Local low dose streptokinase in the treatment of acute peripheral arterial occlusion.

    PubMed

    Breslau, P J; Van der Linden, C J; Janevski, B; Jörning, P J

    1984-06-01

    Case report of local low dose streptokinase therapy in a patient with acute occlusion of the left branch of an aortobifurcation graft. Objective evidence of complete thrombolysis was demonstrated both by arteriography and hemodynamic parameters. In carefully selected cases this thrombolytic therapy is a promising alternative to surgery. PMID:6738887

  4. Ultra-low dose comprehensive cardiac CT imaging in a patient with acute myocarditis.

    PubMed

    Tröbs, Monique; Brand, Michael; Achenbach, Stephan; Marwan, Mohamed

    2014-01-01

    The ability of contrast-enhanced CT to detect "late enhancement" in a fashion similar to magnetic resonance imaging has been previously reported. We report a case of acute myocarditis with coronary CT angiography as well as "late enhancement" imaging with ultra-low effective radiation dose. PMID:25439792

  5. Evaluation of organ doses and effective dose according to the ICRP Publication 110 reference male/female phantom and the modified ImPACT CT patient dosimetry.

    PubMed

    Kobayashi, Masanao; Asada, Yasuki; Matsubara, Kosuke; Matsunaga, Yuta; Kawaguchi, Ai; Katada, Kazuhiro; Toyama, Hiroshi; Koshida, Kichiro; Suzuki, Shouichi

    2014-01-01

    We modified the Imaging Performance Assessment of CT scanners (ImPACT) to evaluate the organ doses and the effective dose based on the International Commission on Radiological Protection (ICRP) Publication 110 reference male/female phantom with the Aquilion ONE ViSION Edition scanner. To select the new CT scanner, the measurement results of the CTDI100,c and CTDI100,p for the 160 (head) and the 320 (body) mm polymethylmethacrylate phantoms, respectively, were entered on the Excel worksheet. To compute the organ doses and effective dose of the ICRP reference male/female phantom, the conversion factors obtained by comparison between the organ doses of different types of phantom were applied. The organ doses and the effective dose were almost identical for the ICRP reference male/female and modified ImPACT. The results of this study showed that, with the dose assessment of the ImPACT, the difference in sex influences only testes and ovaries. Because the MIRD-5 phantom represents a partially hermaphrodite adult, the phantom has the dimensions of the male reference man including testes, ovaries, and uterus but no female breasts, whereas the ICRP male/female phantom includes whole-body male and female anatomies based on high-resolution anatomical datasets. The conversion factors can be used to estimate the doses of a male and a female accurately, and efficient dose assessment can be performed with the modified ImPACT. PMID:25207566

  6. Low Dose Dopamine or Low Dose Nesiritide in Acute Heart Failure with Renal Dysfunction: The ROSE Acute Heart Failure Randomized Trial

    PubMed Central

    Chen, Horng H.; Anstrom, Kevin J.; Givertz, Michael M.; Stevenson, Lynne W.; Semigran, Marc J.; Goldsmith, Steven R.; Bart, Bradley A.; Bull, David A.; Stehlik, Josef; LeWinter, Martin M.; Konstam, Marvin A.; Huggins, Gordon S.; Rouleau, Jean L.; O’Meara, Eileen; Tang, W.H. Wilson; Starling, Randall C.; Butler, Javed; Deswal, Anita; Felker, G. Michael; O’Connor, Christopher M.; Bonita, Raphael E.; Margulies, Kenneth B.; Cappola, Thomas P.; Ofili, Elizabeth O.; Mann, Douglas L.; Dávila-Román, Víctor G.; McNulty, Steven E.; Borlaug, Barry A.; Velazquez, Eric J.; Lee, Kerry L.; Shah, Monica R.; Hernandez, Adrian F.; Braunwald, Eugene; Redfield, Margaret M.

    2014-01-01

    Importance Small studies suggest low dose dopamine or low dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. Objective To test the two independent hypotheses that when compared to placebo, addition of: (1) low dose dopamine (2 ug/kg/min); or (2) low dose nesiritide (0.005 ug/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. Design, Setting and Participants Multicenter, double-blind, placebo-controlled randomized clinical trial (Renal Optimization Strategies Evaluation) of 360 hospitalized participants with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15–60 ml/min/1.73m2), randomized within 24 hours of admission. Participants were randomized from September 2010 to March 2013 across 26 sites in the United States and Canada. Interventions Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategies. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n=122) and nesiritide (n=119) groups were independently compared to the pooled placebo group (n=119). Main outcome measures Co-primary endpoints included 72-hour cumulative urine volume (decongestion endpoint) and the change in serum cystatin-C from enrollment to 72 hours (renal function endpoint). Results Compared to placebo, low dose dopamine had no significant effect on 72-hour cumulative urine volume (8524 ml [95% CI 7917 to 9131 ml] with dopamine vs. 8296 ml [95% CI 7762 to 8830 ml] with placebo, p=0.59) or on the change in cystatin-C (0.12 mg/L [95% CI 0.06 to 0.18 mg/L] with dopamine vs. 0.11 mg/L [95% CI 0.06 to 0.16 mg/L] with placebo, p=0.72). Similarly, low dose nesiritide had no significant effect on 72-hour cumulative

  7. Response of lymphoid organs to low dose rate Cf-252, Cs-137 and acute Co-60

    SciTech Connect

    Feola, J.; Maruyama, Y.; Magura, C.; Hwang, H.N.

    1986-01-01

    RBE of low dose rate (LDR) /sup 252/Cf radiation was studied for thymus using weight loss compared to unirradiated controls. These were compared against LDR /sup 137/Cs and acute /sup 60/Co effects. For thymus, biexponential dose response curves were noted for acute /sup 60/Co and LDR /sup 137/Cs irradiations. No dose rate effect was noted with /sup 137/Cs. D/sub 37/ for the first component D/sub 1/ was 109 cGy and for the second D/sub 2/ was 624 cGy for /sup 60/Co. Relative biological effectiveness (RBE) is a complex endpoint and was different for the low dose (sensitive) and high dose (resistant) responses and for /sup 252/Cf. RBE/sub n/ of the sensitive portion was 1.7 and for overall was 4.0. Spleen response was also determined for the 3 radiations. Biexponential dose-response curves were also observed for resting spleen to acute /sup 60/Co and LDR /sup 137/Cs radiation. D/sub 1/ = 285 cGy and D/sub 2/ = 1538 cGy for acute /sup 60/Co; D/sub 1/ = 205 cGy for /sup 137/Cs and indicated a dose rate effect = 1.04 for /sup 137/Cs. The LDR /sup 137/Cs was 1.3x more effective than acute /sup 60/Co for the sensitive response; it was 1.9 x greater for the resistant response. However, the response to /sup 252/Cf vs. /sup 137/Cs for the spleen indicated that there was a greater sensitivity to dose rate than to LET. RBE/sub n/ for /sup 252/Cf vs. /sup 137/Cs was 1.0. Stimulation of spleen growth after injection of Corynebacterium parvum allowed study of radiation effects of proliferating spleen cells at day 10. Acute /sup 60/Co and LDR /sup 137/Cs ..gamma..-rays had reduced effects compared to LDR /sup 252/Cf radiation and RBE was 4.0 vs. LDR /sup 137/Cs. RBE in lymphoid organs thus depended on organ, on assay and on resting/proliferating status.

  8. Acute Radiation Risk and BRYNTRN Organ Dose Projection Graphical User Interface

    NASA Technical Reports Server (NTRS)

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

    2011-01-01

    The integration of human space applications risk projection models of organ dose and acute radiation risk has been a key problem. NASA has developed an organ dose projection model using the BRYNTRN with SUM DOSE computer codes, and a probabilistic model of Acute Radiation Risk (ARR). The codes BRYNTRN and SUM DOSE are a Baryon transport code and an output data processing code, respectively. The risk projection models of organ doses and ARR take the output from BRYNTRN as an input to their calculations. With a graphical user interface (GUI) to handle input and output for BRYNTRN, the response models can be connected easily and correctly to BRYNTRN. A GUI for the ARR and BRYNTRN Organ Dose (ARRBOD) projection code provides seamless integration of input and output manipulations, which are required for operations of the ARRBOD modules. The ARRBOD GUI is intended for mission planners, radiation shield designers, space operations in the mission operations directorate (MOD), and space biophysics researchers. BRYNTRN code operation requires extensive input preparation. Only a graphical user interface (GUI) can handle input and output for BRYNTRN to the response models easily and correctly. The purpose of the GUI development for ARRBOD is to provide seamless integration of input and output manipulations for the operations of projection modules (BRYNTRN, SLMDOSE, and the ARR probabilistic response model) in assessing the acute risk and the organ doses of significant Solar Particle Events (SPEs). The assessment of astronauts radiation risk from SPE is in support of mission design and operational planning to manage radiation risks in future space missions. The ARRBOD GUI can identify the proper shielding solutions using the gender-specific organ dose assessments in order to avoid ARR symptoms, and to stay within the current NASA short-term dose limits. The quantified evaluation of ARR severities based on any given shielding configuration and a specified EVA or other mission

  9. Gaps in Drug Dosing for Obese Children: A Systematic Review of Commonly Prescribed Acute Care Medications

    PubMed Central

    Rowe, Stevie; Siegel, David; Benjamin, Daniel K.

    2015-01-01

    Purpose Approximately 1 out of 6 children in the United States is obese. This has important implications for drug dosing and safety, as pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiology. Inappropriate drug dosing can limit therapeutic efficacy and increase drug-related toxicity for obese children. Few systematic reviews examining PK and drug dosing in obese children have been performed. Methods We identified 25 acute care drugs from the Strategic National Stockpile and Acute Care Supportive Drugs List and performed a systematic review for each drug in 3 study populations: obese children (2–18 years of age), normal weight children, and obese adults. For each study population, we first reviewed a drug’s Food and Drug Administration (FDA) label, followed by a systematic literature review. From the literature, we extracted drug PK data, biochemical properties, and dosing information. We then reviewed data in 3 age subpopulations (2–7 years, 8–12 years, and 13–18 years) for obese and normal weight children and by route of drug administration (intramuscular, intravenous, by mouth, and inhaled). If sufficient PK data were not available by age/route of administration, a data gap was identified. Findings Only 2/25 acute care drugs (8%) contained dosing information on the FDA label for each obese children and adults compared with 22/25 (88%) for normal weight children. We found no sufficient PK data in the literature for any of the acute care drugs in obese children. Sufficient PK data were found for 7/25 acute care drugs (28%) in normal weight children and 3/25 (12%) in obese adults. Implications Insufficient information exists to guide dosing in obese children for any of the acute care drugs reviewed. This knowledge gap is alarming, given the known PK changes that occur in the setting of obesity. Future clinical trials examining the PK of acute care medications in obese children should be prioritized. PMID

  10. Benchmark dose estimation of cadmium reference level for hypertension in a Chinese population.

    PubMed

    Chen, Xiao; Wang, Zhongqiu; Zhu, Guoying; Liang, Yihuai; Jin, Taiyi

    2015-01-01

    Cadmium exposure can cause high blood pressure or hypertension. Benchmark dose has been used to estimate the reference point of cadmium for kidney and bone damage. In this study, we observed the association of blood pressure and cadmium in blood (BCd) and evaluated the reference level of cadmium for hypertension using benchmark dose (BMD) approach. A total of 441 subjects were included in this study. Blood samples were collected from each individual for BCd determination. Blood pressure was measured by electronic sphygmomanometer. BMD and BMDL were calculated using BMD software corresponding to additional risk of 10%. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of hypertension increased with the increasing of BCd, especially for SBP (χ(2)=3.9, p=0.047 in men; χ(2)=4.3, p=0.037 in women). With a benchmark response of 10%, the BMDL10 for hypertension (high SBP) was 0.95μg/L and 1.02μg/L for women and men, respectively; the BMDL10 for hypertension (high DBP) was 1.8μg/L and 1.66μg/L for women and men, respectively. Our data evidenced that BCd was associated with elevation in blood pressure and hypertension, especially for women. The reference level of cadmium for hypertension with high SBP was lower than that of high DBP. PMID:25528411

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

    PubMed

    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. PMID:25754724

  12. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    PubMed

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  13. Automation of an in vitro cytotoxicity assay used to estimate starting doses in acute oral systemic toxicity tests.

    PubMed

    Bouhifd, Mounir; Bories, Gilles; Casado, Juan; Coecke, Sandra; Norlén, Hedvig; Parissis, Nicholaos; Rodrigues, Robim M; Whelan, Maurice P

    2012-06-01

    Application of High Throughput Screening (HTS) to the regulatory safety assessment of chemicals is still in its infancy but shows great promise in terms of facilitating better understanding of toxicological modes-of-action, reducing the reliance on animal testing, and allowing more data-poor chemicals to be assessed at a reasonable cost. To promote the uptake and acceptance of HTS approaches, we describe in a stepwise manner how a well known cytotoxicity assay can be automated to increase throughput while maintaining reliability. Results generated with selected reference chemicals compared very favourably with data obtained from a previous international validation study concerning the prediction of acute systemic toxicity in rodents. The automated assay was then included in a formal ECVAM validation study to determine if the assay could be used for binary classification of chemicals with respect to their acute oral toxicity, using a threshold equivalent to a dose of 2000 mg/kg b.w. in a rodent bioassay (LD50). This involved the blind-testing of 56 reference chemicals on the HTS platform to produce concentration-response and IC50 data. Finally, the assay was adapted to a format more suited to higher throughput testing without compromising the quality of the data obtained. PMID:22465836

  14. Establishment of air kerma reference standard for low dose rate Cs-137 brachytherapy sources.

    PubMed

    Sharma, Sunil Dutt; Kumar, Sudhir; Srinivasan, P; Chourasiya, G

    2011-01-01

    A guarded cylindrical graphite ionization chamber of nominal volume 1000 cm3 was designed and fabricated for use as a reference standard for low-dose rate 137Cs brachytherapy sources. The air kerma calibration coefficient (N(K)) of this ionization chamber was estimated analytically using Burlin's general cavity theory, as well as by the Monte Carlo simulation and validated experimentally using Amersham CDCS-J-type 137Cs reference source. In the analytical method, the N(K) was calculated for 662 keV gamma rays of 137Cs brachytherapy source. In the Monte Carlo method, the geometry of the measurement setup and physics-related input data of the 137Cs source and the surrounding material were simulated using the Monte Carlo N-Particle code. The photon energy fluence was used to arrive at the reference air kerma rate (RAKR) using mass energy absorption coefficient. The energy deposition rates were used to simulate the value of charge rate in the ionization chamber, and the N(K) was determined. The analytical and Monte Carlo values of N(K) of the cylindrical graphite ionization chamber for 137Cs brachytherapy source are in agreement within 1.07%. The deviation of analytical and Monte Carlo values from experimental values of N(K) is 0.36% and 0.72%, respectively. This agreement validates the analytical value, and establishes this chamber as a reference standard for RAKR or AKS measurement of 137Cs brachytherapy sources. PMID:22089009

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

    NASA Technical Reports Server (NTRS)

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

    2010-01-01

    Solar particle events (SPEs) pose the risk of acute radiation sickness (ARS) to astronauts, because organ doses from large SPEs may reach critical levels during extra vehicular activities (EVAs) or lightly shielded spacecraft. NASA has developed an organ dose projection model of Baryon transport code (BRYNTRN) with an output data processing module of SUMDOSE, and a probabilistic model of acute radiation risk (ARR). BRYNTRN code operation requires extensive input preparation, and the risk projection models of organ doses and ARR take the output from BRYNTRN as an input to their calculations. With a graphical user interface (GUI) to handle input and output for BRYNTRN, these response models can be connected easily and correctly to BRYNTRN in a user friendly way. The GUI for the Acute Radiation Risk and BRYNTRN Organ Dose (ARRBOD) projection code provides seamless integration of input and output manipulations required for operations of the ARRBOD modules: BRYNTRN, SUMDOSE, and the ARR probabilistic response model. The ARRBOD GUI is intended for mission planners, radiation shield designers, space operations in the mission operations directorate (MOD), and space biophysics researchers. Assessment of astronauts organ doses and ARS from the exposure to historically large SPEs is in support of mission design and operation planning to avoid ARS and stay within the current NASA short-term dose limits. The ARRBOD GUI will serve as a proof-of-concept for future integration of other risk projection models for human space applications. We present an overview of the ARRBOD GUI product, which is a new self-contained product, for the major components of the overall system, subsystem interconnections, and external interfaces.

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

    NASA Astrophysics Data System (ADS)

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

    Solar particle events (SPEs) pose the risk of acute radiation sickness (ARS) to astronauts be-cause organ doses from large SPEs may reach critical levels during extra vehicular activities (EVAs) or lightly shielded spacecraft. NASA has developed an organ dose projection model of Baryon transport code (BRYNTRN) with an output data processing module of SUMDOSE, and a probabilistic model of acute radiation risk (ARR). BRYNTRN code operation requires extensive input preparation, and the risk projection models of organ doses and ARR take the output from BRYNTRN as an input to their calculations. With a graphical user interface (GUI) to handle input and output for BRYNTRN, these response models can be connected easily and correctly to BRYNTRN in a user-friendly way. The GUI for the Acute Radiation Risk and BRYNTRN Organ Dose (ARRBOD) projection code provides seamless integration of input and output manipulations required for operations of the ARRBOD modules: BRYNTRN, SUMDOSE, and the ARR probabilistic response model. The ARRBOD GUI is intended for mission planners, radiation shield designers, space operations in the mission operations direc-torate (MOD), and space biophysics researchers. Assessment of astronauts' organ doses and ARS from the exposure to historically large SPEs is in support of mission design and opera-tion planning to avoid ARS and stay within the current NASA short-term dose limits. The ARRBOD GUI will serve as a proof-of-concept for future integration of other risk projection models for human space applications. We present an overview of the ARRBOD GUI prod-uct, which is a new self-contained product, for the major components of the overall system, subsystem interconnections, and external interfaces.

  17. Acute Dystonia Following a Switch in Treatment from Atomoxetine to Low-dose Aripiprazole.

    PubMed

    Başay, Ömer; Basay, Burge Kabukcu; Öztürk, Önder; Yüncü, Zeki

    2016-05-31

    The present report describes the cases of a 17-year-old male patient and a 13-year-old female patient who developed acute dystonia following the administration of low-dose aripiprazole (5 mg/day) after the cessation of atomoxetine treatment. Although aripiprazole-induced dystonia has been previously reported in the literature, it is rare, and most of these cases were associated with doses higher than 5 mg/day. Furthermore, both of the patients in the present study discontinued atomoxetine prior to the initiation of aripiprazole treatment; thus, this report also discussed the possible mechanisms underlying the manifestation of dystonia from the perspective of neurotransmitter activity. PMID:27121436

  18. Acute Dystonia Following a Switch in Treatment from Atomoxetine to Low-dose Aripiprazole

    PubMed Central

    Başay, Ömer; Basay, Burge Kabukcu; Öztürk, Önder; Yüncü, Zeki

    2016-01-01

    The present report describes the cases of a 17-year-old male patient and a 13-year-old female patient who developed acute dystonia following the administration of low-dose aripiprazole (5 mg/day) after the cessation of atomoxetine treatment. Although aripiprazole-induced dystonia has been previously reported in the literature, it is rare, and most of these cases were associated with doses higher than 5 mg/day. Furthermore, both of the patients in the present study discontinued atomoxetine prior to the initiation of aripiprazole treatment; thus, this report also discussed the possible mechanisms underlying the manifestation of dystonia from the perspective of neurotransmitter activity. PMID:27121436

  19. Oral carvedilol in escalating doses in the acute treatment of atrial fibrillation

    PubMed Central

    Chitrapu, Ravi Venkatachelam; Rao, Pentakota Ramana; Reddy, Gangireddy Venkateswara

    2014-01-01

    Objective: To study the efficacy of oral carvedilol in acute treatment of atrial fibrillation (AF) with fast ventricular rate. Materials and Methods: In an open-label, single-arm trial, oral carvedilol was administered to 35 patients of AF in escalating doses from 3.125 mg o.d. to 12.5 mg b.i.d. Results: A successful result was seen in 25 patients (71.4%) with 4 converting to sinus rhythm, rate control to less than 90 bpm in 16 and a 20% rate reduction in 5 patients. Two patients developed hypotension needing withdrawal of the drug. Conclusion: Escalating doses of oral carvedilol can be effectively and safely used in the acute treatment of AF with fast ventricular rate. PMID:25422563

  20. Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

    PubMed

    Cooper, Stephen A; Desjardins, Paul J; Turk, Dennis C; Dworkin, Robert H; Katz, Nathaniel P; Kehlet, Henrik; Ballantyne, Jane C; Burke, Laurie B; Carragee, Eugene; Cowan, Penney; Croll, Scott; Dionne, Raymond A; Farrar, John T; Gilron, Ian; Gordon, Debra B; Iyengar, Smriti; Jay, Gary W; Kalso, Eija A; Kerns, Robert D; McDermott, Michael P; Raja, Srinivasa N; Rappaport, Bob A; Rauschkolb, Christine; Royal, Mike A; Segerdahl, Märta; Stauffer, Joseph W; Todd, Knox H; Vanhove, Geertrui F; Wallace, Mark S; West, Christine; White, Richard E; Wu, Christopher

    2016-02-01

    This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings. PMID:26683233

  1. Developing patient-specific dose protocols for a CT scanner and exam using diagnostic reference levels.

    PubMed

    Strauss, Keith J

    2014-10-01

    The management of image quality and radiation dose during pediatric CT scanning is dependent on how well one manages the radiographic techniques as a function of the type of exam, type of CT scanner, and patient size. The CT scanner's display of expected CT dose index volume (CTDIvol) after the projection scan provides the operator with a powerful tool prior to the patient scan to identify and manage appropriate CT techniques, provided the department has established appropriate diagnostic reference levels (DRLs). This paper provides a step-by-step process that allows the development of DRLs as a function of type of exam, of actual patient size and of the individual radiation output of each CT scanner in a department. Abdomen, pelvis, thorax and head scans are addressed. Patient sizes from newborns to large adults are discussed. The method addresses every CT scanner regardless of vendor, model or vintage. We cover adjustments to techniques to manage the impact of iterative reconstruction and provide a method to handle all available voltages other than 120 kV. This level of management of CT techniques is necessary to properly monitor radiation dose and image quality during pediatric CT scans. PMID:25037975

  2. Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults

    PubMed Central

    Barden, Jodie; Derry, Sheena; McQuay, Henry J; Moore, R Andrew

    2014-01-01

    Background Ketoprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID) used to treat acute and chronic painful conditions. Dexketoprofen is the (S)-enantiomer, which is believed to confer analgesia. Theoretically dexketoprofen is expected to provide equivalent analgesia to ketoprofen at half the dose, with a consequent reduction in gastrointestinal adverse events. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral ketoprofen and dexketoprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to August 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered ketoprofen and dexketoprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fourteen studies compared ketoprofen (968 participants) at mainly 25 mg and 50 mg with placebo (520 participants). Seven studies compared dexketoprofen (681 participants) at mainly 10 mg to 25 mg with placebo (289 participants). Studies were of adequate reporting quality, and participants had pain following dental, orthopaedic, obstetric, gynaecological and general surgery. There was considerable clinical heterogeneity between studies in dental and other types of surgery, particularly bunionectomy, which limited analysis

  3. Phase I study of idarubicin dose escalation for remission induction therapy in acute myeloid leukemia.

    PubMed

    Lee, Mark Hong; Kim, Sung-Yong

    2016-10-01

    The maximum tolerated dose (MTD) of idarubicin should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony-stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m(2)/day for seven days for previously untreated AML. The starting dose of idarubicin was 12 mg/m(2)/day for three days with dose escalations by 3 mg/m(2)/day up to 18 mg/m(2)/day. The study design was adopted from traditional 3 + 3 design for phase I cancer clinical trials. The grade 4 hematologic toxicities were observed at all dose levels; however, these toxicities did not meet the criteria of the hematologic dose-limiting toxicities as defined in this study. There were no instances of grade 4 non-hematologic toxicities at any dose levels. The MTD of idarubicin was not reached in this trial. PMID:26750985

  4. Outcomes for newly diagnosed patients with acute myeloid leukemia dosed on actual or adjusted body weight

    PubMed Central

    Bivona, Cory; Rockey, Michelle; Henry, Dave; Grauer, Dennis; Abhyankar, Sunil; Aljitawi, Omar; Ganguly, Siddhartha; McGuirk, Joseph; Singh, Anurag; Lin, Tara L.

    2015-01-01

    Purpose Data from solid tumor malignancies suggest that actual body weight (ABW) dosing improves overall outcomes. There is the potential to compromise efficacy when chemotherapy dosages are reduced, but the impact of dose adjustment on clinical response and toxicity in hematologic malignancies is unknown. The purpose of this study was to evaluate the outcomes of utilizing a percent of ABW for acute myeloid leukemia (AML) induction chemotherapy dosing. Methods This retrospective, single-center study included 146 patients who received 7 + 3 induction (cytarabine and anthracycline) for treatment of AML. Study design evaluated the relationship between percentage of ABW dosing and complete response (CR) rates in patients newly diagnosed with AML. Results Percentage of ABW dosing did not influence CR rates in patients undergoing induction chemotherapy for AML (p = 0.83); nor did it influence rate of death at 30 days or relapse at 6 months (p = 0.94). When comparing patients dosed at 90–100 % of ABW compared to <90 % ABW, CR rates were not significantly different in patients classified as poor risk (p = 0.907). All favorable risk category patients obtained CR. Conclusions Preemptive dose reductions for obesity did not influence CR rates for patients with AML undergoing induction chemotherapy and did not influence the composite endpoint of death at 30 days or disease relapse at 6 months. PMID:26231954

  5. A chronic oral reference dose for hexavalent chromium-induced intestinal cancer.

    PubMed

    Thompson, Chad M; Kirman, Christopher R; Proctor, Deborah M; Haws, Laurie C; Suh, Mina; Hays, Sean M; Hixon, J Gregory; Harris, Mark A

    2014-05-01

    High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg(-1) day(-1) was derived for diffuse hyperplasia-an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l(-1). This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l(-1)) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l(-1)). PMID:23943231

  6. Less Is More: Low-dose Prothrombin Complex Concentrate Effective in Acute Care Surgery Patients.

    PubMed

    Quick, Jacob A; Meyer, Jennifer M; Coughenour, Jeffrey P; Barnes, Stephen L

    2015-06-01

    Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (± 10%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18-94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) nontrauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking prehospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion. PMID:26031281

  7. Acute and repeated dose (28 days) oral safety studies of ALIBIRD in rats.

    PubMed

    Anadón, Arturo; Martínez, María A; Ares, Irma; Castellano, Victor; Martínez-Larrañaga, Maria R; Corzo, Nieves; Olano, Agustin; Montilla, Antonia; Recio, Isidra; Martínez-Maqueda, Daniel; Miralles, Beatriz; Fornari, Tiziana; García-Risco, Mónica R; Gonzalez, Monserrat; Reglero, Guillermo

    2013-07-01

    ALIBIRD, a test substance composed of oligosaccharides derived from lactulose, a hydrolysate of a whey protein concentrate, and a supercritical extract of rosemary (1:0.5:0.05), was prepared in the laboratory and evaluated for its safety as a multifunctional food additive. In oral toxicity studies (acute and 28 days repeated dose) using Wistar rats, ALIBIRD was administered in a single oral gavage dose of 2,000 mg/kg of body weight and resulted in no adverse events or mortality; a daily dose of 2,000 mg/kg of body weight for 28 days by gavage also resulted in no adverse effects or mortality. No abnormal clinical signs, behavioral changes, body weight changes, or changes in food and water consumption occurred in either study. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. Based on test results, it is concluded that ALIBIRD is well tolerated in rats at an acute and subchronic (28 days) dose of 2,000 mg/kg of body weight. PMID:23834798

  8. In vitro cytotoxicity testing of 30 reference chemicals to predict acute human and animal toxicity

    SciTech Connect

    Barile, F.A.; Arjun, S.; Borges, L. )

    1991-03-11

    This study was conducted in cooperation with the Scandinavian Society of Cell Toxicology, as part of the Multicenter Evaluation for In Vitro Cytotoxicity (MEIC), and was designed to develop an in vitro model for predicting acute human and animal toxicity. The technique relies on the ability of cultured transformed rat lung epithelial cells (L2) to incorporate radiolabled amino acids into newly synthesized proteins in the absence or presence of increasing doses of the test chemical, during a 24-hr incubation. IC50 values were extrapolated from the dose-response curves after linear regression analysis. Human toxic blood concentrations estimated from rodent LD50 values suggest that our experimental IC50's are in close correlation with the former. Validation of the data by the MEIC committee shows that our IC50 values predicted human lethal dosage as efficient as rodent LD50's. It is anticipated that this and related procedures may supplement or replace currently used animal protocols for predicting human toxicity.

  9. Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too Much".

    PubMed

    Lewis, Susan J; Mueller, Bruce A

    2016-03-01

    Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings. Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to help clinicians give "enough but not too much" in these very complicated patients. PMID:25326429

  10. Time trend in depression diagnoses among acute coronary syndrome patients and a reference population from 2001 to 2009 in Denmark.

    PubMed

    Jørgensen, Terese Sara Høj; Mårtensson, Solvej; Ibfelt, Else Helene; Jørgensen, Martin Balslev; Wium-Andersen, Ida Kim; Wium-Andersen, Marie Kim; Prescott, Eva; Osler, Merete

    2016-07-01

    Introduction In the last decade a range of recommendations to increase awareness of depression in acute coronary syndrome patients have been published. To test the impact of those recommendations we examine and compare recent time trends in depression among acute coronary syndrome patients and a reference population. Methods 87 218 patients registered with acute coronary syndrome from 2001-2009 in Denmark and a match reference population were followed through hospital registries and medication prescriptions for early (≤30 days), intermediate (31 days to 6 months) and later (6 months to 2 years) depression in the acute coronary syndrome population and overall depression in the reference population. Cox regression models were used to compare hazard ratios (HRs) for depression over calendar years. Results During the study period, 11.0% and 6.2% were diagnosed with depression in the acute coronary syndrome population and in the reference population, respectively. For the acute coronary syndrome population, the adjusted HRs increased for early (HR (95% CI) 1.04 (1.01-1.06)) and intermediate depression (HR (95% CI) 1.01 (1.00-1.03)), whereas the adjusted HRs did not change for later depression (HR (95% CI) 0.99 (0.98-1.00)). For the reference population the adjusted HRs for depression increased through the study period (HR (95% CI) 1.01 (1.01-1.03)). Conclusion Increase in diagnoses of depressions within 6 months of acute coronary syndrome may be explained by increased focus on depression in this patient group in combination with increased awareness of depression in the general population. PMID:26750515

  11. Acceleration of atherogenesis in ApoE−/− mice exposed to acute or low-dose-rate ionizing radiation

    PubMed Central

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J.; Saran, Anna

    2015-01-01

    There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE−/− mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE−/− females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response. PMID:26359350

  12. Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

    PubMed

    Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

    2015-10-13

    There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response. PMID:26359350

  13. Dose Ranging, Expanded Acute Toxicity and Safety Pharmacology Studies for Intravenously Administered Functionalized Graphene Nanoparticle Formulations

    PubMed Central

    Kanakia, Shruti; Toussaint, Jimmy; Chowdhury, Sayan Mullick; Tembulkar, Tanuf; Lee, Stephen; Jiang, Ya-Ping; Lin, Richard Z.; Shroyer, Kenneth R.; Moore, William; Sitharaman, Balaji

    2014-01-01

    Graphene nanoparticles dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10 – 100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1–500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 minutes, and majority of nanoparticles excreted within 24 hours through feces. Histopathology changes were noted at ≥ 250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application. PMID:24854092

  14. Intrathecal cannabinoid-1 receptor agonist prevents referred hyperalgesia in acute acrolein-induced cystitis in rats

    PubMed Central

    Jones, Marsha Ritter; Wang, Zun-Yi; Bjorling, Dale E

    2015-01-01

    We investigated the capacity of intrathecal arachidonyl-2’-chloroethylamide (ACEA), a cannabinoid-1 receptor (CB1R) agonist, to inhibit referred hyperalgesia and increased bladder contractility resulting from acute acrolein-induced cystitis in rats. 24 female rats were divided into 4 groups: 1) intrathecal vehicle/intravesical saline; 2) intrathecal vehicle/intravesical acrolein; 3) intrathecal ACEA/intravesical saline; and 4) intrathecal ACEA/intravesical acrolein. Bladder catheters were placed 4-6 days prior to the experiment. On the day of the experiment, rats were briefly anesthetized with isoflurane to recover the external end of the cystostomy catheter. After recovery from anesthesia, pre-treatment cystometry was performed, and mechanical sensitivity of the hindpaws was determined. Rats were again briefly anesthetized with isoflurane to inject ACEA or vehicle into the intrathecal space between L5-L6. Beginning 10 minutes after intrathecal injection, saline or acrolein was infused into the bladder for 30 minutes. Post-treatment cystometry and mechanical sensitivity testing were performed. Rats were euthanized, and bladders were collected, weighed, and fixed for histology. The intrathecal vehicle/intravesical acrolein group developed mechanical hyperalgesia with post-treatment mechanical sensitivity of 6 ± 0.3 g compared to pretreatment of 14 ± 0.4 g (p < 0.01). Pre- and post-treatment hind paw mechanical sensitivity was statistically similar in rats that received intrathecal ACEA prior to intravesical infusion of acrolein (15 ± 0.2 g and 14 ± 0.4 g, respectively). Acrolein treatment increased basal bladder pressure and maximal voiding pressure and decreased intercontraction interval and voided volume. However, intrathecal ACEA was ineffective in improving acrolein-related urodynamic changes. In addition, bladder histology demonstrated submucosal and muscularis edema that was similar for all acrolein-treated groups, irrespective of ACEA treatment

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

    NASA Technical Reports Server (NTRS)

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

    2010-01-01

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

  16. Derivation of a reference dose and drinking water equivalent level for 1,2,3-trichloropropane.

    PubMed

    Tardiff, Robert G; Carson, M Leigh

    2010-06-01

    In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100 ppb, resulting from past uses. In subchronic oral studies, TCP produced toxicity in kidneys, liver, and other tissues. TCP administered by corn oil gavage in chronic studies produced tumors at multiple sites in rats and mice; however, interpretation of these studies was impeded by substantial premature mortality. Drinking water equivalent levels (DWELs) were estimated for a lifetime of consumption by applying biologically-based safety/risk assessment approaches, including Monte Carlo techniques, and with consideration of kinetics and modes of action, to possibly replace default assumptions. Internationally recognized Frameworks for human relevance of animal data were employed to interpret the findings. Calculated were a reference dose (=39 microg/kg d) for non-cancer and Cancer Values (CV) (=10-14 microg/kg d) based on non-linear dose-response relationships for mutagenicity as a precursor of cancer. Lifetime Average Daily Intakes (LADI) are 3130 and 790-1120 microg/person-d for non-cancer and cancer, respectively. DWELs, estimated by applying a relative source contribution (RSC) of 50% to the LADIs, are 780 and 200-280 microg/L for non-cancer and cancer, respectively. These DWELs may inform establishment of formal/informal guidelines and standards to protect public health. PMID:20303376

  17. Construction of hybrid Chinese reference adult phantoms and estimation of dose conversion coefficients for muons.

    PubMed

    Dong, Liang; Li, Taosheng; Liu, Chunyu

    2015-04-01

    A set of fluence-to-effective dose conversion coefficients of external exposure to muons were investigated for Chinese hybrid phantom references, which include both male and female. Both polygon meshes and Non-Uniform Rational B-Spline (NURBS) surfaces were used to descried the boundary of the organs and tissues in these phantoms. The 3D-DOCTOR and Rhinoceros software were used to polygonise the colour slice images and generate the NURBS surfaces, respectively. The voxelisation is completed using the BINVOX software and the assembly finished by using MATLAB codes. The voxel resolutions were selected to be 0.22 × 0.22 × 0.22 cm(3) and 0.2 × 0.2 × 0.2 cm(3) for male and female phantoms, respectively. All parts of the final phantoms were matched to their reference organ masses within a tolerance of ±5%. The conversion coefficients for negative and positive muons were calculated with the FLUKA transport code. There were 21 external monoenergetic beams ranging from 0.01 GeV to 100 TeV in 5 different geometrical conditions of irradiation. PMID:25313173

  18. Variability of Antithrombotic Dosing Among Veterans Presenting With Acute Coronary Syndrome

    PubMed Central

    Plomondon, Mary E.; Lambert‐Kerzner, Anne C.; Jennewein, Xuefei; Fagan, Katherine; McCreight, Marina; Fehling, Kelty B.; Tsai, Thomas T.; Ho, P. Michael

    2015-01-01

    Background Antithrombotic therapy for acute coronary syndrome (ACS) patients is recommended by clinical practice guidelines. Appropriate dosing of antithrombotic therapy is necessary to ensure effectiveness and safety and is an American College of Cardiology/American Heart Association ST elevated myocardial infarction/non‐ST elevated myocardial infarction performance measure. This study describes the variability in dosing of unfractionated heparin (UH) and low‐molecular‐weight heparin (LMWH) in an integrated health care system with electronic medical records and computerized physician order entry (CPOE). Methods and Results This was a mixed‐methods study of veterans presenting with ACS at 135 Veterans Health Administration hospitals from 2009 to 2011. Patients hospitalized with ACS and received antithrombotic therapy were included (n=36 682). The cohort was 98% male with an average age of 66 years and median body mass index (BMI) of 28.6. The average percentage of patients by hospital who received an above‐recommended dose of either antithrombotic was 7.5% and ranged 0% to 32.0%. By individual therapy, the average percentage of patients by hospital who received an above‐recommended dose of UH was 1.2% and LMWH was 12.9%. Risk‐adjusted analyses demonstrated that older age and higher BMI were associated with lower risk for receiving a dose above recommended levels. Additionally, there was an association between antithrombotic ordered by a resident and higher risk of the patient receiving an above‐recommended dose. Qualitative interviews supported the quantitative findings by highlighting the need to use current patient weight and the need to adequately train providers on the use of CPOE to improve antithrombotic dosing. Conclusion This study found wide hospital variability in dosing of antithrombotics above the recommended level for patients treated for ACS. PMID:25917444

  19. The acute lethal dose 50 (LD50) of caffeine in albino rats.

    PubMed

    Adamson, Richard H

    2016-10-01

    An acute LD50 is a statistically derived amount of a substance that can be expected to cause death in 50% of the animals when given by a specified route as a single dose and the animals observed for a specified time period. Although conducting routine acute toxicity testing in rodents has been criticized, it can serve useful functions and also have practical implications. Material safety data sheets (MSDS) will reflect the acute toxicity of a substance and may require workers to wear protective gear, if appropriate, based on the LD50. There is no information in the scientific published literature which calculates a mean LD50 and standard deviation for caffeine administered orally to rats, using studies performed under good laboratory practice (GLP) or equivalent. This report does that and should be useful to manufacturers, packagers, transporters and regulators of this material. Using data from studies that are reproducible and reliable, the most accurate estimate of the acute LD50 of caffeine administered orally in male albino rats is hereby reported to be 367/mg/kg. PMID:27461039

  20. [Cytosine-arabinoside in high doses in refractory acute granulocytic leukemia. Apropos of 17 cases].

    PubMed

    Jouet, J P; Simon, M; Fenaux, P; Pollet, J P; Bauters, F

    1985-01-01

    A total of 17 patients, 6 female and 11 male (age range 13 to 56 years), received high dose Ara-C for treatment of refractory acute myelogenous leukemia. Ara-C was given at 3 g/m2 twice daily for 6 days as a 1 infusion. 1 patient (with induced acute leukemia) was treated directly, two after failure of a chemotherapy schedule containing the usual dose Ara-C, 12 for first relapse and 2 for subsequent relapse. Maximum follow up is 16 months. Beside hematological toxicity, systemic tolerance was good with no neurological of cutaneous effects. Despite preventive corticoid eyewash, ocular complications occurred in 6 cases, mild and resolvable in 5 of them. The immediate results were as follows: 3 deaths during induction (18%); 6 failures (35%); 8 complete remissions (CR) (47%). After primary chemo-resistance (two cases) failure was always noted. In 3 cases, after less than 12 infusions had been given, 2 failures and 1 very short CR were noted. In 2 patients, when doxorubicin was added to Ara-C, we observed 1 death during induction and 1 failure. Of the patients achieving CR 8 were treated by periodic courses with high dose Ara-C and 4 of them relapsed. The longest failure free duration was 11 months. Median survival duration of the 17 patients is 5 months. PMID:3862072

  1. Acute phase response in toxicity studies. I. Survey of beagle dogs subjected to single-dose toxicity studies.

    PubMed

    Hoshiya, T; Watanabe, D; Akagi, K; Mizoguchi, Y; Kamiya, K; Mizuguchi, H; Kumahara, M; Toya, H; Nagashima, Y; Okaniwa, A

    2001-05-01

    In the field of routine single-dose toxicity studies, we occasionally meet with transient leukocytosis associated with an increase in fibrinogen in beagle dogs within a few days after treatment with the test article. Only a little is known, however, about the toxicological significance of these changes. However, these changes were thought to belong to the category of "Acute Phase Response, APR," which has been known for a long time in connection with injury, trauma or infection. Aiming at proper understanding of these experiences, we surveyed 25 single-dose toxicity studies (7 intravenous bolus, 5 intravenous infusion, 12 oral and 1 subcutaneous treatment, hereafter referred to simply as i.v. bolus, i.v. infusion, oral and s.c.) in beagle dogs, provided with data from hematological examinations. We set the following criteria as a positive response in the present survey: increases of 50% or more in either or both WBC or fibrinogen compared to the predosing value, transiently from Day 1 to Day 3 of the study. Among 25 studies surveyed, about 1/2 of the studies exhibited increases of 50% or more in either or both fibrinogen or WBC counts compared to the predosing values showing dose-dependency transiently on Day 1 or Day 2. These changes were remarkable after intravenous application. Oral application produced similar effects, although the incidence and severity were low compared to the i.v. routes. Regarding blood chemical and hematological changes other than changes in fibrinogen and WBC counts, there were no essential differences between the groups of studies with and without the changes in fibrinogen and WBC counts. These changes were thought to be characteristic and to have occurred as incidents unrelated to other changes. The reported changes seen in single-dose toxicity studies may belong to the category of APR as the non-specific mechanism of living bodies as stated by Burns et al. (1996). PMID:11429972

  2. Acute mucosal pathogenesis of feline immunodeficiency virus is independent of viral dose in vaginally infected cats

    PubMed Central

    2010-01-01

    Background The mucosal pathogenesis of HIV has been shown to be an important feature of infection and disease progression. HIV-1 infection causes depletion of intestinal lamina propria CD4+ T cells (LPL), therefore, intestinal CD4+ T cell preservation may be a useful correlate of protection in evaluating vaccine candidates. Vaccine studies employing the cat/FIV and macaque/SIV models frequently use high doses of parenterally administered challenge virus to ensure high plasma viremia in control animals. However, it is unclear if loss of mucosal T cells would occur regardless of initial viral inoculum dose. The objective of this study was to determine the acute effect of viral dose on mucosal leukocytes and associated innate and adaptive immune responses. Results Cats were vaginally inoculated with a high, middle or low dose of cell-associated and cell-free FIV. PBMC, serum and plasma were assessed every two weeks with tissues assessed eight weeks following infection. We found that irrespective of mucosally administered viral dose, FIV infection was induced in all cats. However, viremia was present in only half of the cats, and viral dose was unrelated to the development of viremia. Importantly, regardless of viral dose, all cats experienced significant losses of intestinal CD4+ LPL and CD8+ intraepithelial lymphocytes (IEL). Innate immune responses by CD56+CD3- NK cells correlated with aviremia and apparent occult infection but did not protect mucosal T cells. CD4+ and CD8+ T cells in viremic cats were more likely to produce cytokines in response to Gag stimulation, whereas aviremic cats T cells tended to produce cytokines in response to Env stimulation. However, while cell-mediated immune responses in aviremic cats may have helped reduce viral replication, they could not be correlated to the levels of viremia. Robust production of anti-FIV antibodies was positively correlated with the magnitude of viremia. Conclusions Our results indicate that mucosal immune

  3. Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation

    SciTech Connect

    Daila S. Gridley, PhD

    2012-03-30

    FINAL TECHNICAL REPORT Supported by the Low Dose Radiation Research Program, Office of Science U.S. Department of Energy Grant No. DE-FG02-07ER64345 Project ID: 0012965 Award Register#: ER64345 Project Manager: Noelle F. Metting, Sc.D. Phone: 301-903-8309 Division SC-23.2 noelle.metting@science.doe.gov Submitted March 2012 To: https://www.osti.gov/elink/241.3.jsp Title: Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation PI: Daila S. Gridley, Ph.D. Human low dose radiation data have been derived primarily from studies of space and airline flight personnel, nuclear plant workers and others exposed occupationally, as well as victims in the vicinity of atomic bomb explosions. The findings remain inconclusive due to population inconsistencies and complex interactions among total dose, dose rate, radiation quality and age at exposure. Thus, safe limits for low dose occupational irradiation are currently based on data obtained with doses far exceeding the levels expected for the general population and health risks have been largely extrapolated using the linear-nonthreshold dose-response model. The overall working hypothesis of the present study is that priming with low dose, low-linear energy transfer (LET) radiation can ameliorate the response to acute high-dose radiation exposure. We also propose that the efficacy of low-dose induced protection will be dependent upon the form and regimen of the high-dose exposure: photons versus protons versus simulated solar particle event protons (sSPE). The emphasis has been on gene expression and function of CD4+ T helper (Th) lymphocytes harvested from spleens of whole-body irradiated C57BL/6 mice, a strain that provides the genetic background for many genetically engineered strains. Evaluations of the responses of other selected cells, tissues such as skin, and organs such as lung, liver and brain were also initiated (partially funded by other sources). The long-term goal is to provide information

  4. TLD skin dose measurements and acute and late effects after lumpectomy and high-dose-rate brachytherapy only for early breast cancer

    SciTech Connect

    Perera, Francisco . E-mail: francisco.perera@lrcc.on.ca; Chisela, Frank; Stitt, Larry; Engel, Jay; Venkatesan, Varagur

    2005-08-01

    Purpose: This report examines the relationships between measured skin doses and the acute and late skin and soft tissue changes in a pilot study of lumpectomy and high-dose-rate brachytherapy only for breast cancer. Methods and Materials: Thirty-seven of 39 women enrolled in this pilot study of high-dose-rate brachytherapy (37.2 Gy in 10 fractions b.i.d.) each had thermoluminescent dosimetry (TLD) at 5 points on the skin of the breast overlying the implant volume. Skin changes at TLD dose points and fibrosis at the lumpectomy site were documented every 6 to 12 months posttreatment using a standardized physician-rated cosmesis questionnaire. The relationships between TLD dose and acute skin reaction, pigmentation, or telangiectasia at 5 years were analyzed using the GEE algorithm and the GENMOD procedure in the SAS statistical package. Fisher's exact test was used to determine whether there were any significant associations between acute skin reaction and late pigmentation or telangiectasia or between the volumes encompassed by various isodoses and fibrosis or fat necrosis. Results: The median TLD dose per fraction (185 dose points) multiplied by 10 was 9.2 Gy. In all 37 patients, acute skin reaction Grade 1 or higher was observed at 5.9% (6 of 102) of dose points receiving 10 Gy or less vs. 44.6% (37 of 83) of dose points receiving more than 10 Gy (p < 0.0001). In 25 patients at 60 months, 1.5% telangiectasia was seen at dose points receiving 10 Gy or less (1 of 69) vs. 18% (10 of 56) telangiectasia at dose points receiving more than 10 Gy (p 0.004). Grade 1 or more pigmentation developed at 1.5% (1 of 69) of dose points receiving less than 10 Gy vs. 25% (14 of 56) of dose points receiving more than 10 Gy (p < 0.001). A Grade 1 or more acute skin reaction was also significantly associated with development of Grade 1 or more pigmentation or telangiectasia at 60 months. This association was most significant for acute reaction and telangiectasia directly over the

  5. Development of a Reference Dose for Perchlorate: Current Issues and Status

    NASA Technical Reports Server (NTRS)

    Pleus, R. C.; Goodman, G.; Mattie, D. R.

    2000-01-01

    The perchlorate anion (ClO4) is typically manufactured as the ammonium salt. The most common use of ammonium perchlorate is in the aerospace program as a component of solid rocket fuel. The perchlorate anion is exceedingly stable under environmental conditions and has been found in ground and surface waters in CA, NV, UT, AZ, TX, AK, NY, MD, WV and FL. The National Center for Environmental Assessment (NCEA) of the U.S. Environmental Protection Agency (US EPA) is in the process of developing an oral reference dose (RfD) for perchlorate. An oral RfD is a body-weight-adjusted dose that can be consumed daily over an entire lifetime with the expectation of no adverse health effects. Once developed, the new RfD will be used by US EPA as the basis of a safe-drinking-water level (SDWL) guideline. US EPA and regional regulatory agencies will then jointly or separately propose clean-up action levels for ground and surface waters at contaminated sites. The toxicological database on CIO4- as of March 1997 was determined by an expert peer-review panel to be inadequate for the purpose of deriving an oral RfD. For example, little or no experimental data existed on the subchronic, reproductive, or developmental toxicity of perchlorate. To fill gaps in the toxicological database, eight animal studies were designed by a government-industry consortium that included US EPA and AFRL. These studies were performed in 1997-1998. It has been known for many years that in the thyroid, high doses of perchlorate block the function of iodide by competing for iodide binding sites. Perchlorate was used in the 1950s-60s as a treatment for Graves' disease (a hyperthyroid condition). Because of what was already known about the pharmacological mode of action of perchlorate, specific concerns addressed in the design of the recent animal studies included the potential for developmental toxicity, notably neurological development. Upon review of complete study reports from four of the studies and

  6. The Dose-Dependent Effect of Nesiritide on Renal Function in Patients with Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Xiong, Bo; Wang, Chunbin; Yao, Yuanqing; Huang, Yuwen; Tan, Jie; Cao, Yin; Zou, Yanke; Huang, Jing

    2015-01-01

    Background Conflicting renal effects of nesiritide have been reported in patients with acute decompensated heart failure. To answer this controversy, we performed a meta-analysis of randomized controlled trials to evaluate the influence of nesiritide on renal function in patients with acute decompensated heart failure. Methods Articles were obtained from PubMed, Medline, Cochrane Library and reference review. Randomized controlled studies that investigated the effects of continuous infusion of nesiritide on renal function in adult patients with acute decompensated heart failure were included and analyzed. Fixed-effect model was used to estimate relative risk (RR) and weight mean difference (WMD). The quality assessment of each study, subgroup, sensitivity, and publication bias analyses were performed. Results Fifteen randomized controlled trials were eligible for inclusion. Most of included studies had relatively high quality and no publication bias was found. Overall, compared to control therapies, nesiritide might increase the risk of worsening renal function in patients with acute decompensated heart failure (RR 1.08, 95% CI 1.01–1.15, P = 0.023). In subgroup analysis, high-dose nesiritide strongly associated with renal dysfunction (RR 1.54, 95% CI 1.19-2.00, P = 0.001), but no statistical differences were observed in standard-dose (RR 1.04, 95% CI 0.98-1.12, P = 0.213), low-dose groups (RR 1.01, 95% CI 0.74-1.37, P = 0.968) and same results were identified in the subgroup analysis of placebo controlled trials. Peak mean change of serum creatinine from baseline was no significant difference (WMD -2.54, 95% CI -5.76-0.67, P = 0.121). Conclusions In our meta-analysis, nesiritide may have a dose-dependent effect on renal function in patients with acute decompensated heart failure. High-dose nesiritide is likely to increase the risk of worsening renal function, but standard-dose and low-dose nesiritide probably have no impact on renal function. These findings

  7. Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

    PubMed

    Tucker, James D; Divine, George W; Grever, William E; Thomas, Robert A; Joiner, Michael C; Smolinski, Joseph M; Auner, Gregory W

    2013-01-01

    Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to (60)Co gamma rays at doses of 0 (control) to 10 Gy. Blood was obtained from irradiated mice 0.5, 1, 2, 3, 5, and 7 days after exposure. mRNA expression levels of 106 selected genes were obtained by reverse-transcription real time PCR. Stepwise regression of dose received against individual gene transcript expression levels provided optimal dosimetry at each time point. The results indicate that only 4-7 different gene transcripts are needed to explain ≥ 0.69 of the variance (R(2)), and that receiver-operator characteristics, a measure of sensitivity and specificity, of ≥ 0.93 for these statistical models were achieved at each time point. These models provide an excellent description of the relationship between the actual and predicted doses up to 6 Gy. At doses of 8 and 10 Gy there appears to be saturation of the radiation-response signals with a corresponding diminution of accuracy. These results suggest that similar analyses in humans may be advantageous for use in a field-portable device designed to assess exposures in mass casualty situations. PMID:24358280

  8. Single dose oral tiaprofenic acid for acute postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; Moore, Maura; McQuay, Henry J

    2014-01-01

    Background Tiaprofenic acid is a a non-steroidal anti-inflammatory drug (NSAID). It is widely available around the world, with indications for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, periarticular disorders, and strains and sprains. This review sought to evaluate the efficacy and safety of oral tiaprofenic acid in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral tiaprofenic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to June 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered tiaprofenic acid in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We planned to use area under the “pain relief versus time” curve to derive the proportion of participants with tiaprofenic acid experiencing at least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. Main results Not one of eleven studies identified by the searches and examined in detail studied oral tiaprofenic acid against placebo in patients with established postoperative pain and therefore no results are available. Authors’ conclusions In the absence of evidence of efficacy for oral tiaprofenic acid in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly

  9. Protracted low-dose radiation priming and response of liver to acute gamma and proton radiation.

    PubMed

    Gridley, D S; Mao, X W; Cao, J D; Bayeta, E J M; Pecaut, M J

    2013-10-01

    This study evaluated liver from C57BL/6 mice irradiated with low-dose/low-dose-rate (LDR) γ-rays (0.01 Gy, 0.03 cGy/h), with and without subsequent exposure to acute 2 Gy gamma or proton radiation. Analyses were performed on day 56 post-exposure. Expression patterns of apoptosis-related genes were strikingly different among irradiated groups compared with 0 Gy (p < 0.05). Two genes were affected in the Gamma group, whereas 10 were modified in the LDR + Gamma group. In Proton and LDR + Proton groups, there were six and 12 affected genes, respectively. Expression of genes in the Gamma (Traf3) and Proton (Bak1, Birc2, Birc3, Mcl1) groups was no longer different from 0 Gy control group when mice were pre-exposed to LDR γ-rays. When each combined regimen was compared with the corresponding group that received acute radiation alone, two genes in the LDR + Gamma group and 17 genes in the LDR + Proton group were modified; greatest effect was on Birc2 and Nol3 (> 5-fold up-regulated by LDR + Protons). Oxygen radical production in livers from the LDR + Proton group was higher in LDR, Gamma, and LDR + Gamma groups (p < 0.05 vs. 0 Gy), but there were no differences in phagocytosis of E. coli. Sections stained with hematoxylin and eosin (H&E) suggested more inflammation, with and without necrosis, in some irradiated groups. The data demonstrate that response to acute radiation is dependent on radiation quality and regimen and that some LDR γ-ray-induced modifications in liver response were still evident nearly 2 months after exposure. PMID:23869974

  10. High-dose total-body irradiation and autologous marrow reconstitution in dogs: dose-rate-related acute toxicity and fractionation-dependent long-term survival

    SciTech Connect

    Deeg, H.J.; Storb, R.; Weiden, P.L.; Schumacher, D.; Shulman, H.; Graham, T.; Thomas, E.D.

    1981-11-01

    Beagle dogs treated by total-body irradiation (TBI) were given autologous marrow grafts in order to avoid death from marrow toxicity. Acute and delayed non-marrow toxicities of high single-dose (27 dogs) and fractionated TBI (20 dogs) delivered at 0.05 or 0.1 Gy/min were compared. Fractionated TBI was given in increments of 2 Gy every 6 hr for three increments per day. Acute toxicity and early mortality (<1 month) at identical total irradiation doses were comparable for dogs given fractionated or single-dose TBI. With single-dose TBI, 14, 16, and 18 Gy, respectively, given at 0.05 Gy/min, 0/5, 5/5, and 2/2 dogs died from acute toxicity; with 10, 12, and 14 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 5/5 dogs died acutely. With fractionated TBI, 14 and 16 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 2/2 dogs died auctely. Early deaths were due to radiation enteritis with or without associated septicemia (29 dogs; less than or equal to Day 10). Three dogs given 10 Gy of TBI at 0.1 Gy/min died from bacterial pneumonia; one (Day 18) had been given fractionated and two (Days 14, 22) single-dose TBI. Fifteen dogs survived beyond 1 month; eight of these had single-dose TBI (10-14 Gy) and all died within 7 months of irradiation from a syndrome consisting of hepatic damage, pancreatic fibrosis, malnutrition, wasting, and anemia. Seven of the 15 had fractionated TBI, and only one (14 Gy) died on Day 33 from hepatic failure, whereas 6 (10-14 Gy) are alive and well 250 to 500 days after irradiation. In conclusion, fractionated TBI did not offer advantages over single-dose TBI with regard to acute toxicity and early mortality; rather, these were dependent upon the total dose of TBI. The total acutely tolerated dose was dependent upon the exposure rate; however, only dogs given fractionated TBI became healthy long-term survivors.

  11. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

    PubMed

    Chang, Jianhui; Luo, Yi; Wang, Yingying; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic

  12. Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice

    PubMed Central

    Wang, Yingying; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic

  13. Development of Diagnostic Reference Levels Using a Real-Time Radiation Dose Monitoring System at a Cardiovascular Center in Korea.

    PubMed

    Kim, Jungsu; Seo, Deoknam; Choi, Inseok; Nam, Sora; Yoon, Yongsu; Kim, Hyunji; Her, Jae; Han, Seonggyu; Kwon, Soonmu; Park, Hunsik; Yang, Dongheon; Kim, Jungmin

    2015-12-01

    Digital cardiovascular angiography accounts for a major portion of the radiation dose among the examinations performed at cardiovascular centres. However, dose-related information is neither monitored nor recorded systemically. This report concerns the construction of a radiation dose monitoring system based on digital imaging and communications in medicine (DICOM) data and its use at the cardiovascular centre of the University Hospitals in Korea. The dose information was analysed according to DICOM standards for a series of procedures, and the formulation of diagnostic reference levels (DRLs) at our cardiovascular centre represents the first of its kind in Korea. We determined a dose area product (DAP) DRL for coronary angiography of 75.6 Gy cm(2) and a fluoroscopic time DRL of 318.0 s. The DAP DRL for percutaneous transluminal coronary intervention was 213.3 Gy cm(2), and the DRL for fluoroscopic time was 1207.5 s. PMID:25700616

  14. Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

    PubMed

    Jarabek, A M; Menache, M G; Overton, J H; Dourson, M L; Miller, F J

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation. PMID:2606680

  15. Inhalation reference dose (RfDi): An application of interspecies dosimetry modeling for risk assessment of insoluble particles

    SciTech Connect

    Jarabek, A.M.; Menache, M.G.; Overton, J.H. Jr.; Dourson, M.L.; Miller, F.J. )

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses (the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity) for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated. Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

  16. Iterative reconstruction technique with reduced volume CT dose index: diagnostic accuracy in pediatric acute appendicitis

    PubMed Central

    Didier, Ryne A.; Vajtai, Petra L.

    2014-01-01

    Background Iterative reconstruction technique has been proposed as a means of reducing patient radiation dose in pediatric CT. Yet, the effect of such reductions on diagnostic accuracy has not been thoroughly evaluated. Objective This study compares accuracy of diagnosing pediatric acute appendicitis using contrast-enhanced abdominopelvic CT scans performed with traditional pediatric weight-based protocols and filtered back projection reconstruction versus a filtered back projection/iterative reconstruction technique blend with reduced volume CT dose index (CTDIvol). Materials and methods Results of pediatric contrast-enhanced abdominopelvic CT scans done for pain and/or suspected appendicitis were reviewed in two groups: A, 192 scans performed with the hospital’s established weight-based CT protocols and filtered back projection reconstruction; B, 194 scans performed with iterative reconstruction technique and reduced CTDIvol. Reduced CTDIvol was achieved primarily by reductions in effective tube current-time product (mAseff) and tube peak kilovoltage (kVp). CT interpretation was correlated with clinical follow-up and/or surgical pathology. CTDIvol, size specific dose estimates (SSDE) and performance characteristics of the two CT techniques were then compared. Results Between groups A and B, mean CTDIvol was reduced by 45%, and mean SSDE was reduced by 46%. Sensitivity, specificity and diagnostic accuracy were 96%, 97% and 96% in group A vs. 100%, 99% and 99% in group B. Conclusion Accuracy in diagnosing pediatric acute appendicitis was maintained in contrast-enhanced abdominopelvic CT scans that incorporated iterative reconstruction technique, despite reductions in mean CTDIvol and SSDE by nearly half as compared to the hospital’s traditional weight-based protocols. PMID:24996812

  17. In vitro study of acute toxic effects of high iodide doses in human thyroid follicles.

    PubMed

    Many, M C; Mestdagh, C; van den Hove, M F; Denef, J F

    1992-08-01

    The acute effects of increasing doses of sodium iodide were studied on human thyroid follicles isolated from normal paranodular tissue. After 24 h incubation in culture medium, follicles isolated from most thyroids maintained their capacity for 125I accumulation and organification and a normal cellular ultrastructure. 125I accumulation was significantly increased after addition of TSH, whereas 125I organification was not affected. In presence of TSH, numerous follicles had large empty-looking follicular lumina unlabeled on autoradiographies. Follicles incubated for 24 h in the presence of a low concentration (10(-7) M) of iodide retained their function and morphology. However, incubation with a high dose of iodide (10(-3) M) caused marked inhibition of 125I accumulation and organification reaching values similar to those obtained in presence of inhibitors of iodide trapping and organification. At high doses, iodide induced necrosis of thyroid epithelial cells: the percentage of necrotic cells was significantly increased with 10(-5) M and doubled with 10(-3) M as compared to values measured at 10(-7) M. Ultrastructural lesions such as apical blebbing, cytoplasmic fragments desquamation, endoplasmic reticulum vesiculation, and accumulation of lipofuscin in secondary lysosomes were also present. The necrotic effect and the ultrastructural alterations also occurred in the presence of TSH but were prevented by the addition of inhibitors of iodide trapping or organification. These results demonstrate a direct acute toxic effect of iodide in human thyroid cells. The nature of the ultrastructural alterations is in agreement with a mechanism of toxicity involving a free radical attack and lipid peroxidation as observed in other tissues. PMID:1639011

  18. Organ dose conversion coefficients for voxel models of the reference male and female from idealized photon exposures

    NASA Astrophysics Data System (ADS)

    Schlattl, H.; Zankl, M.; Petoussi-Henss, N.

    2007-04-01

    A new series of organ equivalent dose conversion coefficients for whole body external photon exposure is presented for a standardized couple of human voxel models, called Rex and Regina. Irradiations from broad parallel beams in antero-posterior, postero-anterior, left- and right-side lateral directions as well as from a 360° rotational source have been performed numerically by the Monte Carlo transport code EGSnrc. Dose conversion coefficients from an isotropically distributed source were computed, too. The voxel models Rex and Regina originating from real patient CT data comply in body and organ dimensions with the currently valid reference values given by the International Commission on Radiological Protection (ICRP) for the average Caucasian man and woman, respectively. While the equivalent dose conversion coefficients of many organs are in quite good agreement with the reference values of ICRP Publication 74, for some organs and certain geometries the discrepancies amount to 30% or more. Differences between the sexes are of the same order with mostly higher dose conversion coefficients in the smaller female model. However, much smaller deviations from the ICRP values are observed for the resulting effective dose conversion coefficients. With the still valid definition for the effective dose (ICRP Publication 60), the greatest change appears in lateral exposures with a decrease in the new models of at most 9%. However, when the modified definition of the effective dose as suggested by an ICRP draft is applied, the largest deviation from the current reference values is obtained in postero-anterior geometry with a reduction of the effective dose conversion coefficient by at most 12%.

  19. Organ dose conversion coefficients for voxel models of the reference male and female from idealized photon exposures.

    PubMed

    Schlattl, H; Zankl, M; Petoussi-Henss, N

    2007-04-21

    A new series of organ equivalent dose conversion coefficients for whole body external photon exposure is presented for a standardized couple of human voxel models, called Rex and Regina. Irradiations from broad parallel beams in antero-posterior, postero-anterior, left- and right-side lateral directions as well as from a 360 degrees rotational source have been performed numerically by the Monte Carlo transport code EGSnrc. Dose conversion coefficients from an isotropically distributed source were computed, too. The voxel models Rex and Regina originating from real patient CT data comply in body and organ dimensions with the currently valid reference values given by the International Commission on Radiological Protection (ICRP) for the average Caucasian man and woman, respectively. While the equivalent dose conversion coefficients of many organs are in quite good agreement with the reference values of ICRP Publication 74, for some organs and certain geometries the discrepancies amount to 30% or more. Differences between the sexes are of the same order with mostly higher dose conversion coefficients in the smaller female model. However, much smaller deviations from the ICRP values are observed for the resulting effective dose conversion coefficients. With the still valid definition for the effective dose (ICRP Publication 60), the greatest change appears in lateral exposures with a decrease in the new models of at most 9%. However, when the modified definition of the effective dose as suggested by an ICRP draft is applied, the largest deviation from the current reference values is obtained in postero-anterior geometry with a reduction of the effective dose conversion coefficient by at most 12%. PMID:17404459

  20. The reference dose for subchronic exposure of pigs to cadmium leading to early renal damage by benchmark dose method.

    PubMed

    Wu, Xiaosheng; Wei, Shuai; Wei, Yimin; Guo, Boli; Yang, Mingqi; Zhao, Duoyong; Liu, Xiaoling; Cai, Xianfeng

    2012-08-01

    Pigs were exposed to cadmium (Cd) (in the form of CdCl(2)) concentrations ranging from 0 to 32mg Cd/kg feed for 100 days. Urinary cadmium (U-Cd) and blood cadmium (B-Cd) levels were determined as indicators of Cd exposure. Urinary levels of β(2)-microglobulin (β(2)-MG), α(1)-microglobulin (α(1)-MG), N-acetyl-β-D-glucosaminidase (NAG), cadmium-metallothionein (Cd-MT), and retinol binding protein (RBP) were determined as biomarkers of tubular dysfunction. U-Cd concentrations were increased linearly with time and dose, whereas B-Cd reached two peaks at 40 days and 100 days in the group exposed to 32mg Cd/kg. Hyper-metallothionein-urinary (HyperMTuria) and hyper-N-acetyl-β-D-glucosaminidase-urinary (hyperNAGuria) emerged from 80 days onwards in the group exposed to 32mg Cd/kg feed, followed by hyper-β2-microglobulin-urinary (hyperβ2-MGuria) and hyper-retinol-binding-protein-urinary (hyperRBPuria) from 100 days onwards. The relationships between the Cd exposure dose and biomarkers of exposure (as well as the biomarkers of effect) were examined, and significant correlations were found between them (except for α(1)-MG). Dose-response relationships between Cd exposure dose and biomarkers of tubular dysfunction were studied. The critical concentration of Cd exposure dose was calculated by the benchmark dose (BMD) method. The BMD(10)/BMDL(10) was estimated to be 1.34/0.67, 1.21/0.88, 2.75/1.00, and 3.73/3.08mg Cd/kg feed based on urinary RBP, NAG, Cd-MT, and β(2)-MG, respectively. The calculated tolerable weekly intake of Cd for humans was 1.4 μg/kg body weight based on a safety factor of 100. This value is lower than the currently available values set by several different countries. This indicates a need for further studies on the effects of Cd and a re-evaluation of the human health risk assessment for the metal. PMID:22610606

  1. Trebananib With or Without Low-Dose Cytarabine in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-25

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  2. Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

    NASA Astrophysics Data System (ADS)

    Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

    2015-05-01

    The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

  3. A Therapeutic Dose of Ketoprofen Causes Acute Gastrointestinal Bleeding, Erosions, and Ulcers in Rats

    PubMed Central

    Shientag, Lisa J; Wheeler, Suzanne M; Garlick, David S; Maranda, Louise S

    2012-01-01

    Perioperative treatment of several rats in our facility with ketoprofen (5 mg/kg SC) resulted in blood loss, peritonitis, and death within a day to a little more than a week after surgery that was not related to the gastrointestinal tract. Published reports have established the 5-mg/kg dose as safe and effective for rats. Because ketoprofen is a nonselective nonsteroidal antiinflammatory drug that can damage the gastrointestinal tract, the putative diagnosis for these morbidities and mortalities was gastrointestinal toxicity caused by ketoprofen (5 mg/kg). We conducted a prospective study evaluating the effect of this therapeutic dose of ketoprofen on the rat gastrointestinal tract within 24 h. Ketoprofen (5 mg/kg SC) was administered to one group of rats that then received gas anesthesia for 30 min and to another group without subsequent anesthesia. A third group was injected with saline followed by 30 min of gas anesthesia. Our primary hypothesis was that noteworthy gastrointestinal bleeding and lesions would occur in both groups treated with ketoprofen but not in rats that received saline and anesthesia. Our results showed marked gastrointestinal bleeding, erosions, and small intestinal ulcers in the ketoprofen-treated rats and minimal damages in the saline-treated group. The combination of ketoprofen and anesthesia resulted in worse clinical signs than did ketoprofen alone. We conclude that a single 5-mg/kg dose of ketoprofen causes acute mucosal damage to the rat small intestine. PMID:23294892

  4. Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

    PubMed

    Hahn, Margaret Karolina; Wolever, Tom M S; Arenovich, Tamara; Teo, Celine; Giacca, Adria; Powell, Valerie; Clarke, Leigh; Fletcher, Paul; Cohn, Tony; McIntyre, Roger S; Gomes, Sylvia; Chintoh, Araba; Remington, Gary J

    2013-12-01

    Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices. PMID:24100786

  5. Weight-based insulin dosing for acute hyperkalemia results in less hypoglycemia.

    PubMed

    Wheeler, Dauria T; Schafers, Stephen J; Horwedel, Tim A; Deal, Eli N; Tobin, Garry S

    2016-05-01

    Hyperkalemia treatment with intravenous insulin has been associated with hypoglycemia. This single-center, retrospective study compared the effects on hypoglycemia between weight-based insulin dosing (0.1 U/kg of body weight up to a maximum of 10 U) compared to standard flat doses of 10 U among patients weighing less than 95 kg. Of the 132 charts randomly selected for review, hypoglycemic events (blood glucose <70 mg/dL) were reduced from 27.3% in the 10-U group to 12.1% in the weight-based group (P = 0.05). The number of affected patients was reduced with 19.7% in the 10-U group and 10.6% in the weight-based group (P = 0.22). The potassium-lowering effects of these 2 strategies were similar between groups. Female patients and those with baseline glucose values <140 mg/dL were at increased risk for hypoglycemia. Weight-based insulin dosing (0.1 U/kg) for acute hyperkalemia therapy resulted in less hypoglycemia without impacting potassium lowering. Journal of Hospital Medicine 2016;11:355-357. © 2016 Society of Hospital Medicine. PMID:26762588

  6. Acute lethal toxicity of some reference chemicals to freshwater fishes of Scandinavia

    SciTech Connect

    Oikari, A.O.J.

    1987-07-01

    Relevance of the choice of a test organism intended to be representative for a given environment seems to be under continual debate in aquatic ecotoxicology. For instance, it is commonly argue that acute toxicity tests with rainbow trout, the species most often recommended as a standard cold water teleost, were not representative for Nordic countries because the species is an alien in local faunas. A comparative study with several freshwater species was therefore initiated to clarify the validity of this assumption. As a first approximation, standard LC 50 assays were conducted. The species used were chosen only on the basis of their local availability, i.e, they randomly represented the fish fauna of Nordic inland waters. Furthermore, inter-species variation of toxicity response was compared with certain other, quantitatively more important, intra-species sources of variability affecting the toxicity of chemicals. Use of reference toxicants has been recommended as a means of standardizing bioassays. Compounds, characteristic of effluents from the pulp and paper industry, were selected for the present study. The toxicity of organic acids such a phenols and resin acids, as well as that of pupmill effluents, strongly depends on water pH. Because of the possibility that species differences could exist in this respect, effects of water acidity on toxicity of these types of substances to a randomly selected local species was investigated. Finally, as an example of the biological source of assay variability, the effect of yolk absorption was studied with a subsequent crisis period due to moderate starvation under laboratory conditions.

  7. Overview of the ICRP/ICRU adult reference computational phantoms and dose conversion coefficients for external idealised exposures.

    PubMed

    Endo, Akira; Petoussi-Henss, Nina; Zankl, Maria; Bolch, Wesley E; Eckerman, Keith F; Hertel, Nolan E; Hunt, John G; Pelliccioni, Maurizio; Schlattl, Helmut; Menzel, Hans-Georg

    2014-10-01

    This paper reviews the ICRP Publications 110 and 116 describing the reference computational phantoms and dose conversion coefficients for external exposures. The International Commission on Radiological Protection (ICRP) in its 2007 Recommendations made several revisions to the methods of calculation of the protection quantities. In order to implement these recommendations, the DOCAL task group of the ICRP developed computational phantoms representing the reference adult male and female and then calculated a set of dose conversion coefficients for various types of idealised external exposures. This paper focuses on the dose conversion coefficients for neutrons and investigates their relationship with the conversion coefficients of the protection and operational quantities of ICRP Publication 74. Contributing factors to the differences between these sets of conversion coefficients are discussed in terms of the changes in phantoms employed and the radiation and tissue weighting factors. PMID:24285286

  8. Inhalation reference dose (RfDi): An application of interspecies dosimetry modeling for risk assessment of insoluble particles

    SciTech Connect

    Jarabek, A.M.; Menache, M.G.; Overton, H.; Dourson, M.L.; Miller, F.J.

    1989-01-01

    Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses (the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity) for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of the methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. The paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

  9. Organ doses, effective doses, and risk indices in adult CT: Comparison of four types of reference phantoms across different examination protocols

    SciTech Connect

    Zhang Yakun; Li Xiang; Paul Segars, W.; Samei, Ehsan

    2012-06-15

    Purpose: Radiation exposure from computed tomography (CT) to the public has increased the concern among radiation protection professionals. Being able to accurately assess the radiation dose patients receive during CT procedures is a crucial step in the management of CT dose. Currently, various computational anthropomorphic phantoms are used to assess radiation dose by different research groups. It is desirable to better understand how the dose results are affected by different choices of phantoms. In this study, the authors assessed the uncertainties in CT dose and risk estimation associated with different types of computational phantoms for a selected group of representative CT protocols. Methods: Routinely used CT examinations were categorized into ten body and three neurological examination categories. Organ doses, effective doses, risk indices, and conversion coefficients to effective dose and risk index (k and q factors, respectively) were estimated for these examinations for a clinical CT system (LightSpeed VCT, GE Healthcare). Four methods were used, each employing a different type of reference phantoms. The first and second methods employed a Monte Carlo program previously developed and validated in our laboratory. In the first method, the reference male and female extended cardiac-torso (XCAT) phantoms were used, which were initially created from the Visible Human data and later adjusted to match organ masses defined in ICRP publication 89. In the second method, the reference male and female phantoms described in ICRP publication 110 were used, which were initially developed from tomographic data of two patients and later modified to match ICRP 89 organ masses. The third method employed a commercial dosimetry spreadsheet (ImPACT group, London, England) with its own hermaphrodite stylized phantom. In the fourth method, another widely used dosimetry spreadsheet (CT-Expo, Medizinische Hochschule, Hannover, Germany) was employed together with its associated

  10. Computed organ doses to an Indian reference adult during brachytherapy treatment of esophagus, breast, and neck cancers

    PubMed Central

    Keshavkumar, Biju

    2012-01-01

    This study aims to generate the normalized mean organ dose factors (mGy min-1 GBq-1) to healthy organs during brachytherapy treatment of esophagus, breast, and neck cancers specific to the patient population in India. This study is in continuation to the earlier published studies on the estimation of organ doses during uterus brachytherapy treatments. The results are obtained by Monte Carlo simulation of radiation transport through MIRD type anthropomorphic mathematical phantom representing reference Indian adult with 192Ir and 60Co high dose rate sources in the esophagus, breast, and neck of the phantom. The result of this study is compared with a published computational study using voxel-based phantom model. The variation in the organ dose of this study to the published values is within 50%. PMID:22973082

  11. Long-term stability of liquid ionization chambers with regard to their qualification as local reference dosimeters for low dose-rate absorbed dose measurements in water.

    PubMed

    Bahar-Gogani, J; Grindborg, J E; Johansson, B E; Wickman, G

    2001-03-01

    The long-term sensitivity and calibration stability of liquid ionization chambers (LICs) has been studied at a local and a secondary standards dosimetry laboratory over a period of 3 years. The chambers were transported several times by mail between the two laboratories for measurements. The LICs used in this work are designed for absorbed dose measurements in the dose rate region of 0.1-100 mGy min(-1) and have a liquid layer thickness of 1 mm and a sensitive volume of 16.2 mm3. The liquids used as sensitive media in the chambers are mixtures of isooctane (C8H18) and tetramethylsilane (Si(CH3)4) in different proportions (about 2 to 1). Operating at a polarizing voltage of 300 V the leakage current of the chambers was stable and never exceeded 3% of the observable current at a dose rate of about 1 mGy min(-1). The volume sensitivity of the chambers was measured to be of the order of 10(-9) C Gy(-1) mm3. No systematic changes in the absorbed dose to water calibration was observed for any of the chambers during the test period (sigma < 0.2%). Variations in chamber dose response with small changes in the polarizing voltage as well as sensitivity changes with accumulated absorbed dose were also investigated. Measurements showed that the LIC response varies by 0.15% per 1% change in applied voltage around 300 V. No significant change could be observed in the LIC sensitivity after a single absorbed dose of 15 kGy. The results indicate that the LIC can be made to serve as a calibration transfer instrument and a reference detector for absorbed dose to water determinations providing good precision and long-term reproducibility. PMID:11277221

  12. Applying Pharmacokinetics to Optimize Dosing of Anti-TNF Biologics in Acute Severe Ulcerative Colitis

    PubMed Central

    Rosen, Michael J.; Minar, Philip; Vinks, Alexander A.

    2015-01-01

    Background Acute severe ulcerative colitis (ASUC), the most aggressive presentation ulcerative colitis (UC), occurs in 15 percent of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favorable adverse effect profile. Aim To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics. Methods PubMed and recent conference proceedings were searched using the terms “ulcerative colitis”, “acute severe ulcerative colitis”, “anti-TNF”, “pharmacokinetics”, and the generic names of specific anti-TNF agents. Results Outcomes after anti-TNF therapy for ASUC remain suboptimal with aboutone half of children and adults undergoing colectomy. While several randomized controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due pharmacokinetic mechanisms influenced by disease severity. Conclusions Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with ASUC. Personalized anti-TNF dosing strategies that integratepatient factors and early measures of pharmacokinetics and response hold promise for ensuring sustained drug exposure and maximizing early mucosal healing in patients with ASUC. PMID:25809869

  13. Effect of High Dose of Steroid on Plateletcount in Acute Stage of Dengue Fever with Thrombocytopenia

    PubMed Central

    Shashidhara, K.C.; Murthy, K.A. Sudharshan; Gowdappa, H. Basavana; Bhograj, Abhijith

    2013-01-01

    Background: Dengue infection is the most rapidly spreading mosquito-borne viral disease in the world and an estimated 50 million dengue infections reported annually. The pathogenesis of Thrombocytopenia in dengue fever (DF) is not clearly understood. Increased peripheral destruction of antibody coated platelets and acute bone marrow suppression were strongly suspected as the possible mechanism. This often leads to life threatening dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). Steroids are used in the treatment of Idiopathic thrombocytopenic purpura to increase the platelet count which is mediated by auto antibodies .This hypothesis would support the use of steroids in dengue fever. Aim and Objectives: The objective of this study was to test whether an intravenous high dose dexamethasone was efficacious in increasing the platelet count in acute stage of dengue fever with thrombocytopenia. Methods: During the study period between June 2010 - 2011 in JSS Hospital Mysore, 127 patients were screened for dengue fever with thrombocytopenia (<50000/cumm) and 61patients were randomly allocated, 30 to the study group and 31 to the control group, in an open labeled study. The study group received intravenous dexamethasone 8mg initially followed by 4 mg every 8 h thereafter for 4 days and IV fluids whenever required. The control Group received only IV fluids and antipyretics whenever it was indicated. The daily measurement of platelet count was carried out in all patients from the day of enrolment to the fourth day of post treatment. Results: The baseline data (age, sex, and the mean duration of the illness, Hb%, haematocrit, and platelets) were similar in both the groups. The analysis of variance (ANOVA) statistics showed a significant linear association of the mean platelet counts with the days in either group. The mean platelet counts increased steadily in both the groups from days 1 to 4: day1 (0.687), day2 (0.34), day3 (0.530) and day4 (0.844). There was

  14. Single dose rasburicase in the management of tumor lysis syndrome in childhood acute lymphoblastic leukemia: A case series

    PubMed Central

    Latha, S. M.; Krishnaprasadh, D.; Murugapriya, P.; Scott, J. X.

    2015-01-01

    Tumor lysis syndrome (TLS) occurs in malignancies with high proliferative potential and tumor burden, such as lymphomas and leukemias. TLS syndrome is an oncologic emergency, requiring prompt intervention. The metabolic derangements cause acute kidney failure and may lead to cardiac arrhythmias, seizures, and death. With the advent of rasburicase, a recombinant urate oxidase, there has been a decline in the TLS-mediated renal failure and the need for dialysis. The recommended regimen and doses pose a heavy financial burden for patients in developing countries like India. With data and studies proving a similar efficacy for the reduced dose and lesser number of rasburicase, we report here a case series of seven children with acute leukemias, whose TLS was managed by a single dose of rasburicase. A retrospective analysis of case records of seven children with acute lymphoblastic leukemia and TLS, admitted to our Pediatric Oncology Unit of our Hospital between the period 2011 and 2013, was done. All our patients responded to a single dose, indicating that in appropriately monitored patients, single dose followed by as-needed dosing can be cost-saving. PMID:25838646

  15. Acute effect of high dose (48 mg) of piretanide in advanced renal insufficiency.

    PubMed Central

    Hadj Aissa, A; Pozet, N; Labeeuw, M; Pellet, M; Traeger, J

    1981-01-01

    1 The acute effects of a high dose of piretanide, a new potent diuretic were studied in eight patients with severely impaired renal function (GFR between 0.09 and 0.17 ml s-1 1.73 m-2). 2 After hydration and following two control periods, a single dose of 48 mg piretanide was ingested. Thereafter, urine was collected every 30 min for 2 h and every hour for the next 4 h. Urinary fluid losses were replaced orally (100 ml of water ever hour) and intravenously (isotonic saline + glucose infusion). 3 The following measurements were made: urine flow rate, clearances of inulin, PAH, urea, creatinine, uric acid, osmolar and free water clearances, excretion rates of sodium, chloride, potassium, calcium, phosphate, bicarbonate, ammonium, titratable acidity and urine pH. 4 Piretanide (48 mg) appeared to be effective in advanced renal insufficiency, producing a significant increase in urine flow rate, in sodium, chloride, potassium and calcium excretion and in Cosm. 5 There was no significant change in GFR, as measured by inulin clearance, or in the other measured parameters. PMID:7213511

  16. Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site

    PubMed Central

    Stipanovic, Michelle E.; Hajnal, Andras; Lynch, Christopher J.

    2015-01-01

    Atypical antipsychotics (AAPs), such as olanzapine (OLZ), are associated with metabolic side effects, including hyperglycemia. Although a central mechanism of action for the acute effects on glycemia has been suggested, evidence for peripheral versus central effects of AAPs has been mixed and has not been explored for an effect of OLZ on the respiratory exchange ratio (RER). Here, we tested the hypothesis that some inconsistencies in the glycemic responses are likely a result of different doses and central sites of injection. We also compared the effects of central versus peripherally administered OLZ on the RER of unsedated rats. Third ventricle infusion of OLZ at 0.3 mg/kg caused hyperglycemia within 30 minutes, with a higher dose (1.8 mg/kg) needed to elicit a similar response in the lateral ventricles. In contrast, 3 mg/kg of OLZ was needed to raise blood glucose within 30 minutes when given intragastrically, and 10 mg/kg resulted in a prolonged hyperglycemia lasting at least 60 minutes. Third ventricle injection of OLZ significantly decreased RER after 75 minutes, whereas intragastric OLZ resulted in a faster drop in RER after 30 minutes. Since changes in glycemia were most sensitive when OLZ was infused into the third ventricle, but effects on RER were more rapidly and efficaciously observed when the drug was given peripherally, these results raise the likelihood of a dual mechanism of action involving hypothalamic and peripheral mechanisms. Some discrepancies in the literature arising from central administration appear to result from the injection site and dose. PMID:26740814

  17. Influence of Dose on Risk of Acute Urinary Retention After Iodine-125 Prostate Brachytherapy

    SciTech Connect

    Roeloffzen, Ellen M.A.; Battermann, Jan J.; Deursen, Marijke J.H. van; Monninkhof, Evelyn M.; Visscher, Mareije I.; Moerland, Marinus A.; Vulpen, Marco van

    2011-07-15

    Purpose: To assess the influence of dose on the risk of acute urinary retention (AUR) after iodine-125 prostate brachytherapy. Methods and Materials: Between January 2005 and December 2008, 714 consecutive patients with localized prostate cancer were treated with iodine-125 prostate brachytherapy at our department. All patients completed four imaging studies: magnetic resonance imaging before and 4 weeks after treatment and intraoperative three-dimensional transrectal ultrasonography before and after implantation. The development of AUR was prospectively recorded. The evaluated treatment and dosimetric parameters included prostate volume, number of needles and seeds used, intra- and postoperative prostate edema, percentage of prostate volume receiving 100%, 150%, and 200% of the prescribed dose to the prostate, minimal dose received by 90% of the prostate volume, and percentage of the urethra receiving 100%, 150%, and 200% of the prescribed dose. Logistic regression analysis was used to examine which factors were associated with AUR. Results: Of the 714 patients, 57 (8.0%) developed AUR. On univariate analysis, the following treatment and dosimetric factors were significantly associated with AUR: International Prostate Symptom Score (odds ratio [OR], 2.07, per 10-point increase), preimplant prostate volume (OR, 1.06), postimplant prostate volume (OR, 1.04), number of needles used (OR, 1.09), and number of seeds used (OR, 1.03). On multivariate analysis, the only independent predictive factors for AUR were pretreatment prostate volume (OR, 1.05) and International Prostate Symptom Score (OR, 1.76, per 10-point increase). Patients with a pretreatment prostate volume >35 cm{sup 3} had a 10.4% risk of developing AUR compared with 5.4% for those with a prostate volume of {<=}35 cm{sup 3}. No association was found between any of the dosimetric parameters and the development of AUR. Conclusion: The radiation dose, within the range studied, did not influence the risk of AUR

  18. Acute Effects of Classroom Exercise Breaks on Executive Function and Math Performance: A Dose-Response Study

    ERIC Educational Resources Information Center

    Howie, Erin K.; Schatz, Jeffrey; Pate, Russell R.

    2015-01-01

    Purpose: The purpose of this study was to determine the acute dose-response relationship of classroom exercise breaks with executive function and math performance in 9- to 12-year-old children by comparing 5-min, 10-min, or 20-min classroom exercise breaks to 10 min of sedentary classroom activity. Method: This study used a within-subjects…

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

    EPA Science Inventory

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

  20. Demographic data for urinary Acute Kidney Injury (AKI) marker [IGFBP7]·[TIMP2] reference range determinations.

    PubMed

    Chindarkar, Nandkishor S; Chawla, Lakhmir S; Straseski, Joely A; Jortani, Saeed A; Uettwiller-Geiger, Denise; Orr, Robert R; Kellum, John A; Fitzgerald, Robert L

    2015-12-01

    This data in brief describes characteristics of chronic stable comorbid patients who were included in reference range studies of [IGFBP7]·[TIMP-2] "Reference Intervals of Urinary Acute Kidney Injury (AKI) Markers [IGFBP7]·[TIMP2] in Apparently Healthy Subjects and Chronic Comorbid Subjects without AKI" [1]. In order to determine the specificity of [IGFBP7]·[TIMP-2] for identifying patients at risk of developing AKI we studied a cohort with nine broad classification of disease who did not have AKI. Details regarding the population that was targeted for inclusion in the study are also described. Finally, we present data on the inclusion criteria for the healthy subjects used in this investigation to determine the reference range. PMID:26702417

  1. Intensification of acute Trypanosoma cruzi myocarditis in BALB/c mice pretreated with low doses of cyclophosphamide or gamma irradiation.

    PubMed Central

    Silva, J. S.; Rossi, M. A.

    1990-01-01

    This study was carried out to examine the development of acute myocarditis in Trypanosoma cruzi-infected BALB/c mice after they were treated with low doses of cylophosphamide or gamma irradiation. It has been claimed that, in mice, such treatments temporarily interfere with the host-immune suppressor network, but cause no immunodepression. A severe extensive and diffuse acute myocarditis developed in the treated mice infected with T. cruzi, whereas a slight to moderate focal or occasionally diffuse acute myocarditis developed in control mice infected with T. cruzi. It is very likely that the transient abolition of T-suppressor activity facilitates the anti-myocardium immune response in the acute phase of experimental Chagas' disease in mice. Images Fig. 3 PMID:2138024

  2. Toxic Effects of Tetrabromobisphenol A on Thyroid Hormones in SD Rats and the Derived-reference Dose.

    PubMed

    Yang, Yan; Ni, Wei Wei; Yu, Lin; Cai, Ze; Yu, Yun Jiang

    2016-04-01

    The present study determined the thyroid hormone interference of tetrabromobisphenol A (TBBPA) in Sprague-Dawley (SD) rats, and the derived-reference dose (RfD) of different endpoint effects on mammals based on experimental results and data collection. Based on repeated exposure toxicity tests on mammals and extensive research, the present study used BMDS240 Software to derive a benchmark dose, and analyzed the accuracy and uncertainty, and similarity with other studies. Test results on triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) demonstrated that all the indicators presented a non-monotonous dose-effect relationship clearly, except TSH in male rats exposed to 0-1000 mg/kg BW per day. Therefore, RfDs were derived from different critical effects. In summary, RfD for mammals in the present study was found to be 0.6 mg/kg per day. PMID:27241741

  3. A child presenting with acute renal failure secondary to a high dose of indomethacin: a case report

    PubMed Central

    2009-01-01

    Introduction Acute renal failure caused by nonsteroidal anti-inflammatory drugs administered at therapeutic doses is generally mild, non-anuric and transitory. There are no publications on indomethacin toxicity secondary to high doses in children. The aim of this article is to describe acute renal failure secondary to a high dose of indomethacin in a child and to review an error in a supervised drug prescription and administration system. Case presentation Due to a medication error, a 20-day-old infant in the postoperative period of surgery for Fallot's tetralogy received a dose of 10 mg/kg of indomethacin, 50 to 100 times higher than the therapeutic dose. The child presented with acute, oligo-anuric renal failure requiring treatment with continuous venovenous renal replacement therapy, achieving complete recovery of renal function with no sequelae. Conclusion In order to reduce medication errors in critically ill children, it is necessary to develop a supervised drug prescription and administration system, with controls at various levels. PMID:19192282

  4. Patient grouping for dose surveys and establishment of diagnostic reference levels in paediatric computed tomography.

    PubMed

    Vassileva, J; Rehani, M

    2015-07-01

    There has been confusion in literature on whether paediatric patients should be grouped according to age, weight or other parameters when dealing with dose surveys. The present work aims to suggest a pragmatic approach to achieve reasonable accuracy for performing patient dose surveys in countries with limited resources. The analysis is based on a subset of data collected within the IAEA survey of paediatric computed tomography (CT) doses, involving 82 CT facilities from 32 countries in Asia, Europe, Africa and Latin America. Data for 6115 patients were collected, in 34.5 % of which data for weight were available. The present study suggests that using four age groups, <1, >1-5, >5-10 and >10-15 y, is realistic and pragmatic for dose surveys in less resourced countries and for the establishment of DRLs. To ensure relevant accuracy of results, data for >30 patients in a particular age group should be collected if patient weight is not known. If a smaller sample is used, patient weight should be recorded and the median weight in the sample should be within 5-10 % from the median weight of the sample for which the DRLs were established. Comparison of results from different surveys should always be performed with caution, taking into consideration the way of grouping of paediatric patients. Dose results can be corrected for differences in patient weight/age group. PMID:25836695

  5. Comparison of efficacy and adverse effect profile of high dose versus standard dose atorvastatin in acute ST elevation myocardial infarction patients

    PubMed Central

    Sebastian, Gailin B; Anoop, T M; Thomas, Joby K; George, Raju

    2011-01-01

    Objective To compare the efficacy and adverse effects of high and standard dose atorvastatin in ST elevation myocardial infarction (STEMI) patients. Design A prospective, single-centre, randomised, double blind study. Setting A tertiary care centre in Kerala, India, from January to June 2009. Patients 121 consecutive acute STEMI patients eligible for thrombolytic therapy. Interventions Pharmacological thrombolysis and atorvastatin therapy. Main outcome measures Primary end points were mean change in low density lipoprotein and total cholesterol, serum glutamic pyruvic transaminase (SGPT), creatine phosphokinase (CPK) at 3 months of high dose (80 mg) and standard dose (20 mg) of atorvastatin. Results There was no significant difference in the mean cholesterol levels at 3 months of therapy (mean reduction in total cholesterol and low density lipoprotein cholesterol were 48 mg%, 49 mg% in the 20 mg group compared with 54 mg% and 53 mg%, respectively, in the 80 mg group; p 0.39 and 0.4). There was a significant increase in SGPT at 1 week in the 80 mg group and atorvastatin was stopped in a significantly higher number of patients due to the increase in SGPT and CPK at 1 week in the high dose group (12% and 7% of patients; (p=0.04 and p=0.06, respectively). Conclusion In acute STEMI patients treated with pharmacological thrombolysis, standard dose atorvastatin is equally effective as high dose atorvastatin in terms of reduction in cholesterol, with higher and earlier incidence of asymptomatic SGPT and CPK elevation in the high dose group.

  6. Direction distributions of neutrons and reference values of the personal dose equivalent in workplace fields.

    PubMed

    Luszik-Bhadra, M; Bolognese-Milsztajn, T; Boschung, M; Coeck, M; Curzio, G; d'Errico, F; Fiechtner, A; Lacoste, V; Lindborg, L; Reginatto, M; Schuhmacher, H; Tanner, R; Vanhavere, F

    2007-01-01

    Within the EC project EVIDOS, double-differential (energy and direction) fluence spectra were determined by means of novel direction spectrometers. By folding the spectra with fluence-to-dose equivalent conversion coefficients, contributions to H*(10) for 14 directions, and values of the personal dose equivalent Hp(10) and the effective dose E for 6 directions of a person's orientation in the field were determined. The results of the measurements and calculations obtained within the EVIDOS project in workplace fields in nuclear installations in Europe, i.e., at Krümmel (boiling water reactor and transport cask), at Mol (Venus research reactor and fuel facility Belgonucléaire) and at Ringhals (pressurised reactor and transport cask) are presented. PMID:17369265

  7. Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias

    ClinicalTrials.gov

    2010-09-21

    Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia

  8. Acute severe cardiac failure complicating myocardial infarction. Experience with 100 patients referred for consideration of mechanical left ventricular assistance.

    PubMed Central

    O'Rourke, M F; Chang, V P; Windsor, H M; Shanahan, M X; Hickie, J B; Morgan, J J; Gunning, J F; Seldon, A W; Hall, G V; Michell, G; Goldfarb, D; Harrision, D G

    1975-01-01

    One hundred patients were referred with suspected acute cardiac failure following acute myocardial infarction. The diagnosis was confirmed in 72: 31 of these patients underwent elective medical treatment, with 2 survivors (6%); 41 were accepted for counter pulsation, but 9 died before this could be initiated and another 2 died shortly after vain attempts to pass the balloon catheter were abandoned; 30 patients underwent counterpulsation with 14 hospital survivors (47%). Survivor status was usually good. Results of counter pulsation were better in patients who were not shocked (with 5/5 survivors) than in those who were in shock (with 9 of 25 survivors). Results support the view that counterpulsation (alone or combined with corrective surgery) may play an important role in the complications of myocardial infarction provided intervention is early. PMID:1078977

  9. Calculated organ doses using Monte Carlo simulations in a reference male phantom undergoing HDR brachytherapy applied to localized prostate carcinoma

    SciTech Connect

    Candela-Juan, Cristian; Perez-Calatayud, Jose; Ballester, Facundo; Rivard, Mark J.

    2013-03-15

    Purpose: The aim of this study was to obtain equivalent doses in radiosensitive organs (aside from the bladder and rectum) when applying high-dose-rate (HDR) brachytherapy to a localized prostate carcinoma using {sup 60}Co or {sup 192}Ir sources. These data are compared with results in a water phantom and with expected values in an infinite water medium. A comparison with reported values from proton therapy and intensity-modulated radiation therapy (IMRT) is also provided. Methods: Monte Carlo simulations in Geant4 were performed using a voxelized phantom described in International Commission on Radiological Protection (ICRP) Publication 110, which reproduces masses and shapes from an adult reference man defined in ICRP Publication 89. Point sources of {sup 60}Co or {sup 192}Ir with photon energy spectra corresponding to those exiting their capsules were placed in the center of the prostate, and equivalent doses per clinical absorbed dose in this target organ were obtained in several radiosensitive organs. Values were corrected to account for clinical circumstances with the source located at various positions with differing dwell times throughout the prostate. This was repeated for a homogeneous water phantom. Results: For the nearest organs considered (bladder, rectum, testes, small intestine, and colon), equivalent doses given by {sup 60}Co source were smaller (8%-19%) than from {sup 192}Ir. However, as the distance increases, the more penetrating gamma rays produced by {sup 60}Co deliver higher organ equivalent doses. The overall result is that effective dose per clinical absorbed dose from a {sup 60}Co source (11.1 mSv/Gy) is lower than from a {sup 192}Ir source (13.2 mSv/Gy). On the other hand, equivalent doses were the same in the tissue and the homogeneous water phantom for those soft tissues closer to the prostate than about 30 cm. As the distance increased, the differences of photoelectric effect in water and soft tissue, and appearance of other materials

  10. Evidence of dose saving in routine CT practice using iterative reconstruction derived from a national diagnostic reference level survey

    PubMed Central

    Hayton, A; Beveridge, T; Marks, P; Wallace, A

    2015-01-01

    Objective: To assess the influence and significance of the use of iterative reconstruction (IR) algorithms on patient dose in CT in Australia. Methods: We examined survey data submitted to the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) National Diagnostic Reference Level Service (NDRLS) during 2013 and 2014. We compared median survey dose metrics with categorization by scan region and use of IR. Results: The use of IR results in a reduction in volume CT dose index of between 17% and 44% and a reduction in dose–length product of between 14% and 34% depending on the specific scan region. The reduction was highly significant (p < 0.001, Wilcoxon rank-sum test) for all six scan regions included in the NDRLS. Overall, 69% (806/1167) of surveys included in the analysis used IR. Conclusion: The use of IR in CT is achieving dose savings of 20–30% in routine practice in Australia. IR appears to be widely used by participants in the ARPANSA NDRLS with approximately 70% of surveys submitted employing this technique. Advances in knowledge: This study examines the impact of the use of IR on patient dose in CT on a national scale. PMID:26133224

  11. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area

    PubMed Central

    García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

    2015-01-01

    Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

  12. Acute and repeated doses (28 days) oral toxicity study of glycosides based standardized fenugreek seed extract in laboratory mice.

    PubMed

    Kandhare, Amit D; Bodhankar, Subhash L; Mohan, V; Thakurdesai, Prasad A

    2015-07-01

    The objective of the present work was to study acute and subacute (28-days repeated dose) oral toxicity effect of glycosides based standardized fenugreek seed extract (SFSE-G) in vivo. SFSE-G was prepared by resin-based chromatography and standardized to glycosides namely trigoneoside Ib (76%) and vicenin 1 (15%). The acute oral toxicity (AOT) and subacute toxicity studies were performed in Swiss albino mice (5 mice/sex/group) as per OECD 425 (up-and-down procedure) and OCED 407 guidelines respectively. Acute oral administration of 5000mg/kg of SFSE-G showed 40% mortality with no mortality in lower dosages. The subacute oral administration of SFSE-G did not show observational or toxicological effects on the body or organ weights, food consumption, ophthalmic effects, locomotor activity, hematology, blood biochemistry, urinalysis, or histopathology at dose 250mg/kg. However, SFSE-G (1000mg/kg) showed mortality and minor alterations to body weight, relative liver weights, hematology and blood chemistry parameters related to treatment but it was within normal laboratory ranges. In conclusion, SFSE-G showed median lethal dose (LD50) more than 4350mg/kg and no-observed adverse effect levels (NOAEL) of 250mg/kg for both sexes during AOT and sub-acute toxicity study, respectively. PMID:25979642

  13. Acute Hematological Effects in Mice Exposed to the Expected Doses, Dose-rates, and Energies of Solar Particle Event-like Proton Radiation

    PubMed Central

    Sanzari, Jenine K.; Cengel, Keith A.; Wan, X. Steven; Rusek, Adam; Kennedy, Ann R.

    2014-01-01

    NASA has funded several projects that have provided evidence for the radiation risk in space. One radiation concern arises from solar particle event (SPE) radiation, which is composed of energetic electrons, protons, alpha particles and heavier particles. SPEs are unpredictable and the accompanying SPE radiation can place astronauts at risk of blood cell death, contributing to a weakened immune system and increased susceptibility to infection. The doses, dose rates, and energies of the proton radiation expected to occur during a SPE have been simulated at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, delivering total body doses to mice. Hematological values were evaluated at acute time points, up to 24 hrs. post-radiation exposure. PMID:25202654

  14. Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: Investigating dose-volume relationships and role for inverse planning

    SciTech Connect

    Tho, Lye Mun . E-mail: l.tho@beatson.gla.ac.uk; Glegg, Martin; Paterson, Jennifer; Yap, Christina; MacLeod, Alice; McCabe, Marie; McDonald, Alexander C.

    2006-10-01

    Purpose: The relationship between volume of irradiated small bowel (VSB) and acute toxicity in rectal cancer radiotherapy is poorly quantified, particularly in patients receiving concurrent preoperative chemoradiotherapy. Using treatment planning data, we studied a series of such patients. Methods and Materials: Details of 41 patients with locally advanced rectal cancer were reviewed. All received 45 Gy in 25 fractions over 5 weeks, 3-4 fields three-dimensional conformal radiotherapy with daily 5-fluorouracil and folinic acid during Weeks 1 and 5. Toxicity was assessed prospectively in a weekly clinic. Using computed tomography planning software, the VSB was determined at 5 Gy dose intervals (V{sub 5}, V{sub 1}, etc.). Eight patients with maximal VSB had dosimetry and radiobiological modeling outcomes compared between inverse and conformal three-dimensional planning. Results: VSB correlated strongly with diarrheal severity at every dose level (p < 0.03), with strongest correlation at lowest doses. Median VSB differed significantly between patients experiencing Grade 0-1 and Grade 2-4 diarrhea (p {<=} 0.05). No correlation was found with anorexia, nausea, vomiting, abdominal cramps, age, body mass index, sex, tumor position, or number of fields. Analysis of 8 patients showed that inverse planning reduced median dose to small bowel by 5.1 Gy (p = 0.008) and calculated late normal tissue complication probability (NTCP) by 67% (p = 0.016). We constructed a model using mathematical analysis to predict for acute diarrhea occurring at V{sub 5} and V{sub 15}. Conclusions: A strong dose-volume relationship exists between VSB and acute diarrhea at all dose levels during preoperative chemoradiotherapy. Our constructed model may be useful in predicting toxicity, and this has been derived without the confounding influence of surgical excision on bowel function. Inverse planning can reduce calculated dose to small bowel and late NTCP, and its clinical role warrants further

  15. Cancer risks after diagnostic doses of 131I with special reference to thyroid cancer

    SciTech Connect

    Holm, L.E. )

    1991-01-01

    Between 1951 and 1969 a total of 35,074 patients less than 75 years of age (mean = 44 years) were examined with diagnostic doses of 131I. The mean administered activity of 131I was 52 microCi and the radiation dose to the thyroid gland was on the average of 0.5 Gy. The cohort was matched with the Swedish Cancer Register for the years 1958-1984. During this period, 3746 cancers occurred more than 5 years after the 131I examination, and the resulting standardized incidence ratio (SIR) was 1.01 (95% confidence interval (CI) = 0.98 to 1.04). SIR for thyroid cancer was 1.18 (95% CI = 0.88 to 1.56). The risks for both cancer of all sites and for thyroid cancer were highest 5 to 9 years after examination (SIR = 1.07 and 2.06, respectively) and did not differ from unity thereafter. With greater than or equal to 10 years of follow-up, risk was not statistically associated with the dose of 131I.

  16. Estimation of potential health effects from acute exposure to hydrogen fluoride using a "benchmark dose" approach.

    PubMed

    Alexeeff, G V; Lewis, D C; Ragle, N L

    1993-02-01

    Communities across the United States are examining the manufacture, use, transport, and storage of hydrogen fluoride (HF) near residential areas as a consequence of a major release of HF in Texas in 1987. Reference exposure levels for routine and accidental HF emissions are calculated using existing animal and human data. The approach employs a log-probit extrapolation of concentration-response data to the 95% lower confidence limit on the toxic concentration producing a "benchmark dose" of 1% response (TC01), called a practical threshold. Species-specific and chemical-specific adjustment factors are applied to develop exposure levels applicable to the general public. Using this method, the 1-hr reference exposure level to protect the public against any irritation from a routine emission (REL-1) is 0.7 ppm and the level to protect against severe irritation from a once-in-a-lifetime (REL-2) release is 2 ppm. This approach is compared to a modified "uncertainty factor" approach. PMID:8451461

  17. Oral Reference Dose for ethylene glycol based on oxalate crystal-induced renal tubule degeneration as the critical effect

    SciTech Connect

    Snellings, William M.; Corley, Richard A.; McMartin, K. E.; Kirman, Christopher R.; Bobst, Sol M.

    2013-03-31

    Several risk assessments have been conducted for ethylene glycol (EG). These assessments identified the kidney as the primary target organ for chronic effects. None of these assessments have incorporated the robust database of species-specific toxicokinetic and toxicodynamic studies with EG and its metabolites in defining uncertainty factors used in reference value derivation. Pertinent in vitro and in vivo studies related to one of these metabolites, calcium oxalate, and its role in crystal-induced nephropathy are summarized, and the weight of evidence to establish the mode of action for renal toxicity is reviewed. Previous risk assessments were based on chronic rat studies using a strain of rat that was later determined to be less sensitive to the toxic effects of EG. A recently published 12-month rat study using the more sensitive strain (Wistar) was selected to determine the point of departure for a new risk assessment. This approach incorporated toxicokinetic and toxicodynamic data and used Benchmark Dose methods to calculate a Human Equivalent Dose. Uncertainty factors were chosen, depending on the quality of the studies available, the extent of the database, and scientific judgment. The Reference Dose for long-term repeat oral exposure to EG was determined to be 15 mg/kg bw/d.

  18. Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats.

    PubMed

    Braniste, Viorica; Jouault, Aurore; Gaultier, Eric; Polizzi, Arnaud; Buisson-Brenac, Claire; Leveque, Mathilde; Martin, Pascal G; Theodorou, Vassilia; Fioramonti, Jean; Houdeau, Eric

    2010-01-01

    Bisphenol A (BPA), a chemical estrogen widely used in the food-packaging industry and baby bottles, is recovered in human fluids (0.1-10 nM). Recent studies have reported that BPA is hormonally active at low doses, emphasizing the debate of a risk for human health. Estrogen receptors are expressed in the colon, and although the major route of BPA exposure is food, the effects on gut have received no attention. We first examined the endocrine disrupting potency of BPA on colonic paracellular permeability (CPP), experimental colitis, and visceral sensitivity in ovariectomized rats orally exposed to 5 mg/kg/d BPA (i.e., the no observed adverse effect level), 50 microg/kg/d BPA (i.e., tolerable daily intake), or lower doses. BPA dose-dependently decreased basal CPP, with a half-maximal inhibitory dose of 5.2 microg/kg/d, 10-fold below the tolerable daily intake. This correlated with an increase in epithelial tight junction sealing, also observed in Caco-2 cells exposed to 10 nM BPA. When ovariectomized rats were fed with BPA at the no observed adverse effect level, the severity of colitis was reduced, whereas the same dose increased pain sensitivity to colorectal stimuli. We then examined the impact of perinatal exposure to BPA on intestinal permeability and inflammatory response in the offspring. In female rats, but not in male rats, perinatal BPA evoked a decrease of CPP in adulthood, whereas the proinflammatory response of colonic mucosa was strengthened. This study first demonstrates that the xenoestrogen BPA at reference doses influences intestinal barrier function and gut nociception. Moreover, perinatal exposure promotes the development of severe inflammation in adult female offspring only. PMID:20018722

  19. The effects of an acute dose of Rhodiola rosea on endurance exercise performance.

    PubMed

    Noreen, Eric E; Buckley, James G; Lewis, Stephanie L; Brandauer, Josef; Stuempfle, Kristin J

    2013-03-01

    The purpose of this study was to determine the effects of an acute oral dose of 3 mg·kg(-1) of Rhodiola rosea on endurance exercise performance, perceived exertion, mood, and cognitive function. Subjects (n = 18) ingested either R. rosea or a carbohydrate placebo 1 hour before testing in a double-blind, random crossover manner. Exercise testing consisted of a standardized 10-minute warm-up followed by a 6-mile time trial (TT) on a bicycle ergometer. Rating of perceived exertion (RPE) was measured every 5 minutes during the TT using a 10-point Borg scale. Blood lactate concentration, salivary cortisol, and salivary alpha amylase were measured before warm-up, 2 minutes after warm-up, and 2 minutes after TT (n = 15). A Profile of Mood States questionnaire and a Stroop Color Test were completed before warm-up and after TT. Testing was repeated 2-7 days later with the other condition. Rhodiola rosea ingestion significantly decreased heart rate during the standardized warm-up (R. rosea = 136 ± 17 b·min(-1); placebo = 140 ± 17 b·min(-1); mean ± SD; p = 0.001). Subjects completed the TT significantly faster after R. rosea ingestion (R. rosea = 25.4 ± 2.7 minutes; placebo = 25.8 ± 3.0 minutes; p = 0.037). The mean RPE was lower in the R. rosea trial (R. rosea = 6.0 ± 0.9; placebo = 6.6 ± 1.0; p = 0.04). This difference was even more pronounced when a ratio of the RPE relative to the workload was calculated (R. rosea = 0.048 ± 0.01; placebo = 0.057 ± 0.02; p = 0.007). No other statistically significant differences were observed. Acute R. rosea ingestion decreases heart rate response to submaximal exercise and appears to improve endurance exercise performance by decreasing the perception of effort. PMID:23443221

  20. Bladder (ICRU) dose point does not predict urinary acute toxicity in adjuvant isolated vaginal vault high-dose-rate brachytherapy for intermediate-risk endometrial cancer

    PubMed Central

    Aiza, Antonio; Gomes, Maria José Leite; Chen, Michael Jenwei; Pellizzon, Antonio Cassio de Assis; Mansur, David B.; Baiocchi, Glauco

    2015-01-01

    Purpose High-dose-rate brachytherapy (HDR-BT) alone is an adjuvant treatment option for stage I intermediaterisk endometrial cancer after complete surgical resection. The aim of this study was to determine the value of the dose reported to ICRU bladder point in predicting acute urinary toxicity. Oncologic results are also presented. Material and methods One hundred twenty-six patients were treated with postoperative HDR-BT 24 Gy (4 × 6 Gy) per ICRU guidelines for dose reporting. Cox analysis was used to identify variables that affected local control. The mean bladder point dose was examined for its ability to predict acute urinary toxicity. Results Two patients (1.6%) developed grade 1 gastrointestinal toxicity and 12 patients (9.5%) developed grades 1-2 urinary toxicity. No grade 3 or greater toxicity was observed. The mean bladder point dose was 46.9% (11.256 Gy) and 49.8% (11.952 Gy) for the asymptomatic and symptomatic groups, respectively (p = 0.69). After a median follow-up of 36.8 months, the 3-year local failure and 5-year cancer-specific and overall survival rates were 2.1%, 100%, and 94.6%, respectively. No pelvic failure was seen in this cohort. Age over 60 years (p = 0.48), lymphatic invasion (p = 0.77), FIGO histological grade (p = 0.76), isthmus invasion (p = 0.68), and applicator type (cylinder × ovoid) (p = 0.82) did not significantly affect local control. Conclusions In this retrospective study, ICRU bladder point did not correlate with urinary toxicity. Four fractions of 6 Gy HDR-BT effected satisfactory local control, with acceptable urinary and gastrointestinal toxicity. PMID:26622241

  1. Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease.

    PubMed

    Matsumura-Kimoto, Yayoi; Inamoto, Yoshihiro; Tajima, Kinuko; Kawajiri, Akihisa; Tanaka, Takashi; Hirakawa, Tsuneaki; Ino, Kazuko; Asao, Yu; Tamogami, Hiroyuki; Kono, Chika; Takeda, Wataru; Okinaka, Keiji; Fuji, Shigeo; Kurosawa, Saiko; Kim, Sung-Won; Tanosaki, Ryuji; Yamashita, Takuya; Fukuda, Takahiro

    2016-06-01

    This study aimed to characterize the incidence and risk factors of invasive fungal disease, cytomegalovirus infection, other viral diseases, and gram-negative rod infection after glucocorticoid treatment for severe acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation and to elucidate the associations of cumulative steroid dose with the risks of individual infections. The study cohort included 91 consecutive patients who developed maximum grades III and IV acute GVHD at our center. The mean cumulative prednisolone-equivalent dose was 41 mg/kg during the first 4 weeks. The cumulative incidence rates of fungal disease, cytomegalovirus disease, other viral diseases, and gram-negative rod infection at 6 months after glucocorticoid treatment were remarkably high, at 14%, 21%, 28%, and 20%, respectively. GVHD within 26 days after transplantation and low lymphocyte count at GVHD treatment were associated with increased risks of several infections. Cumulative prednisolone-equivalent steroid doses ≥ 55 mg/kg during the first 4 weeks were associated with an increased risk of fungal disease (hazard ratio, 3.65; P = .03) and cumulative doses ≥ 23 mg/kg were associated with an increased risk of non-cytomegalovirus viral diseases (hazard ratio, 4.14; P = .02). Strategies to reduce the risk of infectious complications are needed, particularly for patients who have risk factors and those who receive high cumulative steroid doses. PMID:26968790

  2. Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

    EPA Science Inventory

    Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

  3. Local patient dose diagnostic reference levels in pediatric interventional cardiology in Chile using age bands and patient weight values

    SciTech Connect

    Ubeda, Carlos; Miranda, Patricia; Vano, Eliseo

    2015-02-15

    Purpose: To present the results of a patient dose evaluation program in pediatric cardiology and propose local diagnostic reference levels (DRLs) for different types of procedure and age range, in addition to suggesting approaches to correlate patient dose values with patient weight. This study was the first conducted in Latin America for pediatric interventional cardiology under the auspices of the International Atomic Energy Agency. Methods: Over three years, the following data regarding demographic and patient dose values were collected: age, gender, weight, height, number of cine series, total number of cine frames, fluoroscopy time (FT), and two dosimetric quantities, dose-area product (DAP) and cumulative dose (CD), at the patient entrance reference point. The third quartile values for FT, DAP, CD, number of cine series, and the DAP/body weight ratio were proposed as the set of quantities to use as local DRLs. Results: Five hundred and seventeen patients were divided into four age groups. Sample sizes by age group were 120 for <1 yr; 213 for 1 to <5 yr; 82 for 5 to <10 yr; and 102 for 10 to <16 yr. The third quartile values obtained for DAP by diagnostic and therapeutic procedures and age range were 1.17 and 1.11 Gy cm{sup 2} for <1 yr; 1.74 and 1.90 Gy cm{sup 2} for 1 to <5 yr; 2.83 and 3.22 Gy cm{sup 2} for 5 to <10 yr; and 7.34 and 8.68 Gy cm{sup 2} for 10 to <16 yr, respectively. The third quartile value obtained for the DAP/body weight ratio for the full sample of procedures was 0.17 (Gy cm{sup 2}/kg) for diagnostic and therapeutic procedures. Conclusions: The data presented in this paper are an initial attempt at establishing local DRLs in pediatric interventional cardiology, from a large sample of procedures for the standard age bands used in Europe, complemented with the values of the ratio between DAP and patient weight. This permits a rough estimate of DRLs for different patient weights and the refining of these values for the age bands when there

  4. Meta-analysis of high doses of ambroxol treatment for acute lung injury/acute respiratory distress syndrome based on randomized controlled trials.

    PubMed

    Wu, Xiangdong; Li, Suwei; Zhang, Jiuzhi; Zhang, Yongli; Han, Lili; Deng, Qiuming; Wan, Xianyao

    2014-11-01

    This study seeks to evaluate the potential benefits of high doses of ambroxol treatment for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) by conducting a meta-analysis based on randomized controlled trials (RCTs). We searched the Pubmed, Embase, China National Knowledge Infrastructure, and Wanfang databases through December 2013. Only RCTs evaluating high doses of ambroxol (≥15 mg/kg or 1000 mg/day) treatment for patients with ALI/ARDS were selected. We included 10 RCTs involving 508 patients. Adjuvant treatment with high doses of ambroxol increased PaO(2)/FiO(2) (weight mean differences [WMD] = 69.18, 95% confidence intervals [CI]: 41.71-96.65), PO(2) (WMD = 11.74, 95% CI: 8.50-14.99), and SaO(2) (WMD = 2.15, 95% CI: 1.60-2.71) compared with usual treatment. Treatment with high doses of ambroxol appeared to reduce serum tumor necrosis factor-α level (WMD -7.92 µg/L; 95% CI, -10.94 to -4.9) and interleukin-6 level (WMD = -20.65 µg/L, 95% CI: -24.74 to -16.55) and to increase serum superoxide dismutase level (WMD = 19.07 NU/mL, 95% CI: 6.16-31.97). The findings suggest that treatment with high doses of ambroxol appears to improve PaO(2)/FiO(2), PO(2), and SaO(2), and the benefits might be related to ambroxol's anti-oxidant and anti-inflammatory properties. PMID:25174313

  5. A high throughput passive dosing format for the Fish Embryo Acute Toxicity test.

    PubMed

    Vergauwen, Lucia; Schmidt, Stine N; Stinckens, Evelyn; Maho, Walid; Blust, Ronny; Mayer, Philipp; Covaci, Adrian; Knapen, Dries

    2015-11-01

    High throughput testing according to the Fish Embryo Acute Toxicity (FET) test (OECD Testing Guideline 236) is usually conducted in well plates. In the case of hydrophobic test substances, sorptive and evaporative losses often result in declining and poorly controlled exposure conditions. Therefore, our objective was to improve exposure conditions in FET tests by evaluating a passive dosing format using silicone O-rings in standard 24-well polystyrene plates. We exposed zebrafish embryos to a series of phenanthrene concentrations until 120h post fertilization (hpf), and obtained a linear dilution series. We report effect values for both mortality and sublethal morphological effects based on (1) measured exposure concentrations, (2) (lipid normalized) body residues and (3) chemical activity. The LC50 for 120hpf was 310μg/L, CBR50 (critical body residue) was 2.72mmol/kg fresh wt and La50 (lethal chemical activity) was 0.047. All values were within ranges expected for baseline toxicity. Impaired swim bladder inflation was the most pronounced morphological effect and swimming activity was reduced in all exposure concentrations. Further analysis showed that the effect on swimming activity was not attributed to impaired swim bladder inflation, but rather to baseline toxicity. We conclude that silicone O-rings (1) produce a linear dilution series of phenanthrene in the 120hpf FET test, (2) generate and maintain aqueous concentrations for reliable determination of effect concentrations, and allow for obtaining mechanistic toxicity information, and (3) cause no toxicity, demonstrating its potential as an extension of the FET test when testing hydrophobic chemicals. PMID:26026258

  6. Reference computations of public dose and cancer risk from airborne releases of plutonium. Nuclear safety technical report

    SciTech Connect

    Peterson, V.L.

    1993-12-23

    This report presents results of computations of doses and the associated health risks of postulated accidental atmospheric releases from the Rocky Flats Plant (RFP) of one gram of weapons-grade plutonium in a form that is respirable. These computations are intended to be reference computations that can be used to evaluate a variety of accident scenarios by scaling the dose and health risk results presented here according to the amount of plutonium postulated to be released, instead of repeating the computations for each scenario. The MACCS2 code has been used as the basis of these computations. The basis and capabilities of MACCS2 are summarized, the parameters used in the evaluations are discussed, and results are presented for the doses and health risks to the public, both the Maximum Offsite Individual (a maximally exposed individual at or beyond the plant boundaries) and the population within 50 miles of RFP. A number of different weather scenarios are evaluated, including constant weather conditions and observed weather for 1990, 1991, and 1992. The isotopic mix of weapons-grade plutonium will change as it ages, the {sup 241}Pu decaying into {sup 241}Am. The {sup 241}Am reaches a peak concentration after about 72 years. The doses to the bone surface, liver, and whole body will increase slightly but the dose to the lungs will decrease slightly. The overall cancer risk will show almost no change over this period. This change in cancer risk is much smaller than the year-to-year variations in cancer risk due to weather. Finally, x/Q values are also presented for other applications, such as for hazardous chemical releases. These include the x/Q values for the MOI, for a collocated worker at 100 meters downwind of an accident site, and the x/Q value integrated over the population out to 50 miles.

  7. Derived reference doses for three compounds used in the photovoltaics industry: Copper indium diselenide, copper gallium diselenide, and cadmium telluride

    SciTech Connect

    Moskowitz, P.D.; Bernholc, N.; DePhillips, M.P.; Viren, J.

    1995-07-06

    Polycrystalline thin-film photovoltaic modules made from copper indium diselenide (CIS), copper gallium diselenide (CGS), and cadmium telluride (CdTe) arc nearing commercial development. A wide range of issues are being examined as these materials move from the laboratory to large-scale production facilities to ensure their commercial success. Issues of traditional interest include module efficiency, stability and cost. More recently, there is increased focus given to environmental, health and safety issues surrounding the commercialization of these same devices. An examination of the toxicological properties of these materials, and their chemical parents is fundamental to this discussion. Chemicals that can present large hazards to human health or the environment are regulated often more strictly than those that are less hazardous. Stricter control over how these materials are handled and disposed can increase the costs associated with the production and use of these modules dramatically. Similarly, public perception can be strongly influenced by the inherent biological hazard that these materials possess. Thus, this report: presents a brief background tutorial on how toxicological data are developed and used; overviews the toxicological data available for CIS, CGS and CdTe; develops ``reference doses`` for each of these compounds; compares the reference doses for these compounds with those of their parents; discusses the implications of these findings to photovoltaics industry.

  8. Evaluation of alanine as a reference dosimeter for therapy level dose comparisons in megavoltage electron beams

    NASA Astrophysics Data System (ADS)

    McEwen, Malcolm; Sharpe, Peter; Vörös, Sándor

    2015-04-01

    When comparing absorbed dose standards from different laboratories (e.g. National Measurement Institutes, NMIs, for Key or Supplementary comparisons) it is rarely possible to carry out a direct comparison of primary standard instruments, and therefore some form of transfer detector is required. Historically, air-filled, unsealed ionization chambers have been used because of the long history of using these instruments, very good stability over many years, and ease of transport. However, the use of ion chambers for therapy-level comparisons is not without its problems. Findings from recent investigations suggest that ion chambers are prone to non-random variations, they are not completely robust to standard courier practices, and failure at any step in a comparison can render all measurements potentially useless. An alternative approach is to identify a transfer system that is insensitive to some of these concerns—effectively a dosimeter that is inexpensive, simple to use, robust, but with sufficient precision and of a size relevant to the disseminated quantity in question. The alanine dosimetry system has been successfully used in a number of situations as an audit dosimeter and therefore the purpose of this investigation was to determine whether alanine could also be used as the transfer detector for dosimetric comparisons, which require a lower value for the measurement uncertainty. A measurement protocol was developed for comparing primary standards of absorbed dose to water in high-energy electron beams using alanine pellets irradiated in a water-equivalent plastic phantom. A trial comparison has been carried out between three NMIs and has indicated that alanine is a suitable alternative to ion chambers, with the system used achieving a precision of 0.1%. Although the focus of the evaluation was on the performance of the dosimeter, the comparison results are encouraging, showing agreement at the level of the combined uncertainties (~0.6%). Based on this

  9. The Comparison of Apotel plus Low Dose of Morphine and Full Dose of Morphine in Pain Relief in Patients with Acute Renal Colic

    PubMed Central

    Morteza-Bagi, Hamid Reza; Amjadi, Mohsen; Mirzaii-Sousefidi, Reyhaneh

    2015-01-01

    Background Renal colic is an acute flank pain which may radiate to the groin, lower abdomen, or external genitalia due to the passage of a urinary stones. Pain management is the most important task in emergency wards when a patient with renal colic attends. This study aims to compare intravenous acetaminophen plus a low dose of morphine with a full dose of morphine in renal colic. Methods In present randomized clinical trial, 100 patients with confirmed renal colic were recruited from the Emergency Ward of Imam Reza Teaching Hospital affiliated to Tabriz University of Medical Sciences, Iran, during a one-year period. These patients randomly received either intravenous acetaminophen (Apotel, 1 g) plus a low dose of morphine (n = 50), or a high dose of morphine (5 mg) (n = 50). Visual analogue scale (VAS) was used for reporting pain during 35 minutes. Side effects and rescue analgesic demand were recorded after 30 minutes. Findings The two groups were matched for the patients' age and gender. Intra-group analysis showed significant gradual decreases in pain intensity after 35 minutes for both groups. Inter-group analysis, however, did not show a significant difference between the two groups in this regard. There was no significant difference between the two groups in terms of side effects. The rate of rescue analgesic demand was 36% in the first and 40% in the second group (P = 0.68). Conclusion According to the results study, Apotel plus a low dose of morphine is at least as effective and safe as a full dose of morphine in patients with renal colic. PMID:26322213

  10. ACUTE, 14-DAY REPEATED DOSING, AND 90-DAY SUBCHRONIC TOXICITY STUDIES OF POTASSIUM PICLORAM (JOURNAL VERSION)

    EPA Science Inventory

    Potassium picloram was administered either by gavage (acute studies) or in drinking water to male and female Sprague-Dawley derived rats (14-day and 90-day studies). The acute oral LD50 was 950 mg/kg (812-1120) for males and 686 mg/kg (599-786) for females. Depression, prostratio...

  11. [Retrospective Cytogenetic Dose Evaluation. I. Chromosome Aberration Levels in Remote Periods after Acute External Exposure in Different Situations].

    PubMed

    Nugs, V Yu; Khvostunov, I K; Goloub, E V; Kozlova, M G; Nadejina, N M; Galstian, I A

    2015-01-01

    Cytogenetic analysis of peripheral blood lymphocyte cultures of 22 persons was performed in remote terms after acute external γ-, γ-β- or γ-neutron irradiation as a result of various accidents using the classical me- thod. The initial dose estimates were obtained using physical calculations, the method of measuring the EPR signal in tooth enamel, according to haematological and/or cytogenetic parameters. The purpose of this study was to obtain evidence about the state of the lymphocyte chromosome apparatus of people approxi- mately 17-50 years after an accidental radiation exposure. In general, elevated levels of chromosome aberra- tions were detected. An average correlation was observed between the atypical chromosome frequency and absorbed dose. It is proposed to use the obtained results in the future to explore the possibility of retrospective dose evaluation on the basis of a special computer program. PMID:26601536

  12. Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-08-01

    The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0

  13. Bacteremia complicating acute leukemia with special reference to its incidence and changing etiological patterns.

    PubMed

    Funada, H; Machi, T; Matsuda, T

    1988-09-01

    Over the 15-yr period, 1972-1986, 194 episodes of bacteremia occurred in 132 patients with acute leukemia at the Third Department of Medicine, Kanazawa University Hospital, giving an incidence of 478 episodes per 1,000 hospital admissions. This incidence was at least twice as high as that in patients with chronic leukemia, malignant lymphoma, multiple myeloma or aplastic anemia, and about 40-fold higher than that in patients with all other internal diseases. The rate of occurrence of bacteremia, whether unimicrobial or polymicrobial, remained almost unchanged throughout the study period. The frequency of gram-negative bacilli decreased significantly, however, from 81% of the total isolates for the first 10-yr period to 50% for the second 5-yr period. Escherichia coli and Klebsiella pneumoniae were isolated in markedly decreasing frequency, but Pseudomonas aeruginosa and Enterobacter cloacae in relatively constant frequency. The majority of P. aeruginosa isolates belonged to a limited number of O-antigen groups, suggesting the possibility of nosocomial infection. On the other hand, the frequency of gram-positive cocci increased from 9 to 36%. Staphylococcus epidermidis, Enterococcus species, and Staphylococcus aureus emerged as important pathogens. Such a change in the spectrum of organisms was considered to coincide with the common use of the so-called second- and third-generation cephalosporins and central venous catheters. It is thus suggested that vancomycin be added to empiric antibiotic therapy, especially when gram-positive infections are clinically or microbiologically suspected, and that reducing the acquisition of P. aeruginosa from the hospital environment remains a priority in infection prevention. PMID:3411788

  14. Acute effects of low and high dose alcohol on smoking lapse behavior in a laboratory analogue task

    PubMed Central

    Kahler, Christopher W.; Metrik, Jane; Spillane, Nichea S.; Day, Anne; Leventhal, Adam M.; McKee, Sherry A.; Tidey, Jennifer W.; McGeary, John E.; Knopik, Valerie S.; Rohsenow, Damaris J.

    2014-01-01

    Rationale Smoking lapses (i.e., returns to smoking after quitting) often occur following alcohol consumption with observational data suggesting greater quantities of alcohol lead to greater risk. However, a causal dose-dependent effect of alcohol consumption on smoking lapse behavior has not been established, and the mechanisms that might account for such an effect have not been tested. Objectives In a within-subjects design, we examined effects of low (0.4 g/kg) and high (0.8 g/kg) dose alcohol, relative to placebo, on smokers’ ability to resist initiating smoking after acute smoking abstinence. Methods Participants were 100 heavy alcohol drinkers, smoking 10–30 cigarettes per day. Across three separate days, participants consumed placebo, low, or high dose alcohol following 3 h of smoking abstinence, and 35 min later were offered the opportunity to smoke while resisting smoking was monetarily reinforced proportional to the amount of time delayed. Results Consistent with a dose-response effect, participants smoked 3.35 min (95% CI [−7.09, 0.40], p=.08) earlier following low dose alcohol and 6.36 min (95% CI [−9.99, −2.73], p=.0006) earlier following high dose alcohol compared to drinking a placebo beverage. Effects of dose on smoking behavior were partially mediated by increases in urge to smoke. There was no evidence that alcohol’s effects on urge to smoke or ability to resist smoking were mediated through its stimulating or sedating effects. Conclusions Alcohol can reduce the ability to resist smoking in a dose-dependent fashion, in part, due to its effect on increasing the intensity of smoking urges. PMID:24858377

  15. Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

    SciTech Connect

    Komatsu, K.; Takada, G.; Uemura, K.; Shishido, F.; Kanno, I. )

    1990-09-01

    We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using {sup 18}F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity.

  16. Reference computations of public dose and cancer risk from airborne releases of uranium and Class W plutonium

    SciTech Connect

    Peterson, V.L.

    1995-06-06

    This report presents ``reference`` computations that can be used by safety analysts in the evaluations of the consequences of postulated atmospheric releases of radionuclides from the Rocky Flats Environmental Technology Site. These computations deal specifically with doses and health risks to the public. The radionuclides considered are Class W Plutonium, all classes of Enriched Uranium, and all classes of Depleted Uranium. (The other class of plutonium, Y, was treated in an earlier report.) In each case, one gram of the respirable material is assumed to be released at ground leveL both with and without fire. The resulting doses and health risks can be scaled to whatever amount of release is appropriate for a postulated accident being investigated. The report begins with a summary of the organ-specific stochastic risk factors appropriate for alpha radiation, which poses the main health risk of plutonium and uranium. This is followed by a summary of the atmospheric dispersion factors for unfavorable and typical weather conditions for the calculation of consequences to both the Maximum Offsite Individual and the general population within 80 km (50 miles) of the site.

  17. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C.; Forman, Stephen; Somlo, George; Liu An; Schultheiss, Timothy; Radany, Eric; Palmer, Joycelynne; Stein, Anthony

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  18. Different prescribed doses of high-volume peritoneal dialysis and outcome of patients with acute kidney injury.

    PubMed

    Ponce, Daniela; Brito, Germana Alves; Abrão, Juliana Gera; Balb, André Luis

    2011-01-01

    The optimal dialysis dose for the treatment of acute kidney injury (AKI) is controversial. No studies have directly examined the effects of peritoneal dialysis (PD) dose on outcomes in AKI. From January 2005 to January 2007, we randomly assigned critically ill patients with AKI to receive higher- or lower-intensity PD therapy (prescribed Kt/Vof 0.8 and 0.5 per session respectively). The main outcome measure was death within 30 days. Of the 61 enrolled patients, 30 were randomly assigned to higher-intensity therapy, and 31, to a lower-intensity PD dose. The two study groups had similar baseline characteristics and received treatment for 6.1 days and 5.7 days respectively (p = 0.42). At 30 days after randomization, 17 deaths had occurred in the higher-intensity group (55%), and 16 deaths, in the lower-intensity group (53%, p = 0.83). There was a significant difference between the groups in the PD dose prescribed compared with the dose delivered (higher-intensity group: 0.8 vs. 0.59, p = 0.04; lower-intensity group: 0.5 vs. 0.49, p = 0.89). The groups had similar metabolic control after 4 PD sessions (blood urea nitrogen: 69.3 +/- 14.4 mg/dL and 60.3 +/- 11.1 mg/dL respectively, p = 0. 71). In critically ill patients with AKI, an intensive PD dose did not lower the mortality or improve the recovery of kidney function or metabolic control. The PD dose is limited by dialysate flow and membrane permeability, and clearance per exchange can decrease if a shorter dwell time is applied. PMID:22073842

  19. Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

    ClinicalTrials.gov

    2014-10-23

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  20. Acute necrotizing eosinophilic myocarditis in a patient taking Garcinia cambogia extract successfully treated with high-dose corticosteroids.

    PubMed

    Allen, Scott F; Godley, Robert W; Evron, Joshua M; Heider, Amer; Nicklas, John M; Thomas, Michael P

    2014-12-01

    A previously healthy 48-year-old woman was evaluated for lightheadedness and chest heaviness 2 weeks after starting the herbal supplement Garcinia cambogia. She was found to be hypotensive and had an elevated serum troponin level. The patient had a progressive clinical decline, ultimately experiencing fulminant heart failure and sustained ventricular arrhythmias, which required extracorporeal membrane oxygenation support. Endomyocardial biopsy results were consistent with acute necrotizing eosinophilic myocarditis (ANEM). High-dose corticosteroids were initiated promptly and her condition rapidly improved, with almost complete cardiac recovery 1 week later. In conclusion, we have described a case of ANEM associated with the use of Garcinia cambogia extract. PMID:25475477

  1. Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats.

    PubMed

    Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C; Yu, Shan P; Wei, Ling; Varma, Abhay; Ray, Swapan K; Banik, Naren L

    2016-03-01

    Spinal cord injury (SCI) is a debilitating condition with neurological deficits and loss of motor function that, depending on the severity, may lead to paralysis. The only treatment currently available is methylprednisolone, which is widely used and renders limited efficacy in SCI. Therefore, other therapeutic agents must be developed. The neuroprotective efficacy of estrogen in SCI was studied with a pre-clinical and pro-translational perspective. Acute SCI was induced in rats that were treated with low doses of estrogen (1, 5, 10, or 100 μg/kg) and compared with vehicle-treated injured rats or laminectomy control (sham) rats at 48 h post-SCI. Changes in gliosis and other pro-inflammatory responses, expression and activity of proteolytic enzymes (e.g., calpain, caspase-3), apoptosis of neurons in SCI, and cell death were monitored via Western blotting and immunohistochemistry. Negligible pro-inflammatory responses or proteolytic events and very low levels of neuronal death were found in sham rats. In contrast, vehicle-treated SCI rats showed profound pro-inflammatory responses with reactive gliosis, elevated expression and activity of calpain and caspase-3, elevated Bax:Bcl-2 ratio, and high levels of neuronal death in lesion and caudal regions of the injured spinal cord. Estrogen treatment at each dose reduced pro-inflammatory and proteolytic activities and protected neurons in the caudal penumbra in acute SCI. Estrogen treatment at 10 μg was found to be as effective as 100 μg in ameliorating the above parameters in injured animals. Results from this investigation indicated that estrogen at a low dose could be a promising therapeutic agent for treating acute SCI. Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional

  2. Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

    PubMed Central

    2012-01-01

    Background Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects

  3. Isometric exercise and cognitive function: an investigation of acute dose-response effects during submaximal fatiguing contractions.

    PubMed

    Brown, Denver M Y; Bray, Steven R

    2015-01-01

    The purpose of this study was to explore the dose-response relationship between exercise and cognitive performance using an acute bout of isometric exercise. University students (N = 55) were randomly assigned to control, 30%, 50% and 70% of maximum voluntary handgrip contraction groups. Participants performed a modified Stroop task before and after completion of an isometric handgrip endurance trial at their assigned exercise intensity. Ratings of perceived exertion (RPE) and forearm muscle activation (EMG) showed linear trends of progressively greater RPE and muscle activation at greater exercise intensity levels. Regression analysis showed significant (P < .05) linear degradations in frequency of errors on the Stroop task with increasing exercise intensity. We conclude that performing isometric exercise until exhaustion is associated with reduced cognitive performance and that higher intensity isometric exercise leads to greater performance impairments in a linear dose-response manner. PMID:25260112

  4. REPRODUCTIVE EFFECTS OF LOW ACUTE DOSES OF CADMIUM CHLORIDE IN ADULT MALE RATS

    EPA Science Inventory

    Adult male Sprague-Dawley rats were injected sc with cadmium (Cd, as cadmium chloride) in doses ranging from 1.6 to 152 micromol Cd/kg body weight (body wt). Fourteen days after dosing, animals were evaluated for reproductive damage. Evaluations for each animal included tests, se...

  5. High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: a randomized clinical trial

    PubMed Central

    Billings, Frederic T.; Hendricks, Patricia A.; Schildcrout, Jonathan S.; Shi, Yaping; Petracek, Michael R.; Byrne, John G.; Brown, Nancy J.

    2016-01-01

    Importance Hydroxy-methylglutaryl-coenzyme A reductase inhibitors affect several mechanisms underlying acute kidney injury (AKI). Objective To test the hypothesis that short-term high-dose perioperative atorvastatin would reduce AKI following cardiac surgery Design, Setting, Participants Double-blinded, placebo-controlled, randomized trial of adult cardiac surgery patients conducted November 2009 to October 2014 at Vanderbilt University Medical Center Intervention Statin-naïve patients (n=199) were randomly assigned 80mg atorvastatin the day before surgery, 40mg the morning of surgery, and 40mg daily following surgery (n=102) or matching placebo (n=97). Patients using statins prior to study enrollment (n=416) continued their pre-enrollment statin until the day of surgery, were randomly assigned 80mg atorvastatin the morning of surgery and 40mg the morning after (n=206) or matching placebo (n=210), and resumed their statin on postoperative day 2. Main Outcome AKI, defined as 0.3 mg/dl rise in serum creatinine within 48 hours of surgery (AKIN criteria) Results The DSMB recommended stopping the statin-naïve group due to increased AKI among statin-naïve participants with chronic kidney disease (CKD, estimated glomerular filtration rate <60 ml/min/1.73 m2) receiving atorvastatin and then recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] women, and 202 [32.8%] diabetic) completed the study. Among all participants (n=615), AKI occurred in 64 of 308 participants (20.8%) randomized to atorvastatin versus 60 of 307 participants (19.5%) randomized to placebo (risk ratio [RR], 1.06 [95% CI, 0.78–1.46]; P=0.75). Among statin-naïve participants (n=199), AKI occurred in 22 of 102 (21.6%) receiving atorvastatin versus 13 of 97 (13.4%) receiving placebo (RR, 1.61 [0.86–3.01]; P=0.15), and serum creatinine increased 0.11mg/dl (−0.11 to 0.56) (median [10th to 90th percentile]) in those randomized to atorvastatin versus 0.05 (−0

  6. Acute personalized habitual caffeine doses improve attention and have selective effects when considering the fractionation of executive functions.

    PubMed

    Lanini, Juliana; Galduróz, José Carlos Fernandes; Pompéia, Sabine

    2016-01-01

    Caffeine is widely used, often consumed with food, and improves simple and complex/executive attention under fasting conditions. We investigated whether these cognitive effects are observed when personalized habitual doses of caffeine are ingested by caffeine consumers, whether they are influenced by nutriments and if various executive domains are susceptible to improvement. This was a double-blind, placebo-controlled study including 60 young, healthy, rested males randomly assigned to one of four treatments: placebo fasting, caffeine fasting, placebo meal and caffeine meal. Caffeine doses were individualized for each participant based on their self-reported caffeine consumption at the time of testing (morning). The test battery included measures of simple and sustained attention, executive domains (inhibiting, updating, shifting, dual tasking, planning and accessing long-term memory), control measures of subjective alterations, glucose and insulin levels, skin conductance, heart rate and pupil dilation. Regardless of meal intake, acute habitual doses of caffeine decreased fatigue, and improved simple and sustained attention and executive updating. This executive effect was not secondary to the habitual weekly dose consumed, changes in simple and sustained attention, mood, meal ingestion and increases in cognitive effort. We conclude that the morning caffeine "fix" has positive attentional effects and selectively improved executive updating whether or not caffeine is consumed with food. PMID:26621326

  7. A study of the shape of dose-response curves for acute lethality at low response: a megadaphnia study'

    SciTech Connect

    Sebaugh, J.L.; Wilson, J.D.; Tucker, M.W.; Adams, W.J. )

    1991-12-01

    Dose-response curves were developed for the immobilization response in Daphnia magna to four toxicants. The purpose of this work was to study the effect of the form of the model and the number of concentration levels used on the estimates of typical low-dose effective concentrations (1%, 5%, 10%). The generalized four-parameter logistic model was used as the reference. When using 12 concentration levels, one of the logistic family two- or three-parameter models was shown reliably to represent each of these various sets of dose-response data, and to provide adequate estimates of EC01 and EC05, as well as EC10 and EC50. For two of the toxicants, an asymmetric model was required. When reducing the number of concentrations to five, the EC10 and EC50 were well estimated by the probit model, with acceptable results at the EC05 level.

  8. Profile of the bovine acute-phase response following an intravenous bolus-dose lipopolysaccharide challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two experiments were conducted to further define the acute-phase response to a lipopolysaccharide (LPS) challenge in beef steers. In Exp. 1, 9 crossbred beef steers (449 ± 12 kg BW) were used in a completely random design to determine the effects of 0.5, 1.0, or 2.0 micrograms of LPS/kilogram of bod...

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

    PubMed Central

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

    2012-01-01

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

  10. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy.

    PubMed

    Pusey, C D; Saltissi, D; Bloodworth, L; Rainford, D J; Christie, J L

    1983-01-01

    Nine episodes of drug associated acute interstitial nephritis, in seven patients, were treated between 1972 and 1980. The drugs implicated were cotrimoxazole (three times), ampicillin, Magnapen (ampicillin and flucloxacillin), penicillin, gentamicin, paracetamol and bendrofluazide. The time from exposure to the onset of symptoms ranged from one to 30 days. Presentation was with acute renal failure, which was non-oliguric in five cases, accompanied by rash (four), fever (four), and loin pain (two). Renal biopsy was carried out in all cases, and showed a characteristic interstitial infiltrate comprising substantial numbers of lymphocytes and plasma cells, with a variable number of neutrophils, eosinophils and histiocytes. Immunofluorescence was negative in all four cases studied in the acute phase, and showed scattered deposits of IgG, IgM, IgA and C3 on the tubular basement membrane in one patient during recovery. Significant proteinuria and an abnormal urine deposit were present in all cases, and seven of nine had radiological evidence of enlarged kidneys. Seven episodes were treated with high doses of methyl prednisolone and in all there was a response with a diuresis or spontaneous fall in serum creatinine within 72 hrs, and recovery of virtually normal renal function. Of two cases who did not initially receive steroids, one improved more slowly and one developed chronic renal impairment. PMID:6604293

  11. Dose-Volume Effects on Patient-Reported Acute Gastrointestinal Symptoms During Chemoradiation Therapy for Rectal Cancer

    SciTech Connect

    Chen, Ronald C.; Mamon, Harvey J.; Ancukiewicz, Marek; Killoran, Joseph H.; Crowley, Elizabeth M.; Blaszkowsky, Lawrence S.; Wo, Jennifer Y.; Ryan, David P.; Hong, Theodore S.

    2012-07-15

    Purpose: Research on patient-reported outcomes (PROs) in rectal cancer is limited. We examined whether dose-volume parameters of the small bowel and large bowel were associated with patient-reported gastrointestinal (GI) symptoms during 5-fluorouracil (5-FU)-based chemoradiation treatment for rectal cancer. Methods and Materials: 66 patients treated at the Brigham and Women's Hospital or Massachusetts General Hospital between 2006 and 2008 were included. Weekly during treatment, patients completed a questionnaire assessing severity of diarrhea, urgency, pain, cramping, mucus, and tenesmus. The association between dosimetric parameters and changes in overall GI symptoms from baseline through treatment was examined by using Spearman's correlation. Potential associations between these parameters and individual GI symptoms were also explored. Results: The amount of small bowel receiving at least 15 Gy (V15) was significantly associated with acute symptoms (p = 0.01), and other dosimetric parameters ranging from V5 to V45 also trended toward association. For the large bowel, correlations between dosimetric parameters and overall GI symptoms at the higher dose levels from V25 to V45 did not reach statistical significance (p = 0.1), and a significant association was seen with rectal pain from V15 to V45 (p < 0.01). Other individual symptoms did not correlate with small bowel or large bowel dosimetric parameters. Conclusions: The results of this study using PROs are consistent with prior studies with physician-assessed acute toxicity, and they identify small bowel V15 as an important predictor of acute GI symptoms during 5-FU-based chemoradiation treatment. A better understanding of the relationship between radiation dosimetric parameters and PROs may allow physicians to improve radiation planning to optimize patient outcomes.

  12. DOSE DEPENDENT DISPOSITION OF SODIUM ARSENATE IN MICE FOLLOWING ACUTE ORAL EXPOSURE

    EPA Science Inventory

    The effect of dose on arsenate disposition was studied in adult female B6C3F, mice, dosed po with 0.5 to 5000 ug/kg [73As]-arsenate in water. rine was collected at 1, 2, 4, 8, 12, 24 and 48 hr and feces at 24 and 48 hr postexposure. he mice were sacrificed at 48 hr and tissues we...

  13. Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

    SciTech Connect

    Ray, Anamika; Liu Jing; Ayoubi, Patricia; Pope, Carey

    2010-10-15

    Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clustering while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis (registered) . Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NF{Kappa}B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse

  14. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial

    PubMed Central

    Eddleston, Michael; Juszczak, Edmund; Buckley, Nick A; Senarathna, Lalith; Mohamed, Fahim; Dissanayake, Wasantha; Hittarage, Ariyasena; Azher, Shifa; Jeganathan, K; Jayamanne, Shaluka; Sheriff, MH Rezvi; Warrell, David A

    2008-01-01

    Summary Background The case-fatality for intentional self-poisoning in the rural developing world is 10–50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. Methods We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. Findings Mortality did not differ between the groups. 97 (6·3%) of 1531 participants in the multiple-dose group died, compared with 105 (6·8%) of 1554 in the no charcoal group (adjusted odds ratio 0·96, 95% CI 0·70–1·33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. Interpretation We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed. PMID:18280328

  15. Reference air kerma and kerma-area product as estimators of peak skin dose for fluoroscopically guided interventions

    SciTech Connect

    Kwon, Deukwoo; Little, Mark P.; Miller, Donald L.

    2011-07-15

    Purpose: To determine more accurate regression formulas for estimating peak skin dose (PSD) from reference air kerma (RAK) or kerma-area product (KAP). Methods: After grouping of the data from 21 procedures into 13 clinically similar groups, assessments were made of optimal clustering using the Bayesian information criterion to obtain the optimal linear regressions of (log-transformed) PSD vs RAK, PSD vs KAP, and PSD vs RAK and KAP. Results: Three clusters of clinical groups were optimal in regression of PSD vs RAK, seven clusters of clinical groups were optimal in regression of PSD vs KAP, and six clusters of clinical groups were optimal in regression of PSD vs RAK and KAP. Prediction of PSD using both RAK and KAP is significantly better than prediction of PSD with either RAK or KAP alone. The regression of PSD vs RAK provided better predictions of PSD than the regression of PSD vs KAP. The partial-pooling (clustered) method yields smaller mean squared errors compared with the complete-pooling method.Conclusion: PSD distributions for interventional radiology procedures are log-normal. Estimates of PSD derived from RAK and KAP jointly are most accurate, followed closely by estimates derived from RAK alone. Estimates of PSD derived from KAP alone are the least accurate. Using a stochastic search approach, it is possible to cluster together certain dissimilar types of procedures to minimize the total error sum of squares.

  16. High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

    PubMed Central

    O'Brien, Susan; Schiller, Gary; Lister, John; Damon, Lloyd; Goldberg, Stuart; Aulitzky, Walter; Ben-Yehuda, Dina; Stock, Wendy; Coutre, Steven; Douer, Dan; Heffner, Leonard T.; Larson, Melissa; Seiter, Karen; Smith, Scott; Assouline, Sarit; Kuriakose, Philip; Maness, Lori; Nagler, Arnon; Rowe, Jacob; Schaich, Markus; Shpilberg, Ofer; Yee, Karen; Schmieder, Guenter; Silverman, Jeffrey A.; Thomas, Deborah; Deitcher, Steven R.; Kantarjian, Hagop

    2013-01-01

    Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR. PMID:23169518

  17. Gene expression in Catla catla (Hamilton) subjected to acute and protracted doses of gamma radiation.

    PubMed

    Anbumani, S; Mohankumar, Mary N

    2016-09-01

    Studies on transcriptional modulation after gamma radiation exposure in fish are limited. Cell cycle perturbations and expression of apoptotic genes were investigated in the fish, Catla catla after acute and protracted exposures to gamma radiation over a 90day period. Significant changes in gene expression were observed between day 1 and 90 post-exposure. Gamma radiation induced a significant down-regulation of target genes gadd45α, cdk1 and bcl-2 from day 1 to day 3 after protracted exposure, whereas it persists till day 6 upon acute exposure. From day 12 onwards, Gadd45α, cdk1 and bcl-2 genes were up-regulated following protracted exposure, indicating DNA repair, cell-cycle arrest and apoptosis. There exists a linear correlation between these genes (gadd45α - r=0.85, p=0.0073; cdk1 - r=0.86, p=0.0053; bcl-2 - r=0.89, p=0.0026) at protracted exposures. This is the first report on the dual role of bcl-2 gene in fish exposed to acute and protracted radiation and correlation among the aforementioned genes that work in concert to promote 'repair' and 'death' circuitries in fish blood cells. PMID:27497304

  18. Psychiatric side effects of acute high-dose corticosteroid therapy in neurological conditions.

    PubMed

    Lotan, Itay; Fireman, Liora; Benninger, Felix; Weizman, Abraham; Steiner, Israel

    2016-07-01

    It has been implied that high-dose corticosteroids (CSs) commonly cause psychiatric side effects. Here, we examined the rate and risk factors of psychiatric side effects during high-dose CS treatment in patients with neurological disorders. Patients treated with high-dose intravenous CSs for neurological disorders were evaluated for depression, mania, and psychosis using the Beck Depression Inventory, the Geriatric Depression Scale, the Young Mania Rating Scale, and the Brief Psychiatric Rating Scale before CS treatment, immediately after, and 1 month following treatment. Forty-nine consecutive patients were monitored. There was a reduction in the Beck Depression Inventory and Geriatric Depression Scale scores as well as in the Brief Psychiatric Rating Scale scores throughout the study period and a transitory increase in the Young Mania Rating Scale score immediately after CS administration. Thus, a tendency to develop transient mild euphoria during high-dose CS treatment exists, but is reversible at 1 month, whereas a reduction in depressive symptoms tended to persist. Overall, our data indicate that high-dose CS treatment for neurological diseases is relatively safe with respect to psychiatric complications. PMID:26938038

  19. Acute necrotising pancreatitis derived from low-dose corticosteroid use: an important reminder of clinical management.

    PubMed

    Sabre, Alexander; Guthrie, Morgan Mary; Maleknia, Reza

    2015-01-01

    Although the exact mechanism is unknown, incidence of drug-induced pancreatitis from corticosteroids is well established in the medical literature. Commonly reported in chronic steroid-dependent individuals who require large doses for a wide array of pathologies, the incidence of damage to the pancreas from low-doses have not been well described. We report a case of a 68-year-old woman who presented with severe abdominal pain, nausea and vomiting, 3 days after the initiation of low-dose methylprednisolone for osteoarthritis. Inpatient laboratory analysis revealed an elevated lipase of 1770 U/L and CT scan showing extensive necrotising pancreatitis involving the head, body and tail. Cessation of the causative medication and conservative treatment successfully led to resolution of symptoms. We present this case to inform clinicians of the precipitance of pancreatitis from modest strength corticosteroid management, so that more accurate and improved performance in pharmacological decisions can be made for patient care. PMID:26150628

  20. Acute Pancreatitis Induced by Azathioprine and 6-mercaptopurine Proven by Single and Low Dose Challenge Testing in a Child with Crohn Disease.

    PubMed

    Yi, Geum-Chae-Won; Yoon, Ka-Hyun; Hwang, Jin-Bok

    2012-12-01

    We report here a case of drug-induced acute pancreatitis proved by elimination and single, low dose challenge test in a child with Crohn disease. A 14-year-old boy with moderate/severe Crohn disease was admitted due to high fever and severe epigastric pain during administration of mesalazine and azathioprine. Blood test and abdominal ultrasonography revealed acute pancreatitis. After discontinuance of the medication and supportive care, the symptoms and laboratory findings improved. A single, low dose challenge test was done to confirm the relationship of the adverse drug reaction and acute pancreatitis, and to discriminate the responsible drug. Azathioprine and 6-mercaptopurine showed positive responses, and mesalazine showed a negative response. We introduce the method of single, low dose challenge test and its interpretation for drug-induced pancreatitis. PMID:24010098

  1. SU-E-T-516: Measurement of the Absorbed Dose Rate in Water Under Reference Conditions in a CyberKnife Unit

    SciTech Connect

    Aragon-Martinez, N; Hernandez-Guzman, A; Gomez-Munoz, A; Massillon-JL, G

    2014-06-01

    Purpose: This paper aims to measure the absorbed-dose-rate in a CyberKnife unit reference-field (6cm diameter) using three ionization chambers (IC) following the new IAEA/AAPM formalism and Gafchromic film (MD-V3-55 and EBT3) protocol according to our work reported previously. Methods: The absorbed-dose-rates were measured at 90cm and 70cm SSD in a 10cmx10cm field and at 70cm SSD in a 5.4cmx5.4cm equivalent to 6cm diameter field using a linac Varian iX. All measurements were performed at 10cm depth in water. The correction factors that account for the difference between the IC response on the reference field and the CyberKnife reference field, k-(Q-msr,Q)^(f-msr,f-ref), were evaluated and Gafchromic film were calibrated using the results obtained above. Under the CyberKnife reference conditions, the factors were used to measure the absorbed-dose-rate with IC according to the new formalism and the calibrated film was irradiated in water. The film calibration curve was used to evaluate the absorbed-dose-rate in the CyberKnife unit. Results: Difference up to 2.56% is observed between dose-rate measured with IC in the reference 10cmx10cm field, depending where the chamber was calibrated, which was not reflected in the correction factor k-(Q-msr,Q)^(f-msr,f-ref ) where variations of ~0.15%-0.5% were obtained. Within measurements uncertainties, maximum difference of 1.8% on the absorbed-dose-rate in the CyberKnife reference field is observed between all IC and the films Conclusion: Absorbed-dose-rate to water was measured in a CyberKnife reference field with acceptable accuracy (combined uncertainties ~1.32%-1.73%, k=1) using three IC and films. The MD-V3-55 film as well as the new IAEA/AAPM formalism can be considered as a suitable dosimetric method to measure absorbed-dose-rate to water in small and non-standard CyberKnife fields used in clinical treatments However, the EBT3 film is not appropriated due to the high uncertainty provided (combined uncertainty ~9%, k=1

  2. Dosimetric Coverage of the Prostate, Normal Tissue Sparing, and Acute Toxicity with High-Dose-Rate Brachytherapy for Large Prostate Volumes

    PubMed Central

    Yang, George; Strom, Tobin J.; Wilder, Richard B.; Shrinath, Kushagra; Mellon, Eric A.; Fernandez, Daniel C.; Biagioli, Matthew C.

    2015-01-01

    ABSTRACT Purpose To evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes. Materials and Methods One hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL) were treated with high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38%) unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Results Median follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3%) patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17%) patients developed Grade 2 acute urinary retention. American Urological Association (AUA) symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p=0.04). There was no ≥ Grade 3 acute toxicity. Conclusions Dosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes. PMID:26200536

  3. Patient radiation doses in interventional cardiology in the U.S.: Advisory data sets and possible initial values for U.S. reference levels

    SciTech Connect

    Miller, Donald L.; Hilohi, C. Michael; Spelic, David C.

    2012-10-15

    Purpose: To determine patient radiation doses from interventional cardiology procedures in the U.S and to suggest possible initial values for U.S. benchmarks for patient radiation dose from selected interventional cardiology procedures [fluoroscopically guided diagnostic cardiac catheterization and percutaneous coronary intervention (PCI)]. Methods: Patient radiation dose metrics were derived from analysis of data from the 2008 to 2009 Nationwide Evaluation of X-ray Trends (NEXT) survey of cardiac catheterization. This analysis used deidentified data and did not require review by an IRB. Data from 171 facilities in 30 states were analyzed. The distributions (percentiles) of radiation dose metrics were determined for diagnostic cardiac catheterizations, PCI, and combined diagnostic and PCI procedures. Confidence intervals for these dose distributions were determined using bootstrap resampling. Results: Percentile distributions (advisory data sets) and possible preliminary U.S. reference levels (based on the 75th percentile of the dose distributions) are provided for cumulative air kerma at the reference point (K{sub a,r}), cumulative air kerma-area product (P{sub KA}), fluoroscopy time, and number of cine runs. Dose distributions are sufficiently detailed to permit dose audits as described in National Council on Radiation Protection and Measurements Report No. 168. Fluoroscopy times are consistent with those observed in European studies, but P{sub KA} is higher in the U.S. Conclusions: Sufficient data exist to suggest possible initial benchmarks for patient radiation dose for certain interventional cardiology procedures in the U.S. Our data suggest that patient radiation dose in these procedures is not optimized in U.S. practice.

  4. Comparison between CT-based volumetric calculations and ICRU reference-point estimates of radiation doses delivered to bladder and rectum during intracavitary radiotherapy for cervical cancer

    SciTech Connect

    Pelloski, Christopher E.; Palmer, Matthew B.S.; Chronowski, Gregory M.; Jhingran, Anuja; Horton, John; Eifel, Patricia J. . E-mail: peifel@mdanderson.org

    2005-05-01

    Purpose: To compare CT-based volumetric calculations and International Commission on Radiation Units and Measurements (ICRU) reference-point estimates of radiation doses to the bladder and rectum in patients with carcinoma of the uterine cervix treated with definitive low-dose-rate intracavitary radiotherapy (ICRT). Methods and Materials: Between November 2001 and March 2003, 60 patients were prospectively enrolled in a pilot study of ICRT with CT-based dosimetry. Most patients underwent two ICRT insertions. After insertion of an afterloading ICRT applicator, intraoperative orthogonal films were obtained to ensure proper positioning of the system and to facilitate subsequent planning. Treatments were prescribed using standard two-dimensional dosimetry and planning. Patients also underwent helical CT of the pelvis for three-dimensional reconstruction of the radiation dose distributions. The systems were loaded with {sup 137}Cs sources using the Selectron remote afterloading system according to institutional practice for low-dose-rate brachytherapy. Three-dimensional dose distributions were generated using the Varian BrachyVision treatment planning system. The rectum was contoured from the bottom of the ischial tuberosities to the sigmoid flexure. The entire bladder was contoured. The minimal doses delivered to the 2 cm{sup 3} of bladder and rectum receiving the highest dose (D{sub BV2} and D{sub RV2}, respectively) were determined from dose-volume histograms, and these estimates were compared with two-dimensionally derived estimates of the doses to the corresponding ICRU reference points. Results: A total of 118 unique intracavitary insertions were performed, and 93 were evaluated and the subject of this analysis. For the rectum, the estimated doses to the ICRU reference point did not differ significantly from the D{sub RV2} (p = 0.561); the mean ({+-} standard deviation) difference was 21 cGy ({+-} 344 cGy). The median volume of the rectum that received at least

  5. Preclinical Assessment of Low Doses of Cisplatin in the Management of Acute Promyelocytic Leukemia

    PubMed Central

    Dasari, Shaloam R; Velma, Venkatramreddy; Yedjou, Clement G; Tchounwou, Paul B

    2016-01-01

    Cis-diamminedichloroplatinum (II) (cisplatin) is the most widely used chemotherapeutic drug for various cancers, but its effectiveness is limited by tumor cell resistance and the severe side effects it causes. Since high level of cisplatin is cytotoxic to both cancer and normal cells, the goal of the present study was to explore the effectiveness of prolonged low doses of cisplatin in the management of leukemia. To achieve our goal, human leukemia (HL-60) cells were treated with different doses (1, 2, or 3 µM) of cisplatin for 24, 48, 72 and 96 hours. Cell viability was assessed by MTS assay. Both oxidative stress damage and genotoxicity were estimated by antioxidants, lipid peroxidation, and comet assays, respectively. Data obtained from the MTS assay demonstrated that cisplatin treatment decreased the number of viable tumor cells by direct cell killing or by simply decreasing the rate of cellular proliferation in a dose- and time-dependent fashion. The results of the lipid peroxidation showed a significant increase (p<0.05) of malondialdehyde levels with increasing cisplatin doses. Results obtained from super oxide dismutase and catalase assays showed a gradual increase in antioxidant enzyme activity in cisplatin-treated cells compared to control cells. Data generated from the Comet assay demonstrated a significant dose-dependent increase in genotoxicity with respect to DNA damage as a result of cisplatin treatment. Taken together, our research demonstrated that cisplatin-induced cytotoxicity in HL-60 cells is mediated at least in part via induction of oxidative stress and oxidative damage. PMID:26900603

  6. Acute pulmonary oedema due to single dose acetazolamide taken after cataract surgery.

    PubMed

    Guven Yilmaz, Suzan; Palamar, Melis; Gurgun, Cemil

    2016-01-01

    An increase in intraocular pressure following cataract surgery is very common. The main reason for this condition is viscoelastic agent remaining in the eye, which leads to mechanical obstruction of the trabecular meshwork. Prophylaxis with oral acetazolamide is frequently practised to prevent this early rise in intraocular pressure in the preoperative and postoperative periods. We report a case of an 81-year-old man with acute pulmonary oedema due to prophylactic acetazolamide intake after cataract surgery. The case is presented in order to draw attention to this serious complication. PMID:27170607

  7. Low-Dose (10%) Computed Tomography May Be Inferior to Standard-Dose CT in the Evaluation of Acute Renal Colic in the Emergency Room Setting

    PubMed Central

    Han, Esther; Atalla, Christopher S.; Santucci, Richard A.; O'Neil, Brian; Wynberg, Jason B.

    2016-01-01

    Abstract Introduction: Noncontrast CT is the standard of care to evaluate nephrolithiasis. We evaluated the performance of low-dose CT (LDCT) scan for evaluation of renal colic in the emergency room (ER). Materials and Methods: Patients visiting the ER with suspected nephrolithiasis received a standard-dose CT (SDCT) and an LDCT. Two urologists read the LDCTs and later they read SDCTs. Stone information was recorded on a diagram of the renal system. Findings on SDCTs and LDCTs were correlated through side-by-side comparison of the diagrams. Later, the two urologists adjudicated all nonconcordance between SDCTs and LDCTs in an unblinded manner. Results: Twenty-seven patients were included. SDCTs revealed 27 stones in 18 patients. Mean stone size was 3.81 mm. LDCTs revealed 27 stones in 18 patients with a mean stone size of 4.7 mm (p = 0.23). Overall sensitivity and specificity of LDCTs were 70% and 39%, respectively. There were eight false-positive and eight false-negative stones. All the false-positive stones on LDCTs were placed in the ureter, in which all of the corresponding SDCTs were visible calcifications outside the ureter. Of the eight false-negative stones on LDCTs, seven were visible calcifications on the SDCTs and the eighth stone was 1 mm and was not visible. Conclusion: LDCT may not perform well in the evaluation of suspected nephrolithiasis in the acute setting. LDCT scan accurately demonstrates calcifications; however, accurate placement of calcifications in or out of the urinary tract may be diminished due to impaired resolution of soft tissue structures. PMID:26728321

  8. Acute exposure to a sublethal dose of imidacloprid and coumaphos enhances olfactory learning and memory in the honeybee Apis mellifera.

    PubMed

    Williamson, Sally M; Baker, Daniel D; Wright, Geraldine A

    2013-06-01

    The decline of honeybees and other pollinating insects is a current cause for concern. A major factor implicated in their decline is exposure to agricultural chemicals, in particular the neonicotinoid insecticides such as imidacloprid. Honeybees are also subjected to additional chemical exposure when beekeepers treat hives with acaricides to combat the mite Varroa destructor. Here, we assess the effects of acute sublethal doses of the neonicotinoid imidacloprid, and the organophosphate acaricide coumaphos, on honey bee learning and memory. Imidacloprid had little effect on performance in a six-trial olfactory conditioning assay, while coumaphos caused a modest impairment. We report a surprising lack of additive adverse effects when both compounds were administered simultaneously, which instead produced a modest improvement in learning and memory. PMID:23160709

  9. [Effects on the pulmonary function after single dose of exogenous pulmonary surfactant in children with acute respiratory distress syndrome].

    PubMed

    de Carvalho, W B; Mângia, C M

    1997-01-01

    The Acute Respiratory Distress Syndrome (ARDS) is a pulmonary lesion of multifactorial cause in which the surfactant system is altered owing to inactivation and impairment of composition and metabolism. The use of exogenous pulmonary surfactant is a therapeutic option with the objective to maintain alveolar stability thus improving the pulmonary compliance (increasing the residual functional capacity), oxygenation and ventilatory mechanics. A study carried out on two pediatric patients with ARDS submitted to mechanic pulmonary ventilation, applying a single dose of exogenous pulmonary surfactant is described. The patients were evaluated using arterial and venous gasometry before and after the use of surfactant, observing increment in oxygenation, reduction of shunt fraction, improvement in ventilation immediately after exogenous pulmonary surfactant instillation and return to the previous situation after 240 minutes in case 1 and 120 minutes in case 2. More prospective clinical and randomized studies are needed to effectively evaluate this therapeutic modality. PMID:9336050

  10. Acute transverse myelopathy complicating systemic lupus erythematosus.

    PubMed Central

    Propper, D J; Bucknall, R C

    1989-01-01

    A sixteen year old girl with systemic lupus erythematosus developed acute transverse myelopathy. She was treated with high dose steroids, cyclophosphamide, and plasma exchange and regained partial neurological function. Previous descriptions of transverse myelopathy complicating systemic lupus erythematosus are reviewed, with particular reference to the efficacy of high dose steroid treatment. PMID:2662918

  11. A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma

    PubMed Central

    J Parker, T.; Daley-Yates, P. T.; Wood, S. A.

    1997-01-01

    Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma. Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40 mg (MP equivalents) i.v. 6 hourly for 48 h. The bio-conversion and disposition of a 40 mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase. Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0 h−1vs 5.5 h−1 respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7 h vs 3.0 h), steady-state AUC (2007.0 ng ml−1 h vs 2321.0 ng ml−1 h) and steady-state Cmax (698.4 ng ml−1vs 647.8 ng ml−1 ) for MP suleptanate and MP succinate respectively. Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate. PMID:9205818

  12. Collective radiation biodosimetry for dose reconstruction of acute accidental exposures: a review.

    PubMed Central

    Pass, B

    1997-01-01

    Quantification of the biologically relevant dose is required to establish cause and effect between radiation detriment or burden and important biological outcomes. Most epidemiologic studies of unanticipated radiation exposure fail to establish cause and effect because researchers have not been able to construct a valid quantification of dose for the exposed population. However, no one biodosimetric technique (biophysical or biological) meets all the requirements of an ideal dosimeter. This paper reviews how the collection of biodosimetric data for victims of radiation accidents can be used to create a dosimetric "gold standard." Particular emphasis is placed on the use of electron spin resonance, a standard for radiation accident dosimetry. As an example of this technique, a review will be presented of a previously reported study of an individual exposed to a 60Co sterilization source. PMID:9467051

  13. Evaluation of absorbed and effective doses to patients from radiopharmaceuticals using the ICRP 110 reference computational phantoms and ICRP 103 formulation.

    PubMed

    Hadid, Lama; Gardumi, Anna; Desbrée, Aurélie

    2013-09-01

    In diagnostic nuclear medicine, mean absorbed doses to patients' organs and effective doses are published for standard stylised anatomic models. To provide more realistic and detailed geometries of the human morphology, the International Commission on Radiological Protection (ICRP) has recently adopted male and female voxel phantoms to represent the reference adult. This work investigates the impact of the use of these new computational phantoms. The absorbed doses were calculated for 11 different radiopharmaceuticals currently used in diagnostic nuclear medicine. They were calculated for the ICRP 110 reference computational phantoms using the OEDIPE software and the MCNP extended Monte Carlo code. The biokinetic models were issued from ICRP Publications 53, 80 and 106. The results were then compared with published values given in these ICRP Publications. To discriminate the effect of anatomical differences on organ doses from the effect of the calculation method, the Monte Carlo calculations were repeated for the reference adult stylised phantom. The voxel effect, the influence of the use of different densities and nuclear decay data were also investigated. Effective doses were determined for the ICRP 110 adult reference computational phantom with the tissue weighting factor of ICRP Publication 60 and the tissue weighting factors of ICRP Publication 103. The calculation method and, in particular, the simulation of the electron transport have a significant influence on the calculated doses, especially, for small and walled organs. Overestimates of >200 % were observed for the urinary bladder wall of the stylised phantom compared with the computational phantoms. The unrealistic organ topology of the stylised phantom leads to important dose differences, sometimes by an order of magnitude. The effective doses calculated using the new computational phantoms and the new tissue weighting factors are globally lower than the published ones, except for some

  14. Arterial input functions (AIFs) measured directly from arteries with low and standard doses of contrast agent, and AIFs derived from reference tissues

    PubMed Central

    Wang, Shiyang; Fan, Xiaobing; Medved, Milica; Pineda, Federico D.; Yousuf, Ambereen; Oto, Aytekin; Karczmar, Gregory S.

    2016-01-01

    Measurements of arterial input function (AIF) can have large systematic errors at standard contrast agent doses in dynamic contrast enhanced MRI (DCE-MRI). We compared measured AIFs from low dose (AIFLD) and standard dose (AIFSD) contrast agent injections, as well as the AIF derived from a muscle reference tissue and artery (AIFref). Twenty-two prostate cancer patients underwent DCE-MRI. Data were acquired on a 3 T scanner using an mDixon sequence. Gadobenate dimeglumine was injected twice, at doses of 0.015 and 0.085 mmol/kg. Directly measured AIFs were fitted with empirical mathematical models (EMMs) and compared to the AIF derived from a muscle reference tissue (AIFref). EMMs accurately fitted the AIFs. The 1st and 2nd pass peaks were visualized in AIFLD, but not in AIFSD, thus the peak and shape of AIFSD could not be accurately measured directly. The average scaling factor between AIFSD and AIFLD in the washout phase was only 56% of the contrast dose ratio (~6:1). The shape and magnitude of AIFref closely approximated that of AIFLD after empirically determined dose-dependent normalization. This suggests that AIFref may be a good approximation of the local AIF. PMID:26523650

  15. Acute High-Dose and Chronic Lifetime Exposure to Alcohol Consumption and Differentiated Thyroid Cancer: T-CALOS Korea

    PubMed Central

    Hwang, Yunji; Lee, Kyu Eun; Weiderpass, Elisabete; Park, Young Joo; Chai, Young Jun; Kwon, Hyungju; Park, Do Joon; Cho, BeLong; Choi, Ho-Chun; Kang, Daehee; Park, Sue K.

    2016-01-01

    Background This study evaluated the effects of acute high-dose and chronic lifetime exposure to alcohol and exposure patterns on the development of differentiated thyroid cancer (DTC). Methods The Thyroid Cancer Longitudinal Study (T-CALOS) included 2,258 DTC patients (449 men and 1,809 women) and 22,580 healthy participants (4,490 men and 18,090 women) who were individually matched by age, gender, and enrollment year. In-person interviews were conducted with a structured questionnaire to obtain epidemiologic data. Clinicopathologic features of the patients were obtained by chart reviews. Odds ratios (ORs) and 95% confidence intervals (95%CI) were estimated using conditional regression models. Results While light or moderate drinking behavior was related to a reduced risk of DTC, acute heavy alcohol consumption (151 g or more per event or on a single occasion) was associated with increased risks in men (OR = 2.22, 95%CI = 1.27–3.87) and women (OR = 3.61, 95%CI = 1.52–8.58) compared with never-drinkers. The consumption of alcohol for 31 or more years was a significant risk factor for DTC for both men (31–40 years: OR = 1.58, 95%CI = 1.10–2.28; 41+ years: OR = 3.46, 95%CI = 2.06–5.80) and women (31–40 years: OR = 2.18, 95%CI = 1.62–2.92; 41+ years: OR = 2.71, 95%CI = 1.36–5.05) compared with never-drinkers. The consumption of a large amount of alcohol on a single occasion was also a significant risk factor, even after restricting DTC outcomes to tumor size, lymph node metastasis, extrathyroidal extension and TNM stage. Conclusion The findings of this study suggest that the threshold effects of acute high-dose alcohol consumption and long-term alcohol consumption are linked to an increased risk of DTC. PMID:26985827

  16. Intensity-Modulated Radiotherapy as Primary Therapy for Prostate Cancer: Report on Acute Toxicity After Dose Escalation With Simultaneous Integrated Boost to Intraprostatic Lesion

    SciTech Connect

    Fonteyne, Valerie Villeirs, Geert; Speleers, Bruno; Neve, Wilfried de; Wagter, Carlos de; Lumen, Nicolas; Meerleer, Gert de

    2008-11-01

    Purpose: To report on the acute toxicity of a third escalation level using intensity-modulated radiotherapy for prostate cancer (PCa) and the acute toxicity resulting from delivery of a simultaneous integrated boost (SIB) to an intraprostatic lesion (IPL) detected on magnetic resonance imaging (MRI), with or without spectroscopy. Methods and Materials: Between January 2002 and March 2007, we treated 230 patients with intensity-modulated radiotherapy to a third escalation level as primary therapy for prostate cancer. If an IPL (defined by MRI or MRI plus spectroscopy) was present, a SIB was delivered to the IPL. To report on acute toxicity, patients were seen weekly during treatment and 1 and 3 months after treatment. Toxicity was scored using the Radiation Therapy Oncology Group toxicity scale, supplemented by an in-house-developed scoring system. Results: The median dose to the planning target volume was 78 Gy. An IPL was found in 118 patients. The median dose to the MRI-detected IPL and MRI plus spectroscopy-detected IPL was 81 Gy and 82 Gy, respectively. No Grade 3 or 4 acute gastrointestinal toxicity developed. Grade 2 acute gastrointestinal toxicity was present in 26 patients (11%). Grade 3 genitourinary toxicity was present in 15 patients (7%), and 95 patients developed Grade 2 acute genitourinary toxicity (41%). No statistically significant increase was found in Grade 2-3 acute gastrointestinal or genitourinary toxicity after a SIB to an IPL. Conclusion: The results of our study have shown that treatment-induced acute toxicity remains low when intensity-modulated radiotherapy to 80 Gy as primary therapy for prostate cancer is used. In addition, a SIB to an IPL did not increase the severity or incidence of acute toxicity.

  17. The acute effect of high-dose intravenous vitamin C and other nutrients on blood pressure: a cohort study

    PubMed Central

    Travica, Nikolaj; Sali, Avni

    2016-01-01

    Background Regular intake of vitamin C/ascorbate reduces blood pressure (BP) in hypertensives. High-dose intravenous vitamin C (IVC) achieves higher plasma levels; however, there is a paucity of research on acute BP effects. Our study is the first to investigate the effect of high-dose IVC, with or without concomitant i.v. nutrients, on BP during i.v. treatment. Methods A cohort of adult patients scheduled to receive IVC treatment for infection, cancer or fatigue, as prescribed by their treating doctor, participated at a Melbourne clinic, Australia. Ambulatory BP was assessed every 10 min over 90 min during i.v. treatment. Patients received 15–100 g of IVC alone or in addition to i.v. vitamin B, glutathione, magnesium or zinc. BP change over time adjusted for baseline BP, IVC dosage, i.v. treatment and BMI was analysed. Results A total of 77 mostly normotensive patients participated, with a third receiving IVC alone (42±20 g), and two-thirds also received other i.v. nutrients. IVC alone (>30 g) reduced the mean BP up to 8–9 mmHg in prehypertensive patients. In contrast, concomitant intravenous vitamin B12 (IVB12) significantly increased the mean BP by 11–13 mmHg. Comparison of BP change during IVC versus IVC+IVB12 indicated a highly significant difference [systolic blood pressure: mean difference (SD)=16.6 (17.8) mmHg, P<0.001; diastolic blood pressure: mean difference (SD)=12.5 (16.7) mmHg, P=0.003]. Conclusion Our study suggests an acute BP-reducing effect of high-dose IVC, particularly with dosages above 30 g, and in patients with prehypertension and normal BMI. Furthermore, our study indicated a marked and clinically relevant hypertensive effect of IVB12, suggesting routine BP monitoring during i.v. therapy in clinical practice. PMID:26910646

  18. Effect of single dose administration of methylsulfonylmethane on oxidative stress following acute exhaustive exercise.

    PubMed

    Nakhostin-Roohi, Babak; Niknam, Zahra; Vaezi, Nasrin; Mohammadi, Sadollah; Bohlooli, Shahab

    2013-01-01

    Methylsulfonylmethane (MSM) is a sulfur-containing compound commonly found in diet and known to reduce oxidative stress. This trial was conducted to determine whether single dose supplementation with MSM attenuates post-exercise oxidative stress in healthy untrained young men. Sixteen untrained men volunteered for this study. Participants were randomized in a double-blind placebo-controlled fashion into 2 groups: Methylsulfonylmethane (MSM) (n = 8) and placebo (n = 8). The participants took supplementation or placebo before running on treadmill for 45 min at 75% VO2max. The MSM supplementation was prepared in water as 100 mg/ kg body weight. The placebo group received water. Serum Malondealdehyde (MDA), uric acid, bilirubin, protein carbonyl (PC) and plasma vitamin E levels were determined as the markers of oxidative stress. Plasma GSH (reduced Glutathione) and total antioxidant capacity (TAC) were measured as markers of plasma antioxidant system. MSM supplementation successfully lowered serum PC 2 and 24 h after exercise. Plasma TAC in MSM group was higher at 24 h after exercise. Serum level of uric acid and bilirubin were significantly low immediately after exercise in MSM supplemented group. There was no significant difference between groups in terms of plasma GSH level. These results complement earlier studies showing anti-oxidant effect of MSM and suggest that single dose oral supplementation with MSM lowers exercise induced oxidative stress in healthy untrained young men, but is not adequate to significantly affect plasma GSH level. PMID:24523764

  19. Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis

    PubMed Central

    Ding, Xibing; Jin, Shuqing; Niu, Xiaoyin; Wang, Tingting; Zhao, Xiang; Ren, Hao; Tong, Yao; Li, Quan

    2014-01-01

    Purpose: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. Methods: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. Results: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. Conclusion: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness. PMID:25356103

  20. Human health screening level risk assessments of tertiary-butyl acetate (TBAC): calculated acute and chronic reference concentration (RfC) and Hazard Quotient (HQ) values based on toxicity and exposure scenario evaluations.

    PubMed

    Bus, James S; Banton, Marcy I; Faber, Willem D; Kirman, Christopher R; McGregor, Douglas B; Pourreau, Daniel B

    2015-02-01

    A screening level risk assessment has been performed for tertiary-butyl acetate (TBAC) examining its primary uses as a solvent in industrial and consumer products. Hazard quotients (HQ) were developed by merging TBAC animal toxicity and dose-response data with population-level, occupational and consumer exposure scenarios. TBAC has a low order of toxicity following subchronic inhalation exposure, and neurobehavioral changes (hyperactivity) in mice observed immediately after termination of exposure were used as conservative endpoints for derivation of acute and chronic reference concentration (RfC) values. TBAC is not genotoxic but has not been tested for carcinogenicity. However, TBAC is unlikely to be a human carcinogen in that its non-genotoxic metabolic surrogates tertiary-butanol (TBA) and methyl tertiary butyl ether (MTBE) produce only male rat α-2u-globulin-mediated kidney cancer and high-dose specific mouse thyroid tumors, both of which have little qualitative or quantitative relevance to humans. Benchmark dose (BMD)-modeling of the neurobehavioral responses yielded acute and chronic RfC values of 1.5 ppm and 0.3 ppm, respectively. After conservative modeling of general population and near-source occupational and consumer product exposure scenarios, almost all HQs were substantially less than 1. HQs exceeding 1 were limited to consumer use of automotive products and paints in a poorly ventilated garage-sized room (HQ = 313) and occupational exposures in small and large brake shops using no personal protective equipment or ventilation controls (HQs = 3.4-126.6). The screening level risk assessments confirm low human health concerns with most uses of TBAC and indicate that further data-informed refinements can address problematic health/exposure scenarios. The assessments also illustrate how tier-based risk assessments using read-across toxicity information to metabolic surrogates reduce the need for comprehensive animal testing. PMID:25629921

  1. REDUCING UNCERTAINTY IN AIR TOXICS RISK ASSESSMENT: A MECHANISTIC EXPOSURE-DOSE-RESPONSE (EDR) MODEL FOR ASSESSING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS) BASED UPON A RECEPTOR-MEDIATED MODE OF ACTION

    EPA Science Inventory

    SUMMARY: The major accomplishment of NTD’s air toxics program is the development of an exposure-dose- response model for acute exposure to volatile organic compounds (VOCs), based on momentary brain concentration as the dose metric associated with acute neurological impairments...

  2. (Depth-dose curves of the beta reference fields (147)Pm, (85)Kr and (90)Sr/(90)Y produced by the beta secondary standard BSS2.

    PubMed

    Brunzendorf, Jens

    2012-08-01

    The most common reference fields in beta dosimetry are the ISO 6980 series 1 radiation fields produced by the beta secondary standard BSS2 and its predecessor BSS. These reference fields require sealed beta radiation sources ((147)Pm, (85)Kr or (90)Sr/(90)Y) in combination with a source-specific beam-flattening filter, and are defined only at a given distance from the source. Every radiation sources shipped with the BSS2 is sold with a calibration certificate of the Physikalisch-Technische Bundesanstalt. The calibration workflow also comprises regular depth-dose measurements. This work publishes complete depth-dose curves of the series 1 sources (147)Pm, (85)Kr and (90)Sr/(90)Y in ICRU tissue up to a depth of 11 mm,when all electrons are stopped. For this purpose, the individual depth-dose curves of all BSS2 sources calibrated so far have been determined, i.e. the complete datasets of all BSS2 beta sources have been re-evaluated. It includes 191 depth-dose curves of 116 different sources comprising more than 2200 data points in total. Appropriate analytical representations of the nuclide-specific depth-dose curves are provided for the first time. PMID:22267274

  3. High dose cytosine arabinoside in the initial treatment of adults with acute lymphoblastic leukaemia.

    PubMed Central

    Rohatiner, A. Z.; Bassan, R.; Battista, R.; Barnett, M. J.; Gregory, W.; Lim, J.; Amess, J.; Oza, A.; Barbui, T.; Horton, M.

    1990-01-01

    In a study conducted at St Bartholomew's Hospital between 1972 and 1982, using moderately intensive therapy (OPAL/HEAV'D), a low blast count at presentation (less than 10 x 10(9) 1(-1)) and common ALL (C-ALL) phenotype correlated favourably with duration of remission. Fifty-four patients (age range 15-57, median 32) subsequently received a modification of the previous treatment programme which included high-dose ara-C 2 g m-2 b.d. for 6 days as cycle 3 (OPAL + HD ARA-C). CR was achieved in 36/54 (67%) patients, response correlating favourably with younger age (15-30 years vs 31-57 years, P = 0.02). Three patients died in CR. Overall, there was no difference in survival or remission duration between patients who received high dose ara-C and those in the control group. However, in contrast to the early results, there was a reversal in the relevance of the prognostic factors with a trend in favour of high blast count (greater than 10 x 10(9) 1(-1)) and T-cell phenotype in terms of remission duration. Moreover, comparison of duration of remission for the previously defined prognostic groups according to therapy suggests that the prognosis of patients with 'high risk' disease (T, B, null ALL or high blast count) is improved with more intensive therapy. In contrast, those with 'low risk' disease (C-ALL and low blast count) have a better prognosis with less intensive therapy. These observations confirm those of others and allow for individualization of therapy on the basis of pre-treatment variables. PMID:2206954

  4. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans.

    PubMed

    Schwab, Ursula; Törrönen, Anneli; Meririnne, Esa; Saarinen, Markku; Alfthan, Georg; Aro, Antti; Uusitupa, Matti

    2006-01-01

    Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects. PMID:16365055

  5. Frequency and Effects of Excess Dosing of Anticoagulants in Patients ≤55 Years With Acute Myocardial Infarction Who Underwent Percutaneous Coronary Intervention (from the VIRGO Study).

    PubMed

    Gupta, Aakriti; Chui, Philip; Zhou, Shengfan; Spertus, John A; Geda, Mary; Lorenze, Nancy; Lee, Ike; D' Onofrio, Gail; Lichtman, Judith H; Alexander, Karen P; Krumholz, Harlan M; Curtis, Jeptha P

    2015-07-01

    Excess dosing of anticoagulant agents has been linked to increased risk of bleeding after percutaneous coronary intervention (PCI) for women compared with men, but these studies have largely included older patients. We sought to determine the prevalence and gender-based differences of excess dosing of anticoagulants including glycoprotein IIb/IIIa inhibitors, bivalirudin, and unfractionated heparin in young patients with acute myocardial infarction who underwent PCI and to examine its association with bleeding. Of 2,076 patients enrolled in the Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients study who underwent PCI, we abstracted doses of unfractionated heparin, bivalirudin, and glycoprotein IIb/IIIa inhibitors administered during PCI from the medical records. At least 47.2% received at least 1 excess dose of an anticoagulant, which did not differ by gender. We used logistic regression to determine the predictors of excess dosing and the association of excess dosing with bleeding. In multivariable analysis, only lower body weight and younger age were significant predictors of excess dosing. Bleeding was higher in young women who received excess dosing versus those who did not (9.3% vs 6.0%, p = 0.03) but was comparable among men (5.2% vs 5.9%, p = 0.69) in univariate analysis. In multivariable analysis, there was a trend to an association between excess dosing and bleeding (odds ratio 1.33, 95% confidence interval 0.92 to 1.91) although not statistically significant. In conclusion, approximately half of the patients received excess dosing of anticoagulant drugs during PCI, which did not vary based on gender. There was a trend toward an association between excess dosing and increased bleeding, although not statistically significant. PMID:25937348

  6. Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy

    PubMed Central

    Dean, Jamie A; Wong, Kee H; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

    2016-01-01

    Background and Purpose Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Material and Methods Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. Results The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. Conclusions The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. PMID:27240717

  7. The mechanism of action of a single dose of methylprednisolone on acute inflammation in vivo.

    PubMed Central

    Wiener, S L; Wiener, R; Urivetzky, M; Shafer, S; Isenberg, H D; Janov, C; Meilman, E

    1975-01-01

    A model system for the study of inflammation in vivo has been developed using the 16-h polyvinyl sponge implant in the rat. This system allows for simultaneous measurement of in vivo chemotaxis, volume of fluid influx, and fluid concentrations of lysosomal and lactic dehydrogenase (LDH) enzymes. In addition, the enzyme content of inflammatory fluid neutrophils may also be determined. A parallel time course of neutrophil and lysosomal enzyme influx into sponge implants was observed. This was characterized by an initial lag phase and a rapid increase between 5 and 16 h. The origin of supernatant LDH and lysosomal enzymes was studied with anti-neutrophil serum to produce agranulocytic rats. Inflammatory fluid in these rats was almost acellular and contained decreased concentrations of beta glucuronidase (-96%) and LDH (-74%). In control rats all of the supernatant beta glucuronidase could be accounted for by cell death and lysis, as estimated from measurements of soluble DNA. Only 15-20% of the LDH activity could be accounted for on the basis of cell lysis. The remainder was derived from neutrophil-mediated injury to connective tissue cells. Large intravascular doses of methylprednisolone markedly inhibited neutrophil influx into sponges and adjacent connective tissue. Secondary to decreased neutrophil influx, fewer neutrophils were available for lysis, and lysosomal enzyme levels in inflammatory fluid decreased. No evidence for intracellular or extracellular stabilization of neutrophil lysosomal granules by methylprenisolone was found. Images PMID:1159081

  8. Dose-Volume Relationships for Acute Bowel Toxicity in Patients Treated With Pelvic Nodal Irradiation for Prostate Cancer

    SciTech Connect

    Fiorino, Claudio Alongi, Filippo; Perna, Lucia; Broggi, Sara; Cattaneo, Giovanni Mauro; Cozzarini, Cesare; Di Muzio, Nadia; Fazio, Ferruccio; Calandrino, Riccardo

    2009-09-01

    Purpose: To find correlation between dose-volume histograms (DVHs) of the intestinal cavity (IC) and moderate-severe acute bowel toxicity in men with prostate cancer treated with pelvic nodal irradiation. Methods and Materials: The study group consisted of 191 patients with localized prostate cancer who underwent whole-pelvis radiotherapy with radical or adjuvant/salvage intent during January 2004 to November 2007. Complete planning/clinical data were available in 175 of these men, 91 of whom were treated with a conventional four-field technique (50.4 Gy, 1.8 Gy/fraction) and 84 of whom were treated with IMRT using conventional Linac (n = 26, 50.4 Gy, 1.8 Gy/fraction) or Helical TomoTherapy (n = 58, 50-54 Gy, 1.8-2 Gy/fraction). The IC outside the planning target volume (PTV) was contoured and the DVH for the first 6 weeks of treatment was recovered in all patients. The correlation between a number of clinical and DVH (V10-V55) variables and toxicity was investigated in univariate and multivariate analyses. The correlation between DVHs for the IC outside the PTV and DVHs for the whole IC was also assessed. Results: Twenty-two patients experienced toxicity (3/22 in the IMRT/tomotherapy group). Univariate analyses showed a significant correlation between V20-V50 and toxicity (p = 0.0002-0.001), with a higher predictive value observed for V40-V50. Previous prostatectomy (p = 0.066) and abdominal/pelvic surgery (p = 0.12) also correlated with toxicity. Multivariate analysis that included V45, abdominal/pelvic surgery, and prostatectomy showed that the most predictive parameters were V45 (p = 0.002) and abdominal/pelvic surgery (p = 0.05, HR = 2.4) Conclusions: Our avoidance IMRT approach drastically reduces the incidence of acute bowel toxicity. V40-V50 of IC and, secondarily, previous abdominal/pelvic surgery were the main predictors of acute bowel toxicity.

  9. Boron neutron capture therapy (BNCT) for malignant melanoma with special reference to absorbed doses to the normal skin and tumor.

    PubMed

    Fukuda, H; Hiratsuka, J; Kobayashi, T; Sakurai, Y; Yoshino, K; Karashima, H; Turu, K; Araki, K; Mishima, Y; Ichihashi, M

    2003-09-01

    Twenty-two patients with malignant melanoma were treated with boron neutron capture therapy (BNCT) using 10B-p-boronophenylalanine (BPA). The estimation of absorbed dose and optimization of treatment dose based on the pharmacokinetics of BPA in melanoma patients is described. The doses of gamma-rays were measured using small TLDs of Mg2SiO4 (Tb) and thermal neutron fluence was measured using gold foil and wire. The total absorbed dose to the tissue from BNCT was obtained by summing the primary and capture gamma-ray doses and the high LET radiation doses from 10B(n, alpha)7Li and 14N(n,p)14C reactions. The key point of the dose optimization is that the skin surrounding the tumour is always irradiated to 18 Gy-Eq, which is the maximum tolerable dose to the skin, regardless of the 10B-concentration in the tumor. The neutron fluence was optimized as follows. (1) The 10B concentration in the blood was measured 15-40 min after the start of neutron irradiation. (2) The 10B-concentration in the skin was estimated by multiplying the blood 10B value by a factor of 1.3. (3) The neutron fluence was calculated. Absorbed doses to the skin ranged from 15.7 to 37.1 Gy-Eq. Among the patients, 16 out of 22 patients exhibited tolerable skin damage. Although six patients showed skin damage that exceeded the tolerance level, three of them could be cured within a few months after BNCT and the remaining three developed severe skin damage requiring skin grafts. The absorbed doses to the tumor ranged from 15.7 to 68.5 Gy-Eq and the percentage of complete response was 73% (16/22). When BNCT is used in the treatment of malignant melanoma, based on the pharmacokinetics of BPA and radiobiological considerations, promising clinical results have been obtained, although many problems and issues remain to be solved. PMID:14626847

  10. Acute topiramate differentially affects human aggressive responding at low vs. moderate doses in subjects with histories of substance abuse and antisocial behavior.

    PubMed

    Lane, Scott D; Gowin, Joshua L; Green, Charles E; Steinberg, Joel L; Moeller, F Gerard; Cherek, Don R

    2009-04-01

    Anticonvulsant drugs have demonstrated efficacy in the management of irritability and aggression in a variety of psychiatric populations. We examined the acute effects of topiramate on aggression using a laboratory model of human aggression (PSAP) in individuals at high risk for aggressive and violent behavior.Twelve subjects, on parole/probation and with an Axis-II personality disorder and/or a substance use disorder, received 100, 200, 300, and 400 mg in an ascending sequence, with intervening placebo doses.Subjects participated 2-3 days per week over 4-6 weeks. Due to cognitive side effects at 300 mg, two subjects only completed through the 200 mg dose. Topiramate produced an inverted U-shaped dose response curve, with increases in aggression peaking at 200 mg and a modest decrease at 400 mg. Statistical analysis revealed a polynomial trend for dose (p=0.001). The observed inverted U-shaped function in aggressive responding is consistent with non-human aggression studies of GABA-A modulators. Acute topiramate doses >400 mg may have anti-aggressive effects, but dose levels in the 200-300 mg range may produce increases in aggression and side effects. PMID:19353809

  11. Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

    SciTech Connect

    Robertson, John M.; Soehn, Matthias; Yan Di

    2010-05-01

    Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

  12. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial

    PubMed Central

    Mielcarek, Marco; Furlong, Terrence; Storer, Barry E.; Green, Margaret L.; McDonald, George B.; Carpenter, Paul A.; Flowers, Mary E.D.; Storb, Rainer; Boeckh, Michael; Martin, Paul J.

    2015-01-01

    We conducted a phase III study to test the hypothesis that initial therapy with “lower dose” prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7–53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival. PMID:25682602

  13. No difference in frontal cortical activity during an executive functioning task after acute doses of aripiprazole and haloperidol

    PubMed Central

    Bolstad, Ingeborg; Andreassen, Ole A.; Groote, Inge R.; Haatveit, Beathe; Server, Andres; Jensen, Jimmy

    2015-01-01

    Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning. Methods: Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo before performing an executive functioning task while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. Results: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task-related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontal and temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference. Conclusion: No significant group differences between aripiprazole and haloperidol in frontal cortical activation were obtained when corrected for multiple comparisons. This study is registered in ClinicalTrials.gov (identifier: 2009-016222-14).1 PMID:26074803

  14. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

    PubMed

    Rühs, Hauke; Becker, Achim; Drescher, Anne; Panetta, John C; Pui, Ching-Hon; Relling, Mary V; Jaehde, Ulrich

    2012-01-01

    Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD) model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max) model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course. PMID:23049924

  15. Mitigation Effect of an FGF-2 Peptide on Acute Gastrointestinal Syndrome After High-Dose Ionizing Radiation

    SciTech Connect

    Zhang Lurong; Sun Weimin; Wang Jianjun; Zhang Mei; Yang Shanmin; Tian Yeping; Vidyasagar, Sadasivan; Pena, Louis A.; Zhang Kunzhong; Cao Yongbing; Yin Liangjie; Wang Wei; Zhang Lei; Schaefer, Katherine L.; Saubermann, Lawrence J.; Swarts, Steven G.; Fenton, Bruce M.; Keng, Peter C.; Okunieff, Paul

    2010-05-01

    Purpose: Acute gastrointestinal syndrome (AGS) resulting from ionizing radiation causes death within 7 days. Currently, no satisfactory agent exists for mitigation of AGS. A peptide derived from the receptor binding domain of fibroblast growth factor 2 (FGF-P) was synthesized and its mitigation effect on AGS was examined. Methods and Materials: A subtotal body irradiation (sub-TBI) model was created to induce gastrointestinal (GI) death while avoiding bone marrow death. After 10.5 to 16 Gy sub-TBI, mice received an intramuscular injection of FGF-P (10 mg/kg/day) or saline (0.2 ml/day) for 5 days; survival (frequency and duration) was measured. Crypt cells and their proliferation were assessed by hematoxylin, eosin, and BrdU staining. In addition, GI hemoccult score, stool formation, and plasma levels of endotoxin, insulin, amylase, interleukin (IL)-6, keratinocyte-derived chemokine (KC) monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF)-alpha were evaluated. Results: Treatment with FGF-P rescued a significant fraction of four strains of mice (33-50%) exposed to a lethal dose of sub-TBI. Use of FGF-P improved crypt survival and repopulation and partially preserved or restored GI function. Furthermore, whereas sub-TBI increased plasma endotoxin levels and several pro-inflammation cytokines (IL-6, KC, MCP-1, and TNF-alpha), FGF-P reduced these adverse responses. Conclusions: The study data support pursuing FGF-P as a mitigator for AGS.

  16. Effect of acute doses of controlled-release carbamazepine on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function.

    PubMed

    van der Meyden, C H; Bartel, P R; Sommers, D K; Blom, M; Becker, P; Erasmus, S; Griesel, D

    1992-01-01

    The neurotoxic effect of acute doses of carbamazepine controlled-release (CBZ-CR) divitabs (800, 1,200, and 1,600 mg) was assessed on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function in 10 healthy volunteers in a double-blind, randomised, placebo-controlled, phase I study. Significant changes compared to placebo were demonstrated for the clinical scales, ataxia (AT), convergence of the near-point (CNP), peak saccadic velocity (PSV), critical flicker fusion (CFF), spectral analysis of the EEG, and brainstem auditory evoked potential (BAEP) tests. Digit repetition, digit symbol substitution, Sternberg memory scanning time, Sternberg choice reaction time, saccadic latency, and saccadic accuracy showed important negative findings. Significant clinical tolerance to side effects developed within 20 to 33 h after CBZ-CR dosage during a period in which the mean CBZ blood levels remained virtually unchanged. CBZ-CR, 800, 1,200, and 1,600 mg yielded low, medium, and high therapeutic blood levels, respectively, for +10 to +33 h after dosage without the development of severe clinical side effects. PMID:1547763

  17. Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors

    PubMed Central

    Musha, Atsushi; Shimada, Hirofumi; Shirai, Katsuyuki; Saitoh, Jun-ichi; Yokoo, Satoshi; Chikamatsu, Kazuaki; Ohno, Tatsuya; Nakano, Takashi

    2015-01-01

    Purpose To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. Methods Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. Results The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. Conclusions The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM. PMID:26512725

  18. Quality audit of megavoltage radiotherapy units: intercomparison of dose at a reference point using a mailed TL-dosimetry system.

    PubMed

    Davis, B; Faessler, P

    1993-07-01

    A dosimetry intercomparison based on mailed TL-dosimeters and the well proven IAEA/EORTC phantom is described. Its aim is to identify discrepancies in dosimetry larger than +/- 3%. Dosimeters were mailed to all radiotherapy centres in Switzerland for irradiation with 2 Gy at a reference point in a water container, using photons and electrons. Thirty-six beams were monitored. The results show an agreement of within 2% for the majority of the beams monitored. Two electron beams were at 6% of the reference value. PMID:8234874

  19. Derivation of a bisphenol A oral reference dose (RfD) and drinking-water equivalent concentration.

    PubMed

    Willhite, Calvin C; Ball, Gwendolyn L; McLellan, Clifton J

    2008-02-01

    Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral doses. Controlled ingestion trials in healthy adult volunteers with 5 mg d16-BPA were unable to detect parent BPA in plasma despite exquisitely sensitive (limit of detection = 6 nM) methods, but by 96 h 100% of the administered dose was recovered in urine as the glucuronide. The extensive BPA glucuronidation following ingestion is not seen after parenteral injection; only the parent BPA binds plasma proteins and estrogen receptors (ER). The hypothesis that BPA dose-response may be described by a J- or U-shape curve was not supported by toxicogenomic data collected in fetal rat testes and epididymes (after repeated parenteral exposure at 2-400,000 microg/kg-d), where a clear monotonic dose-response both in the numbers of genes and magnitude of individual gene expression was evident. There is no clear indication from available data that the BPA doses normally consumed by humans pose an increased risk for immunologic or neurologic disease. There is no evidence that BPA poses a genotoxic or carcinogenic risk and clinical evaluations of 205 men and women with high-performance liquid chromatography (HPLC)-verified serum or urinary BPA conjugates showed (1) no objective signs, (2) no changes in reproductive hormones or clinical chemistry parameters, and (3) no alterations in the number of children or sons:daughters ratio. Results of benchmark dose (BMD10 and BMDL10) calculations and no-observed-adverse-effect level (NOAEL) inspections of all available and reproducible rodent studies with oral BPA found BMD and NOAEL values all greater than the 5 mg/kg-d NOAELs from mouse and rat multigeneration reproduction toxicity studies

  20. TU-F-BRE-09: Towards the Establishment of Dosimetric References in Small Fields Using the New Concept of Dose-Area Product

    SciTech Connect

    Dufreneix, S; Bordy, J; Delaunay, F; Delaunay, F; Daures, J; Gouriou, J; Le Roy, M; Ostrowsky, A; Rapp, B; Sommier, L

    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.

  1. Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

    NASA Astrophysics Data System (ADS)

    Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

    2014-02-01

    Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

  2. Comparison of acute proton, photon, and low-dose priming effects on genes associated with extracellular matrix and adhesion molecules in the lungs

    PubMed Central

    2013-01-01

    Background Crew members on space missions inevitably are exposed to low background radiation and can receive much higher doses during solar particle events (SPE) that consist primarily of protons. Ionizing radiation could cause lung pathologies. Cell adhesion molecules (CAM) are believed to participate in fibrogenesis. Interactions between CAM and extracellular matrix (ECM) affect epithelial repair mechanisms in the lung. However, there are very limited data on biological effects of protons on normal lung tissue. Numerous reports have shown that exposure to low-dose/low-dose-rate (LDR) radiation can result in radioadaptation that renders cells more resistant to subsequent acute radiation. The goal of this study was to compare expression of genes associated with ECM and CAM, as well as critical profibrotic mediators, in mouse lungs after acute irradiation with photons and protons, and also determine whether pre-exposure to LDR γ-rays induces an adaptive effect. Results Overall, a marked difference was present in the proton vs. photon groups in gene expression. When compared to 0 Gy, more genes were affected by protons than by photons at both time points (11 vs. 6 on day 21 and 14 vs. 8 on day 56), and all genes affected by protons were upregulated. Many genes were modulated by LDR γ-rays when combined with photons or protons. Col1a1, mmp14, and mmp15 were significantly upregulated by all radiation regimens on day 21. Similarly, the change in expression of profibrotic proteins was also detected after acute and combination irradiation. Conclusion These data show that marked differences were present between acutely delivered protons and photons in modulating genes, and the effect of protons was more profound than that of photons. Pre-exposure to LDR γ-rays ‘normalized’ some genes that were modified by acute irradiation. PMID:23374750

  3. Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities

    PubMed Central

    2013-01-01

    Background To identify predictive factors of radiation-induced skin toxicity in breast cancer patients by the analysis of dosimetric and clinical factors. Methods 339 patients treated between January 2007 and December 2010 are included in the present analysis. Whole breast irradiation was delivered with Conventional Fractionation (CF) (50Gy, 2.0/day, 25 fractions) and moderate Hypofractionated Schedule (HS) (44Gy, 2.75Gy/day, 16 fractions) followed by tumour bed boost. The impact of patient clinical features, systemic treatments and, in particular, dose inhomogeneities on the occurrence of different levels of skin reaction has been retrospectively evaluated. Results G2 and G3 acute skin toxicity were 42% and 13% in CF patients and 30% and 7.5% in HS patients respectively. The retrieval and revaluation of 200 treatment plans showed a strong correlation between areas close to the skin surface, with inhomogeneities >107% of the prescribed dose, and the desquamation areas as described in the clinical records. Conclusions In our experience dose inhomogeneity underneath G2 – G3 skin reactions seems to be the most important predictor for acute skin damage and in these patients more complex treatment techniques should be considered to avoid skin damage. Genetic polymorphisms too have to be investigated as possible promising candidates for predicting acute skin reactions. PMID:23651532

  4. High-dose methylprednisolone treatment of laser-induced retinal injury exacerbates acute inflammation and long-term scarring

    NASA Astrophysics Data System (ADS)

    Schuschereba, Steven T.; Cross, Michael E.; Scales, David K.; Pizarro, Jose M.; Edsall, Peter R.; Stuck, Bruce E.; Marshall, John

    1999-06-01

    Purpose. To evaluate therapeutics for attenuating retinal laser injury. Methods. New Zealand Red rabbits (n=76) were pretreated (IV) with either a single dose of hydroxyethyl starch conjugated deferoxamine (HES-DFO, n=29) (6.1 ml/kg, 16.4 mg/ml) or methylprednisolone sodium succinate (MP, n=22) (30 mg/kg, followed by taper of 30, 20, 20, and 10 mg/kg/day for a total of 5d). Controls were untreated (n=25). Fifteen min later, animals were irradiated with a multiline cw argon laser (285 mW, 10 msec pulse durations, 16 lesions/eye). Funduscopy, fluorescein angiography, histology, and morphometry were performed at 10 min, 1h, 3h, 24h, 1 mo, and 6 mo after irradiation. Leukocytes were counted at lesion centers for retinal and choroidal compartments at 1, 3, and 24h. Results. At 3h, percent area incrase for the lesions was highest for MP (44%) and lowest for HES-DFO (16%)(p<0.05). In hemorrhagic lesions, MP treatment resulted in the highest increase of retinal neotrophils by 24h (p<0.05), and by 1 and 6 mo extensive chorio-retinal scarring occurred in nonhemorrhagic and hemorrhagic lesions. Also, no benefit was demonstrated on sparing of photoreceptors with MP treatment. Conclusions. Treatment of laser-induced retinal injury with methylprednisolone (MP) exacerbates acute inflammation and long-term chorio-retinal scarring; however, hydroxyethyl starch conjugated deferoxamine therapy ameliorates these aspects of injury. Data suggest caution in the use of MP therapy for laser injuries.

  5. Radiation dose in coronary angiography and intervention: initial results from the establishment of a multi-centre diagnostic reference level in Queensland public hospitals

    SciTech Connect

    Crowhurst, James A; Whitby, Mark; Thiele, David; Halligan, Toni; Westerink, Adam; Crown, Suzanne; Milne, Jillian

    2014-09-15

    Radiation dose to patients undergoing invasive coronary angiography (ICA) is relatively high. Guidelines suggest that a local benchmark or diagnostic reference level (DRL) be established for these procedures. This study sought to create a DRL for ICA procedures in Queensland public hospitals. Data were collected for all Cardiac Catheter Laboratories in Queensland public hospitals. Data were collected for diagnostic coronary angiography (CA) and single-vessel percutaneous intervention (PCI) procedures. Dose area product (P{sub KA}), skin surface entrance dose (K{sub AR}), fluoroscopy time (FT), and patient height and weight were collected for 3 months. The DRL was set from the 75th percentile of the P{sub KA.} 2590 patients were included in the CA group where the median FT was 3.5 min (inter-quartile range = 2.3–6.1). Median K{sub AR} = 581 mGy (374–876). Median P{sub KA} = 3908 uGym{sup 2} (2489–5865) DRL = 5865 uGym{sup 2}. 947 patients were included in the PCI group where median FT was 11.2 min (7.7–17.4). Median K{sub AR} = 1501 mGy (928–2224). Median P{sub KA} = 8736 uGym{sup 2} (5449–12,900) DRL = 12,900 uGym{sup 2}. This study established a benchmark for radiation dose for diagnostic and interventional coronary angiography in Queensland public facilities.

  6. Acute and chronic intakes of fallout radionuclides by Marshallese from nuclear weapons testing at Bikini and Enewetak and related internal radiation doses.

    PubMed

    Simon, Steven L; Bouville, André; Melo, Dunstana; Beck, Harold L; Weinstock, Robert M

    2010-08-01

    Annual internal radiation doses resulting from both acute and chronic intakes of all important dose-contributing radionuclides occurring in fallout from nuclear weapons testing at Bikini and Enewetak from 1946 through 1958 have been estimated for the residents living on all atolls and separate reef islands of the Marshall Islands. Internal radiation absorbed doses to the tissues most at risk to cancer induction (red bone marrow, thyroid, stomach, and colon) have been estimated for representative persons of all population communities for all birth years from 1929 through 1968, and for all years of exposure from 1948 through 1970. The acute intake estimates rely on a model using, as its basis, historical urine bioassay data, for members of the Rongelap Island and Ailinginae communities as well as for Rongerik residents. The model also utilizes fallout times of arrival and radionuclide deposition densities estimated for all tests and all atolls. Acute intakes of 63 radionuclides were estimated for the populations of the 20 inhabited atolls and for the communities that were relocated during the testing years for reasons of safety and decontamination. The model used for chronic intake estimates is based on reported whole-body, urine, and blood counting data for residents of Utrik and Rongelap. Dose conversion coefficients relating intake to organ absorbed dose were developed using internationally accepted models but specifically tailored for intakes of particulate fallout by consideration of literature-based evidence to choose the most appropriate alimentary tract absorption fraction (f1) values. Dose estimates were much higher for the thyroid gland than for red marrow, stomach wall, or colon. The highest thyroid doses to adults were about 7,600 mGy for the people exposed on Rongelap; thyroid doses to adults were much lower, by a factor of 100 or more, for the people exposed on the populated atolls of Kwajalein and Majuro. The estimates of radionuclide intake and

  7. ACUTE AND CHRONIC INTAKES OF FALLOUT RADIONUCLIDES BY MARSHALLESE FROM NUCLEAR WEAPONS TESTING AT BIKINI AND ENEWETAK AND RELATED INTERNAL RADIATION DOSES

    PubMed Central

    Simon, Steven L.; Bouville, André; Melo, Dunstana; Beck, Harold L.; Weinstock, Robert M.

    2014-01-01

    Annual internal radiation doses resulting from both acute and chronic intakes of all important dose-contributing radionuclides occurring in fallout from nuclear weapons testing at Bikini and Enewetak from 1946 through 1958 have been estimated for the residents living on all atolls and separate reef islands of the Marshall Islands. Internal radiation absorbed doses to the tissues most at risk to cancer induction (red bone marrow, thyroid, stomach, and colon) have been estimated for representative persons of all population communities for all birth years from 1929 through 1968, and for all years of exposure from 1948 through 1970. The acute intake estimates rely on a model using, as its basis, historical urine bioassay data, for members of the Rongelap Island and Ailinginae communities as well as for Rongerik residents. The model also utilizes fallout times of arrival and radionuclide deposition densities estimated for all tests and all atolls. Acute intakes of 63 radionuclides were estimated for the populations of the 20 inhabited atolls and for the communities that were relocated during the testing years for reasons of safety and decontamination. The model used for chronic intake estimates is based on reported whole-body, urine, and blood counting data for residents of Utrik and Rongelap. Dose conversion coefficients relating intake to organ absorbed dose were developed using internationally accepted models but specifically tailored for intakes of particulate fallout by consideration of literature-based evidence to choose the most appropriate alimentary tract absorption fraction (f1) values. Dose estimates were much higher for the thyroid gland than for red marrow, stomach wall, or colon. The highest thyroid doses to adults were about 7,600 mGy for the people exposed on Rongelap; thyroid doses to adults were much lower, by a factor of 100 or more, for the people exposed on the populated atolls of Kwajalein and Majuro. The estimates of radionuclide intake and

  8. Profiles of 5-HT 1B/1D agonists in acute migraine with special reference to second generation agents.

    PubMed

    Deleu, D; Hanssens, Y

    1999-06-01

    The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan. PMID:10427351

  9. Comparison BIPM.RI(I)-K8 of high dose-rate Ir-192 brachytherapy standards for reference air kerma rate of the PTB and the BIPM

    NASA Astrophysics Data System (ADS)

    Kessler, C.; Allisy-Roberts, P. J.; Selbach, H. J.

    2015-01-01

    An indirect comparison of the standards for reference air kerma rate (RAKR) for 192Ir high dose rate (HDR) brachytherapy sources of the Physikalisch-Technische Bundesanstalt (PTB), Germany, and of the Bureau International des Poids et Mesures (BIPM) was carried out at the PTB in September 2011. The comparison result, based on the calibration coefficients for a transfer standard and expressed as a ratio of the PTB and the BIPM standards for reference air kerma rate, is 1.0003 with a combined standard uncertainty of 0.0099. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCRI, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  10. Comparison BIPM.RI(I)-K8 of high dose-rate Ir-192 brachytherapy standards for reference air kerma rate of the NRC and the BIPM

    NASA Astrophysics Data System (ADS)

    Kessler, C.; Downton, B.; Mainegra-Hing, E.

    2015-01-01

    An indirect comparison of the standards for reference air kerma rate for 192Ir high dose rate (HDR) brachytherapy sources of the National Research Council (NRC), Canada, and of the Bureau International des Poids et Mesures (BIPM) was carried out at the NRC in August 2014. The comparison result, based on the calibration coefficients for a transfer standard and expressed as a ratio of the NRC and the BIPM standards for reference air kerma rate, is 0.9966 with a combined standard uncertainty of 0.0050. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCRI, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  11. Report on the technical review workshop on the reference dose for Aroclor 1016. Held in Washington, DC on May 24-25, 1994

    SciTech Connect

    1994-11-01

    The report includes information and material from a technical review workshop organized by the U.S. Environmental Protection Agency`s (EPA`s) Risk Assessment Forum for EPA`s Reference Dose/Reference Concentration (RfD/RfC) Work Group. The meeting was held in Washington, DC, at the Barcelo Washington Hotel on May 24-25, 1994. The subject of the technical review was the Integrated Risk Information System (IRIS) RfD entry for Aroclor 1016, a polychlorinated biphenyl (PCB). The expert technical review panel was convened to independently evaluate whether the RfD for Aroclor 1016 is based on a scientifically responsible analysis that represents full consideration of the available data and clean articulation of that analysis in the IRIS RfD entry. EPA also requested panel members to consider four broad options for the Aroclor 1016 RfD as potential recommendations to the RfD/RfC Work Group.

  12. Comparison BIPM.RI(I)-K8 of high dose-rate Ir-192 brachytherapy standards for reference air kerma rate of the NMIJ and the BIPM

    NASA Astrophysics Data System (ADS)

    Kessler, C.; Kurosawa, T.; Mikamoto, T.

    2016-01-01

    An indirect comparison of the standards for reference air kerma rate for 192Ir high dose rate (HDR) brachytherapy sources of the National Metrology Institute of Japan (AIST-NMIJ), Japan, and of the Bureau International des Poids et Mesures (BIPM) was carried out at the Japan Radioisotope Association (JRIA) in April 2015. The comparison result, based on the calibration coefficients for a transfer standard and expressed as a ratio of the NMIJ and the BIPM standards for reference air kerma rate, is 1.0036 with a combined standard uncertainty of 0.0054. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCRI, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  13. Acute Type A Aortic Dissection Presenting as ST-Segment Elevation Myocardial Infarction Referred for Primary Percutaneous Coronary Intervention

    PubMed Central

    Wang, Jian-Liung; Chen, Chun-Chi; Wang, Chao-Yung Wang; Hsieh, Ming-Jer; Chang, Shang-Hung; Lee, Cheng-Hung; Chen, Dong-Yi; Hsieh, I-Chang

    2016-01-01

    Background When acute aortic dissection is complicated with acute myocardial infarction, the diagnosis of dissection can be problematic. In these cases, patients might be treated with primary percutaneous coronary intervention (PCI) and suffer acatastrophic outcome. However, there are few reports or algorithm to facilitate the accurate management of this clinical situation. Methods We evaluated 385 consecutive patients who underwent primary PCI arising from an initial diagnosis of STEMI at our hospitalbetween January 2006 and March 2011. Clinical characteristics, coronary angiographic findings, and outcomes were obtained from medical charts and databases. Results Five patients (1.3%) with STEMI secondary to aortic dissection were identified. All patients (100%) had sudden-onset of chest pain and a history of hypertension without diabetes or hyperlipidemia. An increased resistance while advancing the diagnostic catheter was reported by the operators in 3 of 5 patients (60%). Aortography performed by manual contrast-medium injection showed the discrepancy in the diameter between the aortic root and the ascending aorta in 4 patients (100%), and ascending aortic intimal flap dissections were noted in 3 patients (75%). Alternating appearance and disappearance of the coronary artery ostium was observed in 2 patients, and bedside echocardiography showed intimal flap extension inall 4 patients (100%) who underwent this examination. The mortality rate at 30days was 40%. Conclusions We construct an algorithm that incorporated factors including careful history evaluation, bedside echocardiography, resistance encountered while advancing a catheter, and findings of aortography performed with manual injection,which could b evaluable for this clinical situation.

  14. Evaluating the consistency of location of the most severe acute skin reaction and highest skin dose measured by thermoluminescent dosimeter during radiotherapy for breast cancer.

    PubMed

    Sun, Li-Min; Huang, Chih-Jen; Chen, Hsiao-Yun; Chang, Gia-Hsin; Tsao, Min-Jen

    2016-01-01

    We conducted this prospective study to evaluate whether the location of the most severe acute skin reaction matches the highest skin dose measured by thermoluminescent dosimeter (TLD) during adjuvant radiotherapy (RT) for patients with breast cancer after breast conservative surgery. To determine whether TLD measurement can reflect the location of the most severe acute skin reaction, 80 consecutive patients were enrolled in this prospective study. We divided the irradiated field into breast, axillary, inframammary fold, and areola/nipple areas. In 1 treatment session when obvious skin reaction occurred, we placed the TLD chips onto the 4 areas and measured the skin dose. We determined whether the highest measured skin dose area is consistent with the location of the most severe skin reaction. The McNemar test revealed that the clinical skin reaction and TLD measurement are more consistent when the most severe skin reaction occurred at the axillary area, and the p = 0.0108. On the contrary, TLD measurement of skin dose is less likely consistent with clinical observation when the most severe skin reaction occurred at the inframammary fold, breast, and areola/nipple areas (all the p > 0.05). Considering the common site of severe skin reaction over the axillary area, TLD measurement may be an appropriate way to predict skin reaction during RT. PMID:27158022

  15. Letter report: References for radioactive releases to the atmosphere from Hanford operations, 1944--1957. Hanford Environmental Dose Reconstruction Project

    SciTech Connect

    Hall, R.B.

    1991-11-01

    A search was made for published documents related to discharges of radioactive material from Hanford Site facilities to the atmosphere from 1944--1957. The purpose was to list documents that contain data that might be useful in developing a source term for airborne releases. The source term for the radionuclide that contributes most to dose, ioidine-131, is a separate effort. Other source terms will be developed later. This tabulation of published summaries of atmospheric release data shows the type of measurements that were being made from 1944--1957 and the magnitude of the discharges to the atmosphere. In the early years, very little data were collected that related to specific radionuclides. However, most of the key radionuclides were known to be present in effluents from occasional specific radionuclide analyses. 2 refs.

  16. Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

    PubMed Central

    Cornely, Oliver A.; Böhme, Angelika; Schmitt-Hoffmann, Anne

    2015-01-01

    Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n = 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n = 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n = 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.) PMID:25624327

  17. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia.

    PubMed

    Pandina, Gahan J; Lindenmayer, Jean-Pierre; Lull, Julia; Lim, Pilar; Gopal, Srihari; Herben, Virginie; Kusumakar, Vivek; Yuen, Eric; Palumbo, Joseph

    2010-06-01

    This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia. PMID:20473057

  18. Dose to the Bladder Neck Is the Most Important Predictor for Acute and Late Toxicity After Low-Dose-Rate Prostate Brachytherapy: Implications for Establishing New Dose Constraints for Treatment Planning

    SciTech Connect

    Hathout, Lara; Folkert, Michael R.; Kollmeier, Marisa A.; Yamada, Yoshiya; Cohen, Gil'ad N.; Zelefsky, Michael J.

    2014-10-01

    Purpose: To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose-rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT). Methods and Materials: From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC). Results: Grade ≥2 AUT and grade ≥2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001). Conclusions: Bladder neck D2cc >50% was the strongest predictor for grade ≥2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity.

  19. Acute intake assessment: evolution within the Codex Committee on Pesticide Residues. WHO Joint Secretary of the Joint FAO/WHO meeting on pesticide residues JMPR.

    PubMed

    Herrman, J L

    2000-07-01

    The Codex Committee on Pesticide Residues (CCPR), in its development of international standards, has been considering during the last few years the implications of residues of acutely toxic pesticides in food commodities. CCPR has asked its scientific advisory body, the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), for advice on the safety of the standards that are being developed. This work began in 1993. The 1994 JMPR first decided to use the 'acute reference dose' as a toxicological benchmark for a 'short-term ADI'. A number of acute reference doses have been allocated at subsequent meetings. The 1998 JMPR decided to consider the allocation of an acute reference dose whenever a full evaluation of a pesticide is undertaken. General guidance for the allocation of an acute reference dose was provided by the 1998 JMPR, which is discussed in this paper. PMID:10983577

  20. Association of aspirin dose and vorapaxar safety and efficacy in patients with non-ST-segment elevation acute coronary syndrome (from the TRACER Trial).

    PubMed

    Mahaffey, Kenneth W; Huang, Zhen; Wallentin, Lars; Storey, Robert F; Jennings, Lisa K; Tricoci, Pierluigi; White, Harvey D; Armstrong, Paul W; Aylward, Philip E; Moliterno, David J; Van de Werf, Frans; Chen, Edmond; Leonardi, Sergio; Rorick, Tyrus; Held, Claes; Strony, John; Harrington, Robert A

    2014-03-15

    Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies

  1. Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection

    PubMed Central

    Cheng, Chu-Hsun; Lin, Chi-Te; Lee, Meng-Jen; Tsai, May-Jywan; Huang, Wen-Hung; Huang, Ming-Chao; Lin, Yi-Lo; Chen, Ching-Jung

    2015-01-01

    Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in

  2. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    PubMed Central

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Background: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. Conclusion: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile. PMID:21625399

  3. Does Pre-Treatment with High Dose Atorvastatin Prevent Microvascular Dysfunction after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome?

    PubMed Central

    Lee, Bong-Ki; Nam, Chang-Wook; Doh, Joon-Hyung; Chung, Woo-Young; Cho, Byung-Ryul; Fearon, William F.

    2016-01-01

    Background and Objectives There is controversy surrounding whether or not high dose statin administration before percutaneous coronary intervention (PCI) decreases peri-procedural microvascular injury. We performed a prospective randomized study to investigate the mechanisms and effects of pre-treatment high dose atorvastatin on myocardial damage in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing PCI. Subjects and Methods Seventy seven patients with NSTE-ACS were randomly assigned to either the high dose group (atorvastatin 80 mg loading 12 to 24 h before PCI with a further 40 mg loading 2 h before PCI, n=39) or low dose group (atorvastatin 10 mg administration 12 to 24 h before PCI, n=38). Index of microcirculatory resistance (IMR) was measured after stent implantation. Creatine kinase-myocardial band (CK-MB) and high sensitivity C-reactive protein (CRP) levels were measured before and after PCI. Results The baseline characteristics were not different between the two patient groups. Compared to the low dose group, the high dose group had lower post PCI IMR (14.1±5.0 vs. 19.2±9.3 U, p=0.003). Post PCI CK-MB was also lower in the high dose group (median: 1.40 ng/mL (interquartile range [IQR: 0.75 to 3.45] vs. 4.00 [IQR: 1.70 to 7.37], p=0.002) as was the post-PCI CRP level (0.09 mg/dL [IQR: 0.04 to 0.16] vs. 0.22 [IQR: 0.08 to 0.60], p=0.001). Conclusion Pre-treatment with high dose atorvastatin reduces peri-PCI microvascular dysfunction verified by post-PCI IMR and exerts an immediate anti-inflammatory effect in patients with NSTE-ACS. PMID:27482255

  4. Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease After Double-Unit Cord Blood Transplantation

    PubMed Central

    Harnicar, S.; Ponce, D.M.; Hilden, P.; Zheng, J.; Devlin, S.M.; Lubin, M.; Pozotrigo, M.; Mathew, S.; Adel, N.; Kernan, N.A.; O'Reilly, R.; Prockop, S.; Scaradavou, A.; Hanash, A.; Jenq, R.; van den Brink, M.; Giralt, S.; Perales, M.A.; Young, J.W.; Barker, J.N.

    2015-01-01

    While mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit CBT (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 double-unit CBT recipients (median age 39 years, range 1–71) transplanted for hematologic malignancies. Recipients of a MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III-IV acute GVHD (aGVHD) incidence compared with patients who received > 36 mg/kg/day (24% versus 8%, p = 0.008). Recipients of ≤ the median dose who had highly HLA-allele (1-3/6) mismatched dominant units had the highest day 100 grade III-IV aGVHD incidence of 37% (p = 0.009). This finding was confirmed in multivariate analysis (p = 0.053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1-2 trough < 0.5 mcg/mL had an increased day 100 grade III-IV aGVHD of 26% versus 9% (p = 0.063), and those who received a low total daily MMF dose and had a low week 1-2 MPA trough had a 40% incidence (p = 0.008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in mg/kg/day and MPA trough level monitoring early post-transplant in dCBT recipients. PMID:25687796

  5. Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: the effect of dose rate on acute respiratory tract inflammation

    PubMed Central

    2014-01-01

    Background The increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose–response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant. Methods F-344 rats were exposed to the same deposited doses of titanium dioxide (TiO2) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure. Results Although the initial lung burdens of TiO2 were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO2 instillation compared to saline controls and to TiO2 inhalation, whereas TiO2 inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO2 inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends

  6. Assessment of Local Dose Reference Values for Recanalization of Chronic Total Occlusions and Other Occlusions in a High-Volume Catheterization Center.

    PubMed

    Maccia, Carlo; Malchair, Françoise; Gobert, Isabelle; Louvard, Yves; Lefevre, Thierry

    2015-10-15

    The increasing number and complexity of these procedures have led to a higher number of patients at risk for tissue reactions like skin injuries. Monitoring of their dose indicators is essential in recognizing these patients. The aim of this work was to determine local diagnostic reference levels (DRLs) for recanalization of chronic total occlusion (CTO) and other occlusions procedures. All data from patients who underwent cardiac procedures were reviewed and classified according to their complexity. Dose indicators such as fluoroscopy time (FT), dose area product (DAP), and air kerma at patient entrance reference point (AKr) were recorded. Correlations with patient's body mass index, operators, procedure strategy, and complexity were studied. For CTO, the mean DAP, AKr, and FT were 252 ± 234 Gycm(2), 3,985 ± 3,579 mGy, and 47 ± 36 minutes, respectively. To better reflect the non-Gaussian distribution of data, the median and the 75th percentile values were also reported: median DAP, 172 Gycm(2); 75th percentile DAP, 350 Gycm(2); median AKr, 2,714 mGy; and 75th percentile AKr, 5,921 mGy. A tentative new set of values were suggested to take into account the complexity difference in recanalization of total occlusions according to their antegrade or retrograde approach. These approach-specific DRLs for total occlusions were mean DAP (120 ± 114 Gycm(2)), mean AKr (1,789 ± 1,933 mGy), and mean FT (22 ± 18 minutes) for antegrade approach and mean DAP (459 ± 304 Gycm(2)), mean AKr (6,881 ± 4,243 mGy), and mean FT (82 ± 40 minutes) for retrograde approach. The other significant values were median DAP (84 Gycm(2)), 75th percentile DAP (147 Gycm(2)), median AKr (1,160 mGy), and 75th percentile AKr (2,176 mGy) for antegrade approach and median DAP (422 Gycm(2)), 75th percentile DAP (552 Gycm(2)), median AKr (6,295 mGy), and 75th percentile AKr (8,064 mGy) for retrograde approach. In conclusion, a set of local DRL values from a large center were assessed

  7. 5-Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High-Dose Chemotherapy.

    PubMed

    Polishchuk, Veronika; Khazal, Sajad; Berulava, Giorgi; Roth, Michael; Mahadeo, Kris M

    2016-06-01

    Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high-dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5-azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post-HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5-azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy. PMID:26914221

  8. LOCAT (low-dose computed tomography for appendicitis trial) comparing clinical outcomes following low- vs standard-dose computed tomography as the first-line imaging test in adolescents and young adults with suspected acute appendicitis: study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Computed tomography is widely used to diagnose acute appendicitis. Many adolescents and young adults are exposed to the associated radiation. A recent single-institution trial has reported promising results for low-dose computed tomography; however, this technique has not yet been widely adopted. LOCAT (low-dose computed tomography for appendicitis trial), a multi-institution randomized controlled non-inferiority trial, aims to compare low-dose computed tomography and standard-dose computed tomography as the first-line imaging tests for adolescents and young adults, and therefore to test the generalizability of the previous single-institution trial results. Methods/Design Participants with suspected appendicitis are randomly assigned to either the low-dose group (with a typical effective dose of 2 mSv) or the standard-dose group (as used in normal practice at each participating site, typically 8 mSv). The primary end point is the negative appendectomy rate (the percentage of the number of uninflamed appendices that were removed among all non-incidental appendectomies), which is a consequence of false-positive diagnoses, with a non-inferiority margin of 4.5 percentage points. The key secondary end point is the appendiceal perforation rate, which is a consequence of delayed (or false-negative) diagnoses. Participant recruitment will be continued until the number of non-incidental appendectomies for each group exceeds 444. The total number of expected participants approximates 3,000, including those not undergoing appendectomy. Discussion In addition to the study protocol, we elaborate on several challenging or potentially debatable components of the study design, including the broad eligibility criteria, choice of the primary end point, potential effect of using advanced imaging techniques on study results, determining and adjusting the radiation doses, ambiguities in reference standards, rationale for the non-inferiority margin, use of the intention

  9. Cytokine profile of conditioned medium from human tumor cell lines after acute and fractionated doses of gamma radiation and its effect on survival of bystander tumor cells.

    PubMed

    Desai, Sejal; Kumar, Amit; Laskar, S; Pandey, B N

    2013-01-01

    Cytokines are known to play pivotal roles in cancer initiation, progression and pathogenesis. Accumulating evidences suggest differences in basal and stress-induced cytokine profiles of cancers with diverse origin. However, a comprehensive investigation characterising the cytokine profile of various tumor types after acute and fractionated doses of gamma-irradiation, and its effect on survival of bystander cells is not well known in literature. In the present study, we have evaluated the cytokine secretion profile of human tumor cell lines (HT1080, U373MG, HT29, A549 and MCF-7) either before (basal) or after acute (2, 6 Gy) and fractionated doses (3×2 Gy) of gamma-irradiation in culture medium obtained from these cells by multiplex bead array/ELISA. Moreover, clonogenic assays were performed to evaluate the effect of conditioned medium (CM) on the survival and growth of respective cells. Based on the screening of 28 analytes, our results showed that the basal profiles of these cell lines varied considerably in terms of the number and magnitude of secreted factors, which was minimum in MCF-7. Interestingly, TNF-α, IL-1β, PDGF-AA, TGF-β1, fractalkine, IL-8, VEGF and GCSF were found in CM of all the cell lines. However, secretion of certain cytokines was cell line-specific. Moreover, CM caused increase in clonogenic survival of respective tumor cells (in the order HT1080>U373MG>HT29>A549>MCF-7), which was correlated with the levels of IL-1β, IL-6, IL-8, GMCSF and VEGF in their CM. After irradiation, the levels of most of the cytokines increased markedly in a dose dependent manner. The fold change in cytokine levels was lower in irradiated conditioned medium (ICM) of tumor cells collected after fractionated than respective acute dose, except in MCF-7. Interestingly, amongst these cell lines, the radiation-induced fold increase in cytokine levels was maximum in ICM of A549 cells. Moreover, bystander A549 cells treated with respective ICM showed dose dependent

  10. Predictors for Rectal and Intestinal Acute Toxicities During Prostate Cancer High-Dose 3D-CRT: Results of a Prospective Multicenter Study

    SciTech Connect

    Vavassori, Vittorio; Fiorino, Claudio . E-mail: fiorino.claudio@hsr.it; Rancati, Tiziana; Magli, Alessandro; Fellin, Gianni; Baccolini, Michela; Bianchi, Carla; Cagna, Emanuela; Mauro, Flora A.; Monti, Angelo F.; Munoz, Fernando; Stasi, Michele; Franzone, Paola; Valdagni, Riccardo

    2007-04-01

    Purpose: To find predictors for rectal and intestinal acute toxicity in patients with prostate cancer treated with {>=}70 Gy conformal radiotherapy. Methods and Materials: Between July 2002 and March 2004, 1,132 patients were entered into a cooperative study (AIROPROS01-02). Toxicity was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale and by considering the changes (before and after treatment) of the scores of a self-administered questionnaire on rectal/intestinal toxicity. The correlation with a number of parameters was assessed by univariate and multivariate analyses. Concerning the questionnaire, only moderate/severe complications were considered. Results: Of 1,132 patients, 1,123 were evaluable. Of these patients, 375, 265, and 28 had Grade 1, 2, and 3 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity, respectively. The mean rectal dose was the most predictive parameter (p = 0.0004; odds ratio, 1.035) for Grade 2 or worse toxicity, and the use of anticoagulants/antiaggregants (p 0.02; odds ratio, 0.63) and hormonal therapy (p = 0.04, odds ratio, 0.65) were protective. The questionnaire-based scoring revealed that a greater mean rectal dose was associated with a greater risk of bleeding; larger irradiated volumes were associated with frequency, tenesmus, incontinence, and bleeding; hormonal therapy was protective against frequency and tenesmus; hemorrhoids were associated with a greater risk of tenesmus and bleeding; and diabetes associated highly with diarrhea. Conclusion: The mean rectal dose correlated with acute rectal/intestinal toxicity in three-dimensional conformal radiotherapy for prostate cancer, and hormonal therapy and the use of anticoagulants/antiaggregants were protective. According to the moderate/severe injury scores on the self-assessed questionnaire, several clinical and dose-volume parameters were independently predictive for

  11. A comparison of mean glandular dose diagnostic reference levels within the all-digital Irish National Breast Screening Programme and the Irish Symptomatic Breast Services.

    PubMed

    O'Leary, Desiree; Rainford, Louise

    2013-03-01

    Data on image quality, compression and radiation dose were collected from symptomatic breast units within the Republic of Ireland. Quantitative and qualitative data were analysed using SPSS. Recommendations of mean glandular dose (MGD) diagnostic reference levels were made at various levels for film-screen and full field digital mammography units to match levels published worldwide. MGDs received by symptomatic breast patients within Ireland are higher than those received in the all-digital Irish Breast Screening service; 55-65 mm breast: 1.75 mGy (screening) vs. 2.4 mGy (symptomatic) at the 95th percentile; various reasons are proposed for the differences. MGDs achieved in the screening service may be lower because of the exacting requirements for radiographer training, characteristics of the patients and equipment quality assurance levels. More precise imaging guidelines, standards and training of symptomatic radiographers performing mammography are suggested to remediate MGDs delivered to the breasts of Irish women attending the symptomatic breast services. PMID:22740646

  12. Fluence-to-dose conversion coefficients based on the posture modification of Adult Male (AM) and Adult Female (AF) reference phantoms of ICRP 110

    NASA Astrophysics Data System (ADS)

    Galeano, D. C.; Santos, W. S.; Alves, M. C.; Souza, D. N.; Carvalho, A. B.

    2016-04-01

    The aim of this work was to modify the standing posture of the anthropomorphic reference phantoms of ICRP publication 110, AM (Adult Male) and AF (Adult Female), to the sitting posture. The change of posture was performed using the Visual Monte Carlo software (VMC) to rotate the thigh region of the phantoms and position it between the region of the leg and trunk. Scion Image software was used to reconstruct and smooth the knee and hip contours of the phantoms in a sitting posture. For 3D visualization of phantoms, the VolView software was used. In the change of postures, the organ and tissue masses were preserved. The MCNPX was used to calculate the equivalent and effective dose conversion coefficients (CCs) per fluence for photons for six irradiation geometries suggested by ICRP publication 110 (AP, PA, RLAT, LLAT, ROT and ISO) and energy range 0.010-10 MeV. The results were compared between the standing and sitting postures, for both sexes, in order to evaluate the differences of scattering and absorption of radiation for different postures. Significant differences in the CCs for equivalent dose were observed in the gonads, colon, prostate, urinary bladder and uterus, which are present in the pelvic region, and in organs distributed throughout the body, such as the lymphatic nodes, muscle, skeleton and skin, for the phantoms of both sexes. CCs for effective dose showed significant differences of up to 16% in the AP irradiation geometry, 27% in the PA irradiation geometry and 13% in the ROT irradiation geometry. These results demonstrate the importance of using phantoms in different postures in order to obtain more precise conversion coefficients for a given exposure scenario.

  13. The Impact of Comorbid Depression on Educational Inequality in Survival after Acute Coronary Syndrome in a Cohort of 83 062 Patients and a Matched Reference Population

    PubMed Central

    Osler, Merete; Prescott, Eva; Wium-Andersen, Ida Kim; Ibfelt, Else Helene; Jørgensen, Martin Balslev; Andersen, Per Kragh; Jørgensen, Terese Sara Høj; Wium-Andersen, Marie Kim; Mårtensson, Solvej

    2015-01-01

    Background Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression. Methods From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses. Findings During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow-up. Conclusion In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression. PMID:26513652

  14. CATEGORICAL REGRESSION ANALYSIS OF ACUTE INHALATION TOXICITY DATA FOR HYDROGEN SULFIDE

    EPA Science Inventory

    Categorical regression is one of the tools offered by the U.S. EPA for derivation of acute reference exposures (AREs), which are dose-response assessments for acute exposures to inhaled chemicals. Categorical regression is used as a meta-analytical technique to calculate probabi...

  15. Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies.

    PubMed Central

    Lister, P D; Pong, A; Chartrand, S A; Sanders, C C

    1997-01-01

    To evaluate whether increased doses of amoxicillin should be used to treat acute pneumococcal otitis media, an in vitro pharmacokinetic model was used to evaluate the killing of pneumococci by amoxicillin when middle ear pharmacokinetics were simulated. Logarithmic-phase cultures were exposed to peak concentrations of 3, 6, and 9 microg of amoxicillin per ml every 12 h, and an elimination half-life of 1.6 h was simulated. Changes in viable bacterial counts were measured over 36 h. All three doses rapidly decreased the viable bacterial counts of penicillin-susceptible strains below the 10-CFU/ml limit of detection by 6 to 10 h and maintained counts below this limit through 36 h. The 3-microg/ml peak dose was much less effective against two of three strains with intermediate penicillin resistance and all three penicillin-resistant strains, with bacterial counts approaching those in drug-free control cultures by 12 h. The 6-microg/ml peak dose completely eliminated two of three strains with intermediate penicillin resistance and maintained viable counts of the other nonsusceptible strains at 1.5 to 2 logs below the initial inoculum through 36 h. The 9-microg/ml peak dose was most effective, completely eliminating all three strains with intermediate penicillin resistance and maintaining the viable counts of the resistant strains at 3 to 4 logs below the original inoculum. The pharmacodynamics observed in this study suggest that peak concentrations of amoxicillin of 6 to 9 microg/ml may be sufficient for the elimination of penicillin-nonsusceptible pneumococcal strains causing otitis media, especially those with intermediate resistance to amoxicillin. In vivo pharmacokinetic studies are needed to determine if these levels can be achieved in middle ear fluid with amoxicillin at 70 to 90 mg/kg/day divided into two daily doses. If these levels are reliably achieved, then clinical studies are warranted. PMID:9303386

  16. Low CD34 Dose is Associated with Poor Survival after Reduced Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

    PubMed Central

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M.; Laughlin, Mary J.; Lill, Michael; O’Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N.; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-01-01

    Reduced intensity conditioning/non-myeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34+ dose to be important for transplant-outcome using myeloablative conditioning. The role of CD34+ dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced intensity conditioning/non-myeloablative HCT. We studied 1,054 patients aged 45–75 years, with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 106 CD34+/kg were associated with higher non-relapse mortality (HR 2.03, p=0.001), overall mortality (HR 1.48, p=0.008), and lower neutrophil (OR 0.76, p=0.03) and platelet (OR 0.76, p=0.03) recovery. PBPC from unrelated donors with CD34+ dose <6 × 106 CD34+/kg were also associated with higher non-relapse (HR 1.38, p=0.02) and overall mortality (HR 1.20, p=0.05). In contrast to reports after myeloablative HCT, CD34+ dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34+ dose >4 × 106 CD34+/kg and >6 × 106 CD34+/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively. PMID:24892261

  17. Effects of acute doses of sodium fluoride on the morphology and the detectable calcium associated with secretory ameloblasts in rat incisors.

    PubMed

    Monsour, P A; Harbrow, D J; Warshawsky, H

    1989-04-01

    Fluoride in high concentrations is known to have an adverse effect on the formation of enamel. The effect of a single injection of two concentrations of sodium fluoride on inner enamel secretory ameloblasts was investigated morphologically by electron microscopy and functionally by assessing the location and relative amount of available calcium, using the potassium pyroantimonate method. The results showed that acute doses of fluoride interfere with the normal function of secretory ameloblasts. The increase in the population of lysosome-like structures observed after fluoride administration is suggestive of defects in the synthetic pathway. Concomitant with the effect of fluoride on secretory ameloblasts is an inhibition of enamel formation, resulting in incomplete enamel rods and leaving large remnants of Tomes' processes buried in the enamel. The distribution of the calcium pyroantimonate deposits found tends to support the concept of calcium traveling between the cells to the enamel. Acute doses of fluoride also reduce the amount of calcium available for complexing with pyroantimonate in the intercellular region. PMID:2926125

  18. Effects of Total Dose Infusion of Iron Intravenously in Patients With Acute Heart Failure and Anemia (Hemoglobin < 13 g/dl).

    PubMed

    Kaminsky, Bonnie M; Pogue, Kristen T; Hanigan, Sarah; Koelling, Todd M; Dorsch, Michael P

    2016-06-15

    Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p = 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p = 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF. PMID:27161817

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

    PubMed

    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 <1% of harmful compounds were misclassified as non-toxic. Since repeated dose toxicity studies can be performed in vivo until 2013, the proposed approach could have an immediate impact for the testing of cosmetic ingredients. PMID:18977273

  20. Differential effects of high-dose amisulpride versus flupentixol on latent dimensions of depressive and negative symptomatology in acute schizophrenia: an evaluation using confirmatory factor analysis.

    PubMed

    Müller, M J; Wetzel, H; Benkert, O

    2002-09-01

    While many acutely ill schizophrenic patients suffer from depressive symptoms, most studies on the efficacy of antipsychotic drugs focus on positive and negative symptoms. Dimensional models of schizophrenic symptoms, based on confirmatory factor analysis (CFA) using structural equation modelling, offer a methodological alternative to compare antipsychotics on empirically justified latent factors. The present report is a refined analysis of a published double-blind study on the D2/D3-selective antagonist amisulpride (ASP) versus the mixed D1-5/5-HT2 antagonist flupentixol (FPX). CFA was applied to Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Bech-Rafaelsen Melancholia Scale and Simpson-Angus Scale subscores to examine differential effects of high doses of ASP and FPX on negative and depressive symptom dimensions in 126 acutely ill schizophrenic patients. A four-factor model comprising the full spectrum of acute symptomatology and a three-factor model ('negative', 'anhedonia-apathy', 'depressive') restricted to negative and depressive symptoms were yielded with an identical 'depressive' dimension in both models. Analyses of CFA-derived factor scores showed that ASP was significantly superior to FPX regarding the latent 'depressive' dimension, independent of baseline scores, dosage and changes in akinesia. Neither the negative' dimension nor 'anhedonia-apathy' showed significantly different treatment effects. CFA-based analyses appear to be suitable for psychotropic drug evaluation when more refined and data-related information on drug efficacy profiles are required. PMID:12177587

  1. A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection

    PubMed Central

    Dunne, Michael W.; Puttagunta, Sailaja; Giordano, Philip; Krievins, Dainis; Zelasky, Michael; Baldassarre, James

    2016-01-01

    Background. Acute bacterial skin and skin structure infections (ABSSSIs) are a cause of significant morbidity and therapy can be a burden to the healthcare system. New antibiotics that simplify treatment and avoid hospitalization are needed. This study compared the safety and efficacy of a single intravenous infusion of 1500 mg of dalbavancin to the 2-dose regimen. Methods. This study was a randomized, double-blind trial in patients aged >18 years with ABSSSIs. Patients were randomized to dalbavancin 1500 mg either as a single intravenous (IV) infusion or 1000 mg IV on day 1 followed 1 week later by 500 mg IV. The primary endpoint was a ≥20% reduction in the area of erythema at 48–72 hours in the intent-to-treat population. Noninferiority was to be declared if the lower limit of the 95% confidence interval (CI) on the difference in the outcomes was greater than −10%. Clinical outcome was also assessed at days 14 and 28. Results. Six hundred ninety-eight patients were randomized. Demographic characteristics were similar on each regimen, although there were more patients with methicillin-resistant Staphylococcus aureus (MRSA) at baseline on the 2-dose regimen (36/210 [17.1%] vs 61/220 [27.7%]). Dalbavancin delivered as a single dose was noninferior to a 2-dose regimen (81.4% vs 84.2%; difference, −2.9% [95% CI, −8.5% to 2.8%]). Clinical outcomes were also similar at day 14 (84.0% vs 84.8%), day 28 (84.5% vs 85.1%), and day 14 in clinically evaluable patients with MRSA in a baseline culture (92.9% vs 95.3%) in the single- and 2-dose regimens, respectively. Treatment-emergent adverse events occurred in 20.1% of the single-dose patients and 19.9% on the 2-dose regimen. Conclusions. A single 1500-mg infusion of dalbavancin is noninferior to a 2-dose regimen, has a similar safety profile, and removes logistical constraints related to delivery of the second dose. Clinical Trials Registration. NCT02127970. PMID:26611777

  2. Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-04

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  3. Patient Dose During Carotid Artery Stenting With Embolic-Protection Devices: Evaluation With Radiochromic Films and Related Diagnostic Reference Levels According to Factors Influencing the Procedure

    SciTech Connect

    D'Ercole, Loredana; Quaretti, Pietro; Cionfoli, Nicola; Klersy, Catherine; Bocchiola, Milena; Rodolico, Giuseppe; Azzaretti, Andrea; Lisciandro, Francesco; Cascella, Tommaso; Zappoli Thyrion, Federico

    2013-04-15

    To measure the maximum entrance skin dose (MESD) on patients undergoing carotid artery stenting (CAS) using embolic-protection devices, to analyze the dependence of dose and exposure parameters on anatomical, clinical, and technical factors affecting the procedure complexity, to obtain some local diagnostic reference levels (DRLs), and to evaluate whether overcoming DRLs is related to procedure complexity. MESD were evaluated with radiochromic films in 31 patients (mean age 72 {+-} 7 years). Five of 33 (15 %) procedures used proximal EPD, and 28 of 33 (85 %) procedures used distal EPD. Local DRLs were derived from the recorded exposure parameters in 93 patients (65 men and 28 women, mean age 73 {+-} 9 years) undergoing 96 CAS with proximal (33 %) or distal (67 %) EPD. Four bilateral lesions were included. MESD values (mean 0.96 {+-} 0.42 Gy) were <2 Gy without relevant dependence on procedure complexity. Local DRL values for kerma area product (KAP), fluoroscopy time (FT), and number of frames (N{sub FR}) were 269 Gy cm{sup 2}, 28 minutes, and 251, respectively. Only simultaneous bilateral treatment was associated with KAP (odds ratio [OR] 10.14, 95 % confidence interval [CI] 1-102.7, p < 0.05) and N{sub FR} overexposures (OR 10.8, 95 % CI 1.1-109.5, p < 0.05). Type I aortic arch decreased the risk of FT overexposure (OR 0.4, 95 % CI 0.1-0.9, p = 0.042), and stenosis {>=} 90 % increased the risk of N{sub FR} overexposure (OR 2.8, 95 % CI 1.1-7.4, p = 0.040). At multivariable analysis, stenosis {>=} 90 % (OR 2.8, 95 % CI 1.1-7.4, p = 0.040) and bilateral treatment (OR 10.8, 95 % CI 1.1-109.5, p = 0.027) were associated with overexposure for two or more parameters. Skin doses are not problematic in CAS with EPD because these procedures rarely lead to doses >2 Gy.

  4. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation.

    PubMed

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-04-14

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16(INKa) and DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16(INKa) promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16(INKa) and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure. PMID:15063138

  5. Acute and chronic administration of a low-dose combination of topiramate and ondansetron reduces ethanol’s reinforcing effects in male Alcohol Preferring (P) rats

    PubMed Central

    Moore, Catherine F; Lycas, Matthew D; Bond, Colin W; Johnson, Bankole A; Lynch, Wendy J

    2014-01-01

    Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol’s reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N=22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared to the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. While both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (days 1–5), after repeated administration (days 6–10), only the combination produced a sustained reduction in ethanol-maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol’s reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs. PMID:24490709

  6. Dose-Painted Intensity-Modulated Radiation Therapy for Anal Cancer: A Multi-Institutional Report of Acute Toxicity and Response to Therapy

    SciTech Connect

    Kachnic, Lisa A.; Tsai, Henry K.; Coen, John J.; Blaszkowsky, Lawrence S.; Hartshorn, Kevan; Kwak, Eunice L.; Willins, John D.; Ryan, David P.; Hong, Theodore S.

    2012-01-01

    Purpose: Chemoradiation for anal cancer yields effective tumor control, but is associated with significant acute toxicity. We report our multi-institutional experience using dose-painted IMRT (DP-IMRT). Patients and Methods: Between August 2005 and May 2009, 43 patients were treated with DP-IMRT and concurrent chemotherapy for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. DP-IMRT was prescribed as follows: T2N0: 42 Gy, 1.5 Gy/fraction (fx) to elective nodal planning target volume (PTV) and 50.4 Gy, 1.8 Gy/fx to anal tumor PTV; T3-4N0-3: 45 Gy, 1.5 Gy/fx to elective nodal PTV, and 54 Gy, 1.8 Gy/fx to the anal tumor and metastatic nodal PTV >3 cm with 50.4 Gy, 1.68 Gy/fx to nodal PTVs {<=}3 cm in size. Acute and late toxicity was reported by the treating physician. Actuarial analysis was performed using the Kaplan-Meier method. Results: Median age was 58 years; 67% female; 16% Stage I, 37% II; 42% III; 5% IV. Fourteen patients were immunocompromised: 21% HIV-positive and 12% on chronic immunosuppression. Median follow-up was 24 months (range, 0.6-43.5 months). Sixty percent completed chemoradiation without treatment interruption; median duration of treatment interruption was 2 days (range, 2-24 days). Acute Grade 3+ toxicity included: hematologic 51%, dermatologic 10%, gastrointestinal 7%, and genitourinary 7%. Two-year local control, overall survival, colostomy-free survival, and metastasis-free survival were 95%, 94%, 90%, and 92%, respectively. Conclusions: Dose-painted IMRT appears effective and well-tolerated as part of a chemoradiation therapy regimen for the treatment of anal canal cancer.

  7. The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset.

    PubMed

    Taylor, Katy; Andrew, David J; Rego, Laura

    2014-08-01

    A survey conducted on the EU Notification of New Substances (NONS) database suggested that for industrial chemicals with a profile of low toxicity in (sub)acute toxicity tests there is little added value to the conduct of the 90-day repeated dose study. Avoiding unnecessary animal testing is a central aim of the EU REACH chemicals legislation; therefore we sought to verify the profile using additional data. The OECD's eChemPortal was searched for substances that had both a 28-day and a 90-day study and their robust study summaries were then examined from the ECHA CHEM database. Out of 182 substances with high quality 28-day and 90-day study results, only 18 reported no toxicity of any kind in the (sub)acute tests. However, for 16 of these there were also no reported signs of toxicity at or close to the limit dose (1000mg/kgbw/d) in the 90-day study. Restricting the 'low (sub)acute toxicity in a high quality dataset' profile to general industrial chemicals of no known biological activity, whilst allowing irritant substances, increases the data set and improves the prediction to 95% (20 substances out of 21 substances). The low toxicity profile appears to be of low prevalence within industrial chemicals (10-15%), nevertheless, avoidance of the conduct of a redundant 90-day study for this proportion of the remaining REACH phase-in substances would avoid the use of nearly 50,000 animals and save industry 50million Euros, with no impact on the assessment of human health. PMID:24768988

  8. ISOTONIC DOSE-RESPONSE MODELING OF THE TRANSCRIPTIONAL RESPONSE OF RAT CEREBROCORTICAL TISSUE AFTER ACUTE PYRETHROID EXPOSURE IN VIVO.

    EPA Science Inventory

    Pyrethroid insecticides produce neurotoxicity in mammals by disrupting ion channel function in excitable nerve membranes. Pyrethroid use has increased as regulatory guidelines have restricted the use of other pesticide classes. Currently, a sensitive, specific, and dose-responsiv...

  9. Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPAR{alpha} deterioration

    SciTech Connect

    Takahashi, Kyoko; Kamijo, Yuji; Hora, Kazuhiko; Hashimoto, Koji; Higuchi, Makoto; Nakajima, Takero; Ehara, Takashi; Shigematsu, Hidekazu; Gonzalez, Frank J.; Aoyama, Toshifumi

    2011-05-01

    Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPAR{alpha}), suggesting the benefit of PPAR{alpha} activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPAR{alpha} agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPAR{alpha} agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPAR{alpha} deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NF{kappa}B activation. These effects are common to other fibrates and dependent on PPAR{alpha} function. Interestingly, however, clofibrate pretreatment also exerted PPAR{alpha}-independent tubular toxicities in PPAR{alpha}-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPAR

  10. Autologous bone marrow stromal cell transplantation as a treatment for acute radiation enteritis induced by a moderate dose of radiation in dogs.

    PubMed

    Xu, Wenda; Chen, Jiang; Liu, Xu; Li, Hongyu; Qi, Xingshun; Guo, Xiaozhong

    2016-05-01

    Radiation enteritis is one of the most common complications of cancer radiotherapy, and the development of new and effective measures for its prevention and treatment is of great importance. Adult bone marrow stromal stem cells (ABMSCs) are capable of self-renewal and exhibit low immunogenicity. In this study, we investigated ABMSC transplantation as a treatment for acute radiation enteritis. We developed a dog model of acute radiation enteritis using abdominal intensity-modulated radiation therapy in a single X-ray dose of 14 Gy. ABMSCs were cultured in vitro, identified via immunofluorescence and flow cytometry, and double labeled with CM-Dil and superparamagnetic iron oxide (SPIO) before transplantation, which took place 48 hours after abdominal irradiation in a single fraction. The dog model of acute radiation enteritis was transplanted with cultured ABMSCs labeled with CM-Dil and SPIO into the mesenteric artery through the femoral artery. Compared with untreated control groups, dogs treated with ABMSCs exhibited substantially longer survival time and improved relief of clinical symptoms. ABMSC transplantation induced the regeneration of the intestinal epithelium and the recovery of intestinal function. Furthermore, ABMSC transplantation resulted in elevated serum levels of the anti-inflammatory cytokine interleukin-11 (IL10) and intestinal radioprotective factors, such as keratinocyte growth factor, basic fibroblast growth factor-2, and platelet-derived growth factor-B while reducing the serum level of the inflammatory cytokine IL17. ABMSCs induced the regeneration of the intestinal epithelium and regulated the secretion of serum cytokines and the expression of radioprotective proteins and thus could be beneficial in the development of novel and effective mitigators of and protectors against acute radiation enteritis. PMID:26763584

  11. Anatomy-based inverse optimization in high-dose-rate brachytherapy combined with hypofractionated external beam radiotherapy for localized prostate cancer: Comparison of incidence of acute genitourinary toxicity between anatomy-based inverse optimization and geometric optimization

    SciTech Connect

    Akimoto, Tetsuo . E-mail: takimoto@showa.gunma-u.ac.jp; Katoh, Hiroyuki; Kitamoto, Yoshizumi; Shirai, Katsuyuki; Shioya, Mariko; Nakano, Takashi

    2006-04-01

    Purpose: To evaluate the advantages of anatomy-based inverse optimization (IO) in planning high-dose-rate (HDR) brachytherapy. Methods and Materials: A total of 114 patients who received HDR brachytherapy (9 Gy in two fractions) combined with hypofractionated external beam radiotherapy (EBRT) were analyzed. The dose distributions of HDR brachytherapy were optimized using geometric optimization (GO) in 70 patients and by anatomy-based IO in the remaining 44 patients. The correlation between the dose-volume histogram parameters, including the urethral dose and the incidence of acute genitourinary (GU) toxicity, was evaluated. Results: The averaged values of the percentage of volume receiving 80-150% of the prescribed minimal peripheral dose (V{sub 8}-V{sub 15}) of the urethra generated by anatomy-based IO were significantly lower than the corresponding values generated by GO. Similarly, the averaged values of the minimal dose received by 5-50% of the target volume (D{sub 5}-D{sub 5}) obtained using anatomy-based IO were significantly lower than those obtained using GO. Regarding acute toxicity, Grade 2 or worse acute GU toxicity developed in 23% of all patients, but was significantly lower in patients for whom anatomy-based IO (16%) was used than in those for whom GO was used (37%), consistent with the reduced urethral dose (p <0.01). Conclusion: The results of this study suggest that anatomy-based IO is superior to GO for dose optimization in HDR brachytherapy for prostate cancer.

  12. Acute and late toxicity following adjuvant high-dose chemotherapy for high-risk primary operable breast cancer--a quality assessment study.

    PubMed

    Svane, Inge M; Homburg, Keld M; Kamby, Claus; Nielsen, Dorte L; Roer, Ole; Sliffsgaard, Dorte; Johnsen, Hans E; Hansen, Steen W

    2002-01-01

    From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged < or = 56 years with primary operable breast cancer and > or = 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n = 36), fatigue (n = 14), arthralgia/myalgia (n = 10), neurotoxicity (n = 9) and memory loss (n = 4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies. PMID:14651213

  13. Acute Administration of Clozapine and Risperidone Altered Dopamine Metabolism More in Rat Caudate than in Nucleus Accumbens: A Dose-Response Relationship

    PubMed Central

    Batool, Farhat; Haleem, Muhammad A.; Haleem, Darakhshan J.

    2010-01-01

    The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin1A receptors in the pathophysiology of schizophrenia is also discussed. PMID:21179339

  14. Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation.

    PubMed

    Deeg, H J; Sullivan, K M; Buckner, C D; Storb, R; Appelbaum, F R; Clift, R A; Doney, K; Sanders, J E; Witherspoon, R P; Thomas, E D

    1986-12-01

    Seventy-five patients with acute nonlymphoblastic leukemia (ANL) in first remission were treated with cyclophosphamide, 60 mg/kg on each of two consecutive days followed by total body irradiation (TBI) at an exposure rate of 4-6 cGy/min from two opposing 60Co sources. The first 22 patients were given 9.2 Gy of TBI as a single dose. Subsequently 53 patients were randomized to receive either 10 Gy single dose TBI (n = 27) or 6 x 2 Gy fractionated TBI (n = 26). All patients received marrow transplants from HLA-identical siblings and all had sustained engraftment. Patients given 10 Gy of TBI had more early toxicity, especially veno-occlusive disease of the liver, than patients given 9.2 or 6 x 2 Gy of TBI. Idiopathic interstitial pneumonitis appeared to be more frequent in patients given 9.2 or 10 Gy single-dose TBI than in patients given 6 x 2 Gy fractionated TBI. Patients have now been followed from 5 to 9 years. Survival (+/- 95% confidence limits) at 5 years is 54 +/- 31% among patients given 9.2 Gy single dose TBI, 33 +/- 31% among patients given 10 Gy single dose TBI, and 54 +/- 26% among patients given 6 x 2 Gy fractionated TBI (P = 0.04). These results indicate that about half the patients with ANL transplanted while in first chemotherapy-induced remission can be expected to become long-term survivors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3332129

  15. Viral Dose and Immunosuppression Modulate the Progression of Acute BVDV-1 Infection in Calves: Evidence of Long Term Persistence after Intra-Nasal Infection

    PubMed Central

    Strong, Rebecca; La Rocca, Severina Anna; Paton, David; Bensaude, Emmanuelle; Sandvik, Torstein; Davis, Leanne; Turner, Jane; Drew, Trevor; Raue, Rudiger; Vangeel, Ilse; Steinbach, Falko

    2015-01-01

    Bovine viral diarrhoea virus (BVDV) infection of cattle causes a diverse range of clinical outcomes from being asymptomatic, or a transient mild disease, to producing severe cases of acute disease leading to death. Four groups of calves were challenged with a type 1 BVDV strain, originating from a severe outbreak of BVDV in England, to study the effect of viral dose and immunosuppression on the viral replication and transmission of BVDV. Three groups received increasing amounts of virus: Group A received 102.55TCID50/ml, group B 105.25TCID50/ml and group C 106.7TCID 50/ml. A fourth group (D) was inoculated with a medium dose (105.25TCID50/ml) and concomitantly treated with dexamethasone (DMS) to assess the effects of chemically induced immunosuppression. Naïve calves were added as sentinel animals to assess virus transmission. The outcome of infection was dose dependent with animals given a higher dose developing severe disease and more pronounced viral replication. Despite virus being shed by the low-dose infection group, BVD was not transmitted to sentinel calves. Administration of dexamethasone (DMS) resulted in more severe clinical signs, prolonged viraemia and virus shedding. Using PCR techniques, viral RNA was detected in blood, several weeks after the limit of infectious virus recovery. Finally, a recently developed strand-specific RT-PCR detected negative strand viral RNA, indicative of actively replicating virus, in blood samples from convalescent animals, as late as 85 days post inoculation. This detection of long term replicating virus may indicate the way in which the virus persists and/or is reintroduced within herds. PMID:25955849

  16. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers.

    PubMed

    Tildesley, N T J; Kennedy, D O; Perry, E K; Ballard, C G; Wesnes, K A; Scholey, A B

    2005-01-17

    Members of the Sage family, such as Salvia officinalis and Salvia lavandulaefolia, have a long history of use as memory-enhancing agents coupled with cholinergic properties that may potentially be relevant to the amelioration of the cognitive deficits associated with Alzheimer's disease. The current study utilised a placebo-controlled, double-blind, balanced, crossover design in order to comprehensively assess any mood and cognition modulation by S. lavandulaefolia. Twenty-four participants received single doses of placebo, 25 microl and 50 microl of a standardised essential oil of S. lavandulaefolia in an order dictated by a Latin square. Doses were separated by a 7-day washout period. Cognitive performance was assessed prior to the day's treatment and at 1, 2.5, 4 and 6 h thereafter using the Cognitive Drug Research (CDR) computerised test battery. Subjective mood ratings were measured using Bond-Lader visual analogue scales. The primary outcome measures were scores on the five cognitive factors that can be derived by factor analysis of the task outcomes from the CDR battery. The results showed that administration of S. lavandulaefolia resulted in a consistent improvement for both the 25- and 50-microl dose on the 'Speed of Memory' factor. There was also an improvement on the 'Secondary Memory' factor for the 25-microl dose. Mood was consistently enhanced, with increases in self-rated 'alertness', 'calmness' and 'contentedness' following the 50-microl dose and elevated 'calmness' following 25 microl. These results represent further evidence that Salvia is capable of acute modulation of mood and cognition in healthy young adults. The data also suggest that previous reports of memory enhancement by Salvia may be due to more efficient retrieval of target material. PMID:15639154

  17. Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association With Genetic Polymorphisms in DNA DSB Repair Genes

    SciTech Connect

    Werbrouck, Joke Ruyck, Kim de; Duprez, Frederic; Veldeman, Liv; Claes, Kathleen; Eijkeren, Marc van; Boterberg, Tom; Willems, Petra; Vral, Anne; Neve, Wilfried de; Thierens, Hubert

    2009-03-15

    Purpose: To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. Materials and Methods: The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. Results: The mean dose (D{sub mean}) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. Conclusions: The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D{sub mean} to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.

  18. Salmonella Typhi–Induced Septic Shock and Acute Respiratory Distress Syndrome in a Previously Healthy Teenage Patient Treated With High-Dose Dexamethasone

    PubMed Central

    Ugas, Melissa Brosset; Carroll, Timothy; Kovar, Lacey; Chavez-Bueno, Susana

    2016-01-01

    Typhoid fever is commonly characterized by fever and abdominal pain. Rare complications include intestinal hemorrhage, bowel perforation, delirium, obtundation, and septic shock. Herein we describe the case of a previously healthy 16-year-old male without history of travel, diagnosed with typhoid fever complicated by septic shock and acute respiratory distress syndrome treated with high-dose dexamethasone. This case details severe complications of typhoid fever that are uncommonly seen in developed countries, and the successful response to high-dose dexamethasone as adjunct therapy. High-dose dexamethasone treatment has reportedly decreased Salmonella Typhi mortality, but controlled studies specifically performed in children are lacking, and most reports of its use are over 30 years old and all have originated in developing countries. Providers should include Salmonella Typhi in the differential diagnosis of the pediatric patient with fever, severe abdominal pain, and enteritis, and be aware of its potentially severe complications and the limited data on safety and efficacy of adjunctive therapies that can be considered in addition to antibiotics. PMID:27294165

  19. Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Liu, Yan; Yin, You; Sheng, Qi; Lu, Xiaotong; Wang, Fang; Lin, Zhiyan; Tian, Huaiping; Xu, Ajing; Zhang, Jian

    2014-01-01

    Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the −24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The −24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the −24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment. PMID:24404132

  20. Salmonella Typhi-Induced Septic Shock and Acute Respiratory Distress Syndrome in a Previously Healthy Teenage Patient Treated With High-Dose Dexamethasone.

    PubMed

    Ugas, Melissa Brosset; Carroll, Timothy; Kovar, Lacey; Chavez-Bueno, Susana

    2016-01-01

    Typhoid fever is commonly characterized by fever and abdominal pain. Rare complications include intestinal hemorrhage, bowel perforation, delirium, obtundation, and septic shock. Herein we describe the case of a previously healthy 16-year-old male without history of travel, diagnosed with typhoid fever complicated by septic shock and acute respiratory distress syndrome treated with high-dose dexamethasone. This case details severe complications of typhoid fever that are uncommonly seen in developed countries, and the successful response to high-dose dexamethasone as adjunct therapy. High-dose dexamethasone treatment has reportedly decreased Salmonella Typhi mortality, but controlled studies specifically performed in children are lacking, and most reports of its use are over 30 years old and all have originated in developing countries. Providers should include Salmonella Typhi in the differential diagnosis of the pediatric patient with fever, severe abdominal pain, and enteritis, and be aware of its potentially severe complications and the limited data on safety and efficacy of adjunctive therapies that can be considered in addition to antibiotics. PMID:27294165

  1. A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients

    PubMed Central

    2013-01-01

    Background New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. Methods In this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. Results Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. Conclusions The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. Trial registration ClinicalTrials.gov: http://NCT00706680 PMID:23369458

  2. Dose-additivity modeling for acute and repeated exposure to a mixture of N-methycarbamate Pesticides

    EPA Science Inventory

    The toxicity of N-methylcarbamate pesticides is attributed to the reversible inhibition of cholinesterase (ChE) enzymes in the central and peripheral nervous system. The inhibition of ChE following a single exposure to this class of pesticides has been modeled using a dose-additi...

  3. Derived Reference Doses (RfDs) for the environmental degradates of the herbicides alachlor and acetochlor: results of an independent expert panel deliberation.

    PubMed

    Gadagbui, Bernard; Maier, Andrew; Dourson, Michael; Parker, Ann; Willis, Alison; Christopher, John P; Hicks, Lebelle; Ramasamy, Santhini; Roberts, Stephen M

    2010-01-01

    An independent peer expert panel was convened under the auspices of the Alliance for Risk Assessment (ARA) to review toxicology data and derive oral Reference Doses (RfDs) for four environmental degradates of the acetanilide herbicides, alachlor and acetochlor. The degradates included in this evaluation were (1) alachlor tertiary-ethanesulfonic acid (ESA), (2) alachlor tertiary-oxanilic acid (OXA), (3) acetochlor ESA, and (4) acetochlor OXA. Each degradate was judged to have sufficient data for developing low to medium confidence RfD, with use of an additional uncertainty factor (UF) to cover data gaps. Body weight decreases were identified as the most sensitive treatment-related adverse effect for RfD development. A composite UF of 1000 (10 for human variability in sensitivity, 10 for interspecies differences in sensitivity, and 10 for subchronic to chronic and database deficiency combined; i.e., 10(A)x10(H)x10(S&D)) for each degradate was considered reasonable, while noting that an argument could be made for an UF of 3000 (10(A)x10(H)x30(S&D)). Based on the available data, an oral RfD of 0.2 mg/kg-day is recommended for both acetochlor ESA and acetochlor OXA and an oral RfD of 0.8 mg/kg-day is recommended for both alachlor ESA and alachlor OXA. PMID:20206657

  4. Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats.

    PubMed

    Cohen, Ori S; Varlinskaya, Elena I; Wilson, Carey A; Glatt, Stephen J; Mooney, Sandra M

    2013-12-01

    Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350 mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post-translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior. PMID:24055786

  5. Acute toxicity of methyl isocyanate: a preliminary study of the dose response for eye and other effects.

    PubMed

    Salmon, A G; Kerr Muir, M; Andersson, N

    1985-12-01

    Acute toxic effects of methyl isocyanate in the rat were determined for two hour exposures to concentrations in the range 11 ppm (very slight effect) to 65 ppm (lethality: pulmonary oedema). Changes in the eye, lungs, and behaviour were noted. Eye changes were confined to erosions of the corneal epithelium and were most severe at intermediate levels of exposure. A comparison was made of the effects noted in rats with reported effects on survivors of the Bhopal disaster. Urinary thiocyanate concentrations in exposed rats were found to be reduced relative to control values. PMID:4074650

  6. High Doses of Daunorubicin during Induction Therapy of Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Prospective Clinical Trials

    PubMed Central

    Gong, Qiang; Zhou, Lixin; Xu, Shuangnian; Li, Xi; Zou, Yunding; Chen, Jieping

    2015-01-01

    The right dose of daunorubicin (DNR) for the treatment of newly diagnosed acute myeloid leukemia (AML) is uncertain. Previous trials have shown conflicting results concerning the efficacy of high or low doses of daunorubicin to induction chemotherapy for newly diagnosed AML. A systematic review and meta-analysis was conducted to resolve this controversial issue. We compared the efficacy and safety of high doses of daunorubicin (HD-DNR) and traditional low doses of daunorubicin (LD-DNR) or idarubicin (IDA) during induction therapy of newly diagnosed AML. Data of 3,824 patients from 1,796 articles in the literature were retrieved and six randomized controlled trials were analyzed. The primary outcomes were overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The secondary outcomes included complete remission (CR), relapse, and toxicity. The meta-analysis results suggest that comparing HD-DNR with LD-DNR, there were significant differences in CR (RR = 1.19, 95%CI[1.12,1.18], p<0.00001), OS(HR = 0.88, 95%CI[0.79,0.99], p = 0.002), and EFS (HR = 0.86, 95%CI [0.74, 1.00], p = 0.008), but not in DFS, relapse, and toxicity. There were no statistically significant differences in any other outcomes between HD-DNR and IDA. The analysis indicates that compared with LD-DNR, HD-DNR can significantly improve CR, OS and EFS but not DFS, and did not increase occurrence of relapse and toxicity. PMID:25993000

  7. Population pharmacokinetics of mefloquine, administered as a fixed-dose combination of artesunate-mefloquine in Indian patients for the treatment of acute uncomplicated Plasmodium falciparum malaria

    PubMed Central

    2014-01-01

    Background Fixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics. Methods A single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach. Results Seventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h-1 (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%. Conclusions The lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria. Trial Registration Clinical Trial Registration: ISRCTN70618692 PMID:24886117

  8. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study.

    PubMed

    Gruenig, Ekkehard; Michelakis, Evangelos; Vachiéry, Jean-Luc; Vizza, Carmine Dario; Meyer, F Joachim; Doelberg, Martin; Bach, Doris; Dingemanse, Jasper; Galiè, Nazzareno

    2009-11-01

    This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (>or=18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21%, -8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (-15%; 95% confidence limits: -21%, -10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds. PMID:19755415

  9. Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy.

    PubMed

    Jabbour, Elias; Daver, Naval; Champlin, Richard; Mathisen, Michael; Oran, Betul; Ciurea, Stefan; Khouri, Issa; Cornelison, A Megan; Ghanem, Hady; Cardenas-Turanzas, Marylou; Popat, Uday; Ravandi, Farhad; Giralt, Sergio; Garcia-Manero, Guillermo; Cortes, Jorge; Kantarjian, Hagop; de Lima, Marcos

    2014-04-01

    Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high-dose Cytarabine (HiDAC)-based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC-based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P < 0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus-host-disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P < 0.001); the 3-year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy. PMID:24375514

  10. Allogeneic Stem Cell transplantation as Initial Salvage for Patients with Acute Myeloid Leukemia Refractory to High-Dose Cytarabine-Based Induction Chemotherapy

    PubMed Central

    Jabbour, Elias; Daver, Naval; Champlin, Richard; Mathisen, Michael; Oran, Betul; Ciurea, Stefan; Khouri, Issa; Cornelison, A Megan; Ghanem, Hady; Cardenas-Turanzas, Marylou; Popat, Uday; Ravandi, Farhad; Giralt, Sergio; Garcia-Manero, Guillermo; Kantarjian, Hagop; de Lima, Marcos

    2014-01-01

    Purpose Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high-dose Cytarabine (HiDAC)-based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Methods Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC-based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Results Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P<0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus-host-disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P<0.001); the 3-year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Conclusion Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy. PMID:24375514

  11. The Dose-Volume Relationship of Small Bowel Irradiation and Acute Grade 3 Diarrhea During Chemoradiotherapy for Rectal Cancer

    SciTech Connect

    Robertson, John M. Lockman, David; Yan Di; Wallace, Michelle

    2008-02-01

    Purpose: Previous work has found a highly significant relationship between the irradiated small-bowel volume and development of Grade 3 small-bowel toxicity in patients with rectal cancer. This study tested the previously defined parameters in a much larger group of patients. Methods and Materials: A total of 96 consecutive patients receiving pelvic radiation therapy for rectal cancer had treatment planning computed tomographic scans with small-bowel contrast that allowed the small bowel to be outlined with calculation of a small-bowel dose-volume histogram for the initial intended pelvic treatment to 45 Gy. Patients with at least one parameter above the previously determined dose-volume parameters were considered high risk, whereas those with all parameters below these levels were low risk. The grade of diarrhea and presence of liquid stool was determined prospectively. Results: There was a highly significant association with small-bowel dose-volume and Grade 3 diarrhea (p {<=} 0.008). The high-risk and low-risk parameters were predictive with Grade 3 diarrhea in 16 of 51 high-risk patients and in 4 of 45 low-risk patients (p = 0.01). Patients who had undergone irradiation preoperatively had a lower incidence of Grade 3 diarrhea than those treated postoperatively (18% vs. 28%; p = 0.31); however, the predictive ability of the high-risk/low-risk parameters was better for preoperatively (p = 0.03) than for postoperatively treated patients (p = 0.15). Revised risk parameters were derived that improved the overall predictive ability (p = 0.004). Conclusions: The highly significant dose-volume relationship and validity of the high-risk and low-risk parameters were confirmed in a large group of patients. The risk parameters provided better modeling for the preoperative patients than for the postoperative patients.

  12. Measurement of brevetoxin levels by radioimmunoassay of blood collection cards after acute, long-term, and low-dose exposure in mice.

    PubMed Central

    Woofter, Ricky; Dechraoui, M-Yasmine Bottein; Garthwaite, Ian; Towers, Neale R; Gordon, Christopher J; Córdova, José; Ramsdell, John S

    2003-01-01

    We developed a radioimmunoassay (RIA) using a sheep anti-brevetoxin antiserum to evaluate detection of brevetoxin on blood collection cards from mice treated with the brevetoxin congener PbTx-3. The RIA has high affinity for PbTx-3 [half-maximal effective concentration (EC(50)) +/- SE = 1.2 +/- 0.2 nM; n = 10] and recognizes both type 1 and type 2 brevetoxins, but not ciguatoxin. Direct comparison of the RIA with a radiolabeled [(3)H]-PbTx-3 receptor-binding assay (RBA) revealed excellent sensitivity, congener selectivity, and minimal interference from blood matrix. We first analyzed blood samples from an acute time course exposure, using a maximal nonlethal dose [180 microg/kg body weight (bw)] for 0.5, 1, 2, 4, and 24 hr. Mean blood brevetoxin levels were 36 nM at 30 min and stayed above 20 nM during the 1-4 hr time points. We next analyzed blood brevetoxin levels after longer exposure (0.5, 1, 2, 3, 4, or 7 days). Mean blood brevetoxin levels were 26.0 nM at 0.5 days, decreased to 8.2 nM at 1.0 day, and maintained a significant level (p < 0.05) of 1.3 nM at day 2. We next determined the lowest measurable dose using increasing concentrations of PbTx-3 (10-300 micro g/kg bw). Analysis of the blood samples at 60 min revealed a linear relationship between administered and internal doses (r(2) = 0.993). All doses of brevetoxin administered were detectable at 1 hr, with significant levels found for the lowest administered dose of 10 micro g/kg bw--a dose that was 10-fold lower than the lowest observable effect level. This RIA provides an optimal first-tier detection of brevetoxin from blood collection cards and, used in combination with the RBA and liquid chromatography-mass spectrometry, should provide a complete panel of methods to biomonitor brevetoxin exposure. PMID:14527838

  13. High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia-is more better or more of the same?

    PubMed

    Wolach, Ofir; Itchaki, Gilad; Bar-Natan, Michal; Yeshurun, Moshe; Ram, Ron; Herscovici, Corina; Shpilberg, Ofer; Douer, Dan; Tallman, Martin S; Raanani, Pia

    2016-03-01

    Cytarabine is the backbone of most chemotherapeutic regimens for acute myeloid leukemia (AML), yet the optimal dose for salvage therapy of refractory or relapsed AML (RR-AML) has not been established. Very high dose single-agent cytarabine at 36 g/m(2) (ARA-36) was previously shown to be effective and tolerable in RR-AML. In this retrospective analysis, we aim to describe the toxicity and efficacy of ARA-36 as salvage therapy for patients with AML who are primary refractory to intensive daunorubicin-containing induction or those relapsing after allogeneic stem cell transplant (alloSCT). Fifteen patients, median age 53 years, were included in the analysis. Six patients were treated for induction failure, one had resistant APL, and eight relapsed after alloSCT. Complete remission was achieved in 60% of patients. Surviving patients were followed for a median of 8.5 months. One-year overall survival was 54% (95% CI 30%-86%), and relapse rate from remission (n = 9) was 56%. Grade III/IV pulmonary, infectious, ocular and gastrointestinal toxicities occurred in 26%, 20%, 20% and 20% of patients respectively. Salvage therapy with ARA-36 regimen for RR-AML has considerable efficacy with manageable toxicity in patients with induction failure or post-transplant relapse. Overall survival in these high-risk patients still remains poor. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25689584

  14. Acute effect of high-dose isoflavones from Pueraria lobata (Willd.) Ohwi on lipid and bone metabolism in ovariectomized mice.

    PubMed

    Cho, Hee Joon; Jun, Hee-jin; Lee, Ji Hae; Jia, Yaoyao; Hoang, Minh Hien; Shim, Jae-Hoon; Park, Kwan-Hwa; Lee, Sung-Joon

    2012-12-01

    We investigated the acute metabolic effects of isoflavones from Pueraria lobata (Willd.) Ohwi (IPL) in ovariectomized (OVX) mice. After 4 weeks of IPL feeding at 500 mg/day/kg body weight (OVX500), plasma 17β-estradiol concentrations were significantly higher (+25%, p < 0.05), whereas plasma triglyceride levels were significantly lower in OVX mice (-15%, p < 0.05) compared with controls. Abdominal adipose tissue weight was marginally reduced in IPL-fed groups compared with OVX controls and the plasma levels of liver enzymes were unchanged. In addition, IPL significantly inhibited the reduction of bone mineral density in the femurs of OVX mice (OVX200, +22%; OVX500, +26%; p < 0.05) compared with controls after 4 weeks of IPL feeding. In quantitative polymerase chain reaction analysis the expression of aromatase was significantly suppressed and SULT1E1 was increased by IPL feeding, showing that IPL feeding may not alter the risk for breast cancer in mice. Our results suggest that IPL could ameliorate menopausal symptoms in mice. Further studies will confirm the effects of IPL in humans. PMID:22422661

  15. Detailed gene dose analysis reveals recurrent focal gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia.

    PubMed

    Ivanov Öfverholm, Ingegerd; Tran, Anh Nhi; Olsson, Linda; Zachariadis, Vasilios; Heyman, Mats; Rudd, Eva; Syk Lundberg, Elisabeth; Nordenskjöld, Magnus; Johansson, Bertil; Nordgren, Ann; Barbany, Gisela

    2016-09-01

    To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p < 0.001). A majority of BTLA deletions (7/11; 64%) affected samples with gain of 21q chromosome material, suggesting that BTLA deletions are associated with both germline and somatic gain of chromosome 21. In cases without known risk-associated cytogenetic markers, CNAs associated with adverse prognosis were identified in 50% (10/20), indicating that a majority of these cases could be assigned to distinct genetic subtypes. PMID:27090575

  16. [Duration of bronchodilator effect of inhaled Salmeterol (dry powder x metered dose inhaler) in children with acute asthma attack].

    PubMed

    Solé, D; Rizzo, M C; Porto, I M; Gomez, I D; Sano, F; Figueiredo, M A; Naspitz, C K

    1996-01-01

    Patients during a mild to moderate acute attack of asthma (FEV1: 50 - 80% of predicted) were treated with Salmeterol MDI - 50mcg or Rotadisk - 50mcg or Salbutamol (MDI -200mcg). The children were followed by Spirometry, measuring FEV1 (basal) and after treatment: at 30 minutes, 60 minutes and thereafter every 60 minutes until 780 minutes, if the patients maintained the FEV1 above 80% of the predicted value and/or an increment of 20% in the VEF1 basal value. The Salmeterol group showed a significant bronchodilation at 60 minutes which was maintained in half of the patients up to 9 hours. This was not observed in the Salbutamol group: the peak bronchodilatation was observed at 30 minutes and the bronchodilation effect was observed in half of the patients up to 6 hours. There were no significant differences between both presentations of Salmeterol. This drug allowed a prolonged bronchodilator effect and is, according to the several consensus on management of asthma, an adequate option in the treatment of moderate to severe asthma. PMID:14688969

  17. Low-Dose Heparin Anticoagulation During Extracorporeal Life Support for Acute Respiratory Distress Syndrome in Conscious Sheep

    PubMed Central

    Prat, Nicolas J.; Meyer, Andrew D.; Langer, Thomas; Montgomery, Robbie K.; Parida, Bijaya K.; Batchinsky, Andriy I.; Cap, Andrew P.

    2015-01-01

    ABSTRACT Background: Over 32% of burned battlefield causalities develop trauma-induced hypoxic respiratory failure, also known as acute respiratory distress syndrome (ARDS). Recently, 9 out of 10 US combat soldiers’ survived life-threatening trauma-induced ARDS supported with extracorporeal membrane oxygenation (ECMO), a portable form of cardiopulmonary bypass. Unfortunately, the size, incidence of coagulation complications, and the need for systematic anticoagulation for traditional ECMO devices have prevented widespread use of this lifesaving technology. Therefore, a compact, mobile, ECMO system using minimal anticoagulation may be the solution to reduce ARDS in critically ill military and civilian patients. Methods: We conducted a prospective cohort laboratory investigation to evaluate the coagulation function in an ovine model of oleic acid induced ARDS supported with veno-venous ECMO. The experimental design approximated the time needed to transport from a battlefield setting to an advanced facility and compared bolus versus standard heparin anticoagulation therapy. Results: Comprehensive coagulation and hemostasis assays did not show any difference because of ECMO support over 10 h between the two groups but did show changes because of injury. Platelet count and function did decrease with support on ECMO, but there was no significant bleeding or clot formation during the entire experiment. Conclusions: A bolus heparin injection is sufficient to maintain ECMO support for up to 10 h in an ovine model of ARDS. With a reduced need for systematic anticoagulation, ECMO use for battlefield trauma could reduce significant morbidity and mortality from ventilator-induced lung injury and ARDS. Future studies will investigate the mechanisms and therapies to support patients for longer periods on ECMO without coagulation complications. Level of Evidence: V—therapeutic animal experiment. PMID:26263439

  18. Effects of high doses of dexamethasone on hemodynamic and immunohistochemical characteristics of acute paraquat intoxication in rat kidneys.

    PubMed

    Ekerbicer, N; Gurpinar, T; Tarakci, F; Turkoz Uluer, E; İnan, S

    2016-01-01

    Paraquat (1,1'-dimethyl-4,4'-bipyridinium) (PQ), is a nonselective contact herbicide that is highly toxic to humans. The kidney is affected during PQ intoxication. Dexamethasone (Dexa) has anti-inflammatory effects and is used to treat cases of PQ poisoning. We investigated in rat kidney hemodynamic effects and immunohistochemical characteristics of Dexa treatment in acute PQ poisoning. Adult male rats were divided into four groups: 1, untreated control; 2, treated with 100 mg/kg Dexa; 3, treated with 25 mg/kg PQ; 4, treated with PQ + Dexa. Mean arterial pressure (MAP) and heart rate (HR) were recorded during the experimental period (2 h). Tissues were removed after 2 h and immunohistochemistry was performed after 24 h. Paraffin sections of kidney were prepared and anti-cyclo-oxygenase-1 (COX-1), anti-cyclo-oxygenase-2 (COX-2), anti-angiotensin converting enzyme (ACE), anti-aquaporin-1 (AQU-1), anti-vascular cell adhesion molecule (VCAM) primary antibodies were used for immunohistochemical examination. Immunoreactivities were scored as: (1) minimal, (2) weak, (3) mild, (4) moderate, (5) strong and (6) very strong. MAP and HR were measured at 10 min, 20 min, 1 h and 2 h. MAP at 10 and 20 min and 1 h was increased in the Dexa group. HR also was increased in all groups compared to controls at 2 h. Compared to groups 2 and 4, MAP values decreased significantly in group 3 at 1 h. The intensity of all of immunoreactivities was decreased in group 2. In group 3, immunoreactivities of COX-1, COX-2 and ACE were decreased compared to the control and the other groups, whereas AQU-1 and VCAM immunoreactivities were the same as the control group. ACE and VCAM immunoreactivities were decreased in group 4 compared to the control group, while COX-1, COX-2 and AQU-1 immunoreactivities were close to those of the control group. Dexa appears to be useful for treating PQ intoxication. PMID:26796020

  19. Medium dose ultraviolet A1 phototherapy and mRNA expression of interleukin 8, interferon γ, and chemokine receptor 4 in acute skin lesions in atopic dermatitis

    PubMed Central

    Malinowska, Karolina; Sysa-Jedrzejowska, Anna; Wozniacka, Anna

    2016-01-01

    Introduction Mechanisms responsible for UVA1 efficacy in atopic dermatitis (AD) are not fully elucidated. Aim To investigate IL-8, CCR-4, and IFN-γ mRNA expression in AD before and after UVA1, to identify correlations among them, and to determine whether and to what degree mRNA expression is influenced by UVA1. Material and methods Twenty-five patients with AD underwent medium dose UVA1-phototherapy at daily dosages of 10, 20, 30, 45, and then continuing 45 J/cm2 up to 20 days, from Monday to Friday for 4 weeks. Before and after UVA1, biopsies from acute skin lesions were studied using reverse-transcription and RT-PCR. Results The levels of CCR-4 mRNA correlated with those of IFN-γ, both before and after UVA1 phototherapy (p < 0.05). A significant correlation was found after UVA1 between mRNA levels of IL-8 and IFN-γ (p < 0.05). After UVA1 an increase in IL-8 mRNA expression in comparison to the baseline assessment (p = 0.02) was found, while no significant difference was revealed in the expression of CCR-4 and IFN-γ mRNA. UVA1 improved both SCORAD and severity of AD (p < 0.001). SCORAD and the severity of AD did not correlate with the degree of expression of measured cytokine mRNA, neither before nor after UVA1. Conclusions CCR-4 is expressed in parallel with IFN-γ in acute skin lesions of patients with AD both before and after UVA1 phototherapy. UVA1 significantly improves SCORAD index, lessens the severity of AD and increases the expression of IL-8, with no direct effects on other studied molecules. PMID:27512350

  20. Attempts to counteract phosgene-induced acute lung injury by instant high-dose aerosol exposure to hexamethylenetetramine, cysteine or glutathione.

    PubMed

    Pauluhn, Jürgen; Hai, Chun Xue

    2011-01-01

    Phosgene is an important high-production-volume intermediate with widespread industrial use. Consistent with other lung irritants causing ALI (acute lung injury), mode-of-action-based countermeasures remain rudimentary. This study was conducted to analyze whether extremely short high-level exposure to phosgene gas could be mitigated using three different inhaled nucleophiles administered by inhalation instantly after exposure to phosgene. Groups of young adult male Wistar rats were acutely exposed to carbonyl chloride (phosgene) using a directed-flow nose-only mode of exposure of 600 mg/m³ for 1.5 min (225 ppm × min). Immediately after exposure to phosgene gas the rats were similarly exposed to three strong nucleophiles with and without antioxidant properties for 5 or 15 min. The following nucleophiles were used: hexamethylenetetramine (HMT), l-cysteine (Cys), and l-glutathione (GSH). The concentration of the aerosol (mass median aerodynamic diameter 1.7-2 µm) was targeted to be in the range of 1 mg/L. Cys and GSH have antioxidant properties in addition. The calculated alveolar molar dosage of phosgene was 9 µmol/kg. At 15-min exposure duration, the respective inhaled dose of HMT, Csy, and GSH were 111, 103, and 46 µmol/kg, respectively. The alveolar dose of drugs was ~10-times lower. The efficacy of treatment was judged by protein concentrations in bronchoalveolar lavage fluid (BALF) collected 1 day post-exposure. In spite of using optimized aerosolization techniques, none of the nucleophiles chosen had any mitigating effect on BALF-protein extravasation. This finding appear to suggest that inhaled phosgene gas acylates instantly nucleophilic moieties at the site of initial deposition and that the resultant reaction products can not be reactivated even following instant inhalation treatment with competing nucleophilic agents. In spite of using maximal technically attainable concentrations, it appears to be experimentally challenging to deliver

  1. [Efficacy, side effects and blood concentration monitoring of high-dose methotrexate in treatment of 180 children with acute lymphoblastic leukemia].

    PubMed

    Wang, Hong; Chi, Zuo-Fei; Li, Shuang; Wang, Xiu-Li; Hao, Liang-Chun

    2011-08-01

    This study was purposed to investigate the effects of high-dose methotrexate (HD-MTX)-CF + VDT protocol on pediatric acute lymphoblastic leukemia (ALL) by means of retrospective analysis. MTX plasma concentration was dynamically detected and evaluated so as to avoid or reduce the side effects of HD-MTX, and adjust the time and dosage of calcium folinate (CF) or carry out the plasma exchange as occasion requires. Totally 180 cases of ALL were enrolled in this study, and received 380 administration of HD-MTX-CF + VDT protocol, including 122 patients with induction therapy as well as 58 cases during maintenance therapy, among which 68 cases were defined as low risk, 80 cases as middle risk and 32 cases as high risk. 2.0 g/m(2) MTX, 3.0 g/m(2) MTX, and 5.0 g/m(2) MTX were individually used according to low risk, middle risk or T immunohistochemical expression. The results indicated that 36.3% cases showed the side-effects of HD-MTX including mucocutaneous lesions, gastrointestinal reaction, hepatic dysfunction, renal damage, fever, myelosuppression, cardiotoxicity, infection and allergic response. All of these side effects were reversible through treatment. The elimination delay of MTX occurred in 110 cases, out of which 3 cases got MTX concentration > 10 µmol/L at 24 hours, 50 cases > 1.0 µmol/L at 44 hours, the remaining 57 cases > 0.1 µmol/L at 68 hours. CF dosage was adjusted according to the concentration of MTX until it was less than 0.1 µmol/L. 1 case had renal interstitial inflammation and acute renal failure, but finally he was cured. No patients received plasma exchange or died. It is concluded that the extramedullary leukemia control protocol, in which MTX is main drug, is effective therapy for obtaining long-term remission and event-free survival rate in ALL patients, but the side effects and risks increase along with the increase of MTX dose. The metabolic level of HD-MTX has found to be obvious individual, so the dynamic monitoring of MTX

  2. Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse.

    PubMed

    Pilorge, Sylvain; Rigaudeau, Sophie; Rabian, Florence; Sarkozy, Clémentine; Taksin, Anne L; Farhat, Hassan; Merabet, Fathia; Ghez, Stéphanie; Raggueneau, Victoria; Terré, Christine; Garcia, Isabelle; Renneville, Aline; Preudhomme, Claude; Castaigne, Sylvie; Rousselot, Philippe

    2014-04-01

    Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse. PMID:24375467

  3. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.

    PubMed

    Edwards, Jayne E; McQuay, Henry J; Moore, R Andrew

    2002-02-01

    The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from seven randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over six and eight hours and global evaluations of treatment effect after eight hours were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity. PMID:11844632

  4. REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia

    PubMed Central

    Stuart, Robert K; Cripe, Larry D; Maris, Michael B; Cooper, Maureen A; Stone, Richard M; Dakhil, Shaker R; Turturro, Francesco; Stock, Wendy; Mason, James; Shami, Paul J; Strickland, Stephen A; Costa, Luciano J; Borthakur, Gautam; Michelson, Glenn C; Fox, Judith A; Leavitt, Richard D; Ravandi, Farhad

    2015-01-01

    This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m2 d 1, 8, 15; B: 72 mg/m2 d 1, 8; C: 72 mg/m2 or 90 mg/m2 d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m2) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m2 d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997. PMID:25403830

  5. Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia.

    PubMed

    Martínez-Cuadrón, David; Montesinos, Pau; Oriol, Albert; Salamero, Olga; Vidriales, Belén; Bergua, Juan; Herrera, Pilar; Vives, Susanna; Sanz, Jaime; Carpio, Cecilia; Rodríguez-Veiga, Rebeca; Moscardó, Federico; Sanz, Miguel A

    2014-01-01

    Previous studies have shown that clofarabine plus low-dose cytarabine (LDAC) could induce roughly 60 % of complete remissions (CR) with acceptable toxicity and induction mortality in elderly acute myeloid leukemia (AML) patients not suitable for intensive chemotherapy. The Programa Español de Tratamientos en Hematología group conducted a trial for patients diagnosed with untreated AML aged 60 years and older, using the combination of clofarabine (20 mg/m(2) × 5 days) plus low-dose cytarabine (20 mg/m(2) × 14 days). The protocol was flexible regarding the use of antifungal and antibacterial prophylaxis, and outpatient induction therapy was allowed. Although the planned recruitment goal was 75 patients, only 11 patients were enrolled (median age, 74 years) after observing high toxicity and unacceptable mortality (46 and 73 % at 4 and 8 weeks, respectively). The response assessment showed three CR (27 %), three resistant diseases (27 %), and five induction deaths (46 %). Induction was administered in an outpatient modality in five patients, while antifungal and antibacterial prophylaxis was not given in seven and five patients, respectively. In our context, induction therapy with the combination of clofarabine (20 mg/m(2)) plus LDAC was associated with high toxicity and unacceptable mortality in elderly AML patients, leading to the early interruption of the trial. Tight patients' clinical monitoring, follow-up, and intensive supportive care seem crucial to achieve at least acceptable clinical outcomes in elderly AML patients receiving clofarabine plus LDAC. This trial is registered at www.clinicaltrials.gov as no. NCT01193400. PMID:24081577

  6. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.

    PubMed

    Burnett, Alan K; Milligan, Donald; Goldstone, Anthony; Prentice, Archibald; McMullin, Mary-Frances; Dennis, Michael; Sellwood, Elizabeth; Pallis, Monica; Russell, Nigel; Hills, Robert K; Wheatley, Keith

    2009-05-01

    The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress. PMID:19291085

  7. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

    SciTech Connect

    Freeman, A.I.; Weinberg, V.; Brecher, M.L.; Jones, B.; Glicksman, A.S.; Sinks, L.F.; Weil, M.; Pleuss, H.; Hananian, J.; Burgert, E.O. Jr.

    1983-03-03

    The authors compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation. The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group. Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate; there was no difference in the rate of hematologic relapse. Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

  8. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

    SciTech Connect

    Freeman, A.I.; Weinberg, V.; Brecher, M.L.

    1983-03-03

    We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P . 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P . 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P . 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

  9. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: effects of epinephrine and oxygen therapies.

    PubMed

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G; Xu, Fadi; Russell, Robert G; Sopori, Mohan L

    2014-01-15

    Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD50 sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD50 sarin-exposed animals were administered the bronchodilator epinephrine, >90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50 sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. PMID:24269878

  10. Effect of low dose acetylsalicylic acid on the frequency and hematologic activity of left ventricular thrombus in anterior wall acute myocardial infarction

    SciTech Connect

    Kuepper, A.J.V.; Verheugt, F.W.; Peels, C.H.; Galema, T.W.; den Hollander, W.; Roos, J.P.

    1989-04-15

    In this prospective, randomized, placebo-controlled trial the effect of 100 mg acetylsalicylic acid (ASA) once daily on the incidence, hematologic activity and embolic potential of left ventricular (LV) thrombosis was studied in 100 consecutive patients with a first anterior wall acute myocardial infarction (AMI). Patients were randomized to ASA or placebo less than 12 hours after onset of symptoms. Heparin, 5,000 IU subcutaneously twice daily, was given to all patients during immobilization. Echocardiography was performed less than 24 hours, 48 to 72 hours and 1, 2, and 12 weeks after AMI. LV thrombosis was detected by echocardiography in 30 (33%) of the 92 evaluable patients (15 patients given ASA and 15 given placebo). Indium-111 platelet scintigraphy was done in 17 of the 22 patients with an LV thrombus at the second week echocardiogram. Among 7 ASA-treated patients, 4 had positive images; among 10 placebo patients, 5 had positive images. LV thrombus resolution was noted in 3 of 9 patients with a positive scan and in 5 of 8 patients with a negative platelet scan. In 7 of 10 ASA-treated patients and 5 of 12 placebo-treated patients thrombus resolution was observed (difference not significant). Systemic embolism occurred in 2 patients, both given ASA, during the first week after AMI. Thus, low dose ASA has no effect on the incidence, hematologic activity and embolic potential of LV thrombosis in anterior wall AMI.

  11. Efficacy of salbutamol by nebulizer versus metered dose inhaler with home-made non-valved spacer in acute exacerbation of childhood asthma.

    PubMed

    Yasmin, S; Mollah, A H; Basak, R; Islam, K T; Chowdhury, Y S

    2012-01-01

    This study was done to evaluate and to compare the efficacy of jet nebulizer and metered dose inhaler (MDI) with home-made non-valved spacer (HM NVS) to deliver aerosolized salbutamol in acute exacerbation of asthma in children. HM NVS was made by 500ml plastic mineral water bottle. It was perforated at the bottom for the insertion of MDI and proximal end was cut for placing the mouth. This prospective randomized study was conducted in the department of Pediatrics, Dhaka Medical College Hospital, during April 2007 to March 2008 with 50 known cases (2-12 years) of bronchial asthma with acute exacerbation. After randomized enrollment, each patient received three doses of salbutamol either through a jet nebulizer or through a HM NVS. Oxygen saturation (SaO2), wheeze, heart rate, respiratory rate were recorded throughout the treatment period. Data were analyzed with SPSS for Windows 10.0 at p value <0.05 was considered significant. The mean age of patients was 59.8 months in nebulizer group versus 69.4 months in MDI with HM NVS group. Baseline clinical characteristics in nebulizer group were SaO2 87.7±2.5 versus 89.0±1.8 percent, RR 59.2±7.3 vs. 63.2±4.8 per minute, HR 155.4±11.8 versus 149.0±10.8 per minute and wheeze in 22(88.0%) cases versus 21(84.0%) cases respectively (p>0.05). After therapy improvement was noted among the nebulizer group (SaO2 87.7±2.5 vs. 94.3±2.8 percent; RR 59.2±7.3 vs. 39.3±4.9 per minute; HR 155.4±11.8 vs. 151.60±17.3 per minute; wheeze 88% vs. 8%) as well as in the MDI with HM NVS group (SaO2 89.0±1.8 vs. 94.8±1.8 percent; RR 63.2±4.8 vs. 38.7±6.4 per minute; HR 149.0±10.8 vs. 144.5±13.5 per minute; wheeze 84% vs. 16%) [p<0.001; CI:95%]. However, these improvements did not differ significantly between the nebulizer group and HM NVS group (SaO2 94.3±2.8 vs. 94.8±1.8 percent, RR 39.3±4.9 vs. 38.7±6.4 per minute, HR 151.60±17.3 vs. 144.5±13.5 per minute and wheeze persisted in 2(8.0%) cases versus 4(16.0%) cases

  12. Diversification of existing reference phantoms in nuclear medicine: Calculation of specific absorbed fractions for 21 mathematical phantoms and validation through dose estimates resulting from the administration of (18)F-FDG.

    PubMed

    Blaickner, Matthias; Kindl, Peter

    2008-12-01

    Current dose assessment in nuclear medicine patient studies relies on published S-values, which are, in turn, based on calculated specific absorbed fractions (SAFs) available for a limited number of anthro-pomorphic computational phantoms. In order to take the individual physiognomy of patients more into account, this study aimed to broaden the supply of phantoms and their respective SAFs. An ensemble of 21 mathematical phantoms was submitted to the Monte Carlo Code MCNP4c2 for the purpose of calculation of SAFs for annihilation radiation. These values were incorporated into an internal dose assessment following the Medical Internal Radiation Dose (MIRD) schema and relying on published biokinetic data for intravenous administration of (18)F-FDG. The results were compared with data from the ICRP, MIRD reports and concurrent calculations with OLINDA/EXM. A very good agreement with sources relying on the SAFs of Cristy and Eckerman (i.e., the ICRP and OLINDA/EXM) was observed, with the absorbed dose in lung being the only exception. In the case of dose to red marrow, the King Spiers factors were omitted in the three-factor approximation, which led to a precise accordance with the Cristy/Eckerman values. Summarizing, one can say that the coincidence with published data justifies the method chosen and demonstrates successfully the expansion of available reference phantoms for dose assessment in nuclear medicine. PMID:19111050

  13. Comparison of internal doses calculated using the specific absorbed fractions of the average adult Japanese male phantom with those of the reference computational phantom-adult male of ICRP publication 110

    NASA Astrophysics Data System (ADS)

    Manabe, Kentaro; Sato, Kaoru; Endo, Akira

    2014-03-01

    In order to study the effects of body sizes and masses of organs and tissues on internal dose assessment, the values corresponding to effective dose coefficients for intakes of radionuclides were calculated using the specific absorbed fractions (SAFs) of two phantoms: the average adult Japanese male phantom (JM-103) and the reference computational phantom-adult male (RCP-AM) of the International Commission on Radiological Protection. SAFs were evaluated using the phantoms and Monte Carlo radiation transport code MCNPX or were taken from published data. As a result of a comparison for 2894 cases of 923 radionuclides, the maximum discrepancy in the effective dose coefficients between the JM-103 and RCP-AM was about 40%. However, the discrepancies were smaller than 10% in 97% of all cases.

  14. The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji

    PubMed Central

    Kimura, Eisaku

    2011-01-01

    Diethylcarbamazine (DEC), first introduced in 1947, was shown to have strong efficacy and safety for treatment of human lymphatic filariasis, which is caused mostly by a species Wuchereria bancrofti. Many studies to optimize the dosage and treatment schedule of DEC followed, and, based on the results, control programs with various regimens were implemented in different endemic areas/countries. By the mid 1970s, with endorsement by the WHO Expert Committee on Filariasis (3rd report, 1974), the standard DEC regimen for W. bancrofti infection in mass treatment had been established in principle: a total dose of 72 mg/kg of body weight given in 12 divided doses, once weekly or monthly, at 6 mg/kg each. Not long after the committee report, the efficacy of annual single-dose treatment at 6 mg/kg, which is only one twelfth of the WHO-recommended dose in a year, was reported effective in French Polynesia (study period: 1973-78), and later in Samoa (study period: 1979-81). These results were published between 1978 and 1985 in the Bulletin of WHO but received little attention. In the mid 1980s, the efficacy of ivermectin, the first-choice drug for onchocerciasis, against lymphatic filariae came to light. Since the effect at a single dose was remarkable, and often better than DEC, it was predicted that the newly introduced drug would replace DEC. Treatment experiments with ivermectin increased quickly in number. Meanwhile, annual single-dose mass drug administration (MDA) with DEC at 6 mg/kg was under scrutiny in Samoa and Fiji. In the early 1990s, the Samoan study, which covered the entire population of 160,000 with 3 annual MDAs, reported a significant reduction in microfilaria (mf) prevalence and mean mf density, while in Fiji, the efficacy of 5 rounds of annual MDA (total dose, 30 mg/kg) was shown to be as effective as 28 multi-dose MDA spread over 2 years (6 weekly plus 22 monthly treatments at 5 mg/kg; total dose, 140 mg/kg). Several additional studies carried out in

  15. The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji.

    PubMed

    Kimura, Eisaku

    2011-03-01

    Diethylcarbamazine (DEC), first introduced in 1947, was shown to have strong efficacy and safety for treatment of human lymphatic filariasis, which is caused mostly by a species Wuchereria bancrofti. Many studies to optimize the dosage and treatment schedule of DEC followed, and, based on the results, control programs with various regimens were implemented in different endemic areas/countries. By the mid 1970s, with endorsement by the WHO Expert Committee on Filariasis (3rd report, 1974), the standard DEC regimen for W. bancrofti infection in mass treatment had been established in principle: a total dose of 72 mg/kg of body weight given in 12 divided doses, once weekly or monthly, at 6 mg/kg each. Not long after the committee report, the efficacy of annual single-dose treatment at 6 mg/kg, which is only one twelfth of the WHO-recommended dose in a year, was reported effective in French Polynesia (study period: 1973-78), and later in Samoa (study period: 1979-81). These results were published between 1978 and 1985 in the Bulletin of WHO but received little attention. In the mid 1980s, the efficacy of ivermectin, the first-choice drug for onchocerciasis, against lymphatic filariae came to light. Since the effect at a single dose was remarkable, and often better than DEC, it was predicted that the newly introduced drug would replace DEC. Treatment experiments with ivermectin increased quickly in number. Meanwhile, annual single-dose mass drug administration (MDA) with DEC at 6 mg/kg was under scrutiny in Samoa and Fiji. In the early 1990s, the Samoan study, which covered the entire population of 160,000 with 3 annual MDAs, reported a significant reduction in microfilaria (mf) prevalence and mean mf density, while in Fiji, the efficacy of 5 rounds of annual MDA (total dose, 30 mg/kg) was shown to be as effective as 28 multi-dose MDA spread over 2 years (6 weekly plus 22 monthly treatments at 5 mg/kg; total dose, 140 mg/kg). Several additional studies carried out in

  16. High-dose albumin treatment for acute ischaemic stroke (ALIAS): a phase 3, randomised, double-blind, placebo-controlled trial

    PubMed Central

    Ginsberg, Myron D.; Palesch, Yuko Y.; Hill, Michael D.; Martin, Renee H.; Moy, Claudia S.; Barsan, William G.; Waldman, Bonnie D.; Tamariz, Diego; Ryckborst, Karla J.

    2014-01-01

    Background In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioral outcome. In a pilot clinical trial, albumin doses as high as 2 g per kg were safely tolerated. Trial Design and Methods This was a randomised, parallel-group, double-blind trial to test the superiority of 25% albumin (dose 2 g [8 ml] per kg; maximum, 750 ml) over an equivalent volume of isotonic saline in improving the outcome of acute ischaemic stroke. Eligibility criteria were an ischaemic (i.e., non-haemorrhagic) stroke with baseline National Institutes of Health Stroke Scale (NIHSS) score of 6 or above, ability to treat within 5 hours of onset, age 18 through 83 years, and written informed consent. The major exclusion criteria were cardiovascular. The objective was to test the hypothesis that the primary outcome (defined as either a modified Rankin Scale score of 0 or 1, or a NIHSS score of 0 or 1, or both, at 90 days) with albumin treatment was superior to saline by an absolute margin of 10 percentage points. Centralised web-based randomisation was by a minimisation-plus-biased-coin algorithm. Thrombolytic therapies were permitted. The trial is registered with ClinicalTrials.gov, Identifier: NCT00235495. Findings The trial was stopped prematurely for futility after 841 participants were randomised (422 patients to albumin and 419 to saline). The primary outcome did not differ by treatment assignment (albumin, 44.1%; saline, 44.2%; relative benefit, 0.96; 95% confidence interval [CI] 0.84 – 1.10 adjusted for baseline NIHSS score and thrombolysis stratum). Secondary outcomes were also neutral. The chief adverse event was mild-to-moderate pulmonary edema, which was more common with albumin than saline (13.1% and 1.2%, respectively), as was symptomatic intracranial haemorrhage within 24 hours (albumin, 4.1%; saline, 1.7%). While the favourable outcome rate in albumin-treated subjects remained consistent at 44–45% over the course of the trial, the

  17. Effects of Acute Low-Dose Exposure to the Chlorinated Flame Retardant Dechlorane 602 and Th1 and Th2 Immune Responses in Adult Male Mice

    PubMed Central

    Feng, Yu; Tian, Jijing; Xie, Heidi Qunhui; She, Jianwen; Xu, Sherry Li; Xu, Tuan; Tian, Wenjing; Fu, Hualing; Li, Shuaizhang; Tao, Wuqun; Wang, Lingyun; Chen, Yangsheng; Zhang, Songyan; Zhang, Wanglong; Guo, Tai L.; Zhao, Bin

    2016-01-01

    , Zhang S, Zhang W, Guo TL, Zhao B. 2016. Effects of acute low-dose exposure to the chlorinated flame retardant dechlorane 602 and Th1 and Th2 immune responses in adult male mice. Environ Health Perspect 124:1406–1413; http://dx.doi.org/10.1289/ehp.1510314 PMID:27081854

  18. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

    SciTech Connect

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.; Xu, Fadi; Russell, Robert G.; Sopori, Mohan L.

    2014-01-15

    Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily.

  19. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography

    PubMed Central

    Abe, Y; Muro, T; Sakanoue, Y; Komatsu, R; Otsuka, M; Naruko, T; Itoh, A; Yoshiyama, M; Haze, K; Yoshikawa, J

    2005-01-01

    Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling. PMID:15797931

  20. Treatment with Low-Dose Cytarabine in Elderly Patients (Age 70 Years or Older) with Acute Myeloid Leukemia: A Single Institution Experience

    PubMed Central

    Heiblig, Maël; Elhamri, Mohamed; Tigaud, Isabelle; Plesa, Adriana; Barraco, Fiorenza; Labussière, Hélène; Ducastelle, Sophie; Michallet, Mauricette; Nicolini, Franck; Plesa, Claudiu; Wattel, Eric; Salles, Gilles; Thomas, Xavier

    2016-01-01

    Objectives Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in elderly patients with acute myeloid leukemia (AML) ‘unfit’ for intensive chemotherapy. In this study, we reported our experience with LD-AraC in patients ≥ 70 years old and compared the results to those of intensive chemotherapy, best supportive care (BSC), or hypomethylating agents in the same age population. Methods Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by subcutaneous injection for 10 consecutive days every 4–6 weeks. Results Complete remission rate with LD-AraC was 7% versus 56% with intensive chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was better than with BSC only (P = 0.001). Although not statistically significant, intensive chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS (median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for cytogenetics. There was a trend for a better OS in LD-AraC treated patients in the setting of clinical trials as compared with those treated outside of a clinical trial. Conclusions Despite a trend in favor of intensive chemotherapy and hypomethylating agents over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a significant advantage comparatively to BSC. All this tends to confirm that LD-AraC can still represent a baseline against which new promising agents may be compared either alone or in combination. PMID:26740870

  1. G-CSF priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm.

    PubMed

    Becker, Pamela S; Medeiros, Bruno C; Stein, Anthony S; Othus, Megan; Appelbaum, Frederick R; Forman, Stephen J; Scott, Bart L; Hendrie, Paul C; Gardner, Kelda M; Pagel, John M; Walter, Roland B; Parks, Cynthia; Wood, Brent L; Abkowitz, Janis L; Estey, Elihu H

    2015-04-01

    Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G-CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse-free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m(-2) day(-1) × 5 and cytarabine at 2 g m(-2) day(-1) × 5 after G-CSF priming in 50 newly-diagnosed patients ages 18-64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64-88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71-93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well-tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. PMID:25545153

  2. Nongenomic effects of estrogen mediate the dose-related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats

    PubMed Central

    El-Mas, Mahmoud M.

    2013-01-01

    Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remains unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg iv) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE2 rats, suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher LV 1) generation of reactive oxygen species (ROS), 2) expression of malondialdehyde and 4-hydroxynonenal protein adducts, 3) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and 4) catalase activity. ERK1/2 inhibition by PD-98059 (1 mg/kg iv) abrogated the myocardial dysfunction, hypotension, and the elevation in myocardial ROS generation caused by ethanol. We conclude that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats. PMID:24368668

  3. A FIM Study to Assess Safety and Exposure of Inhaled Single Doses of AP301—A Specific ENaC Channel Activator for the Treatment of Acute Lung Injury

    PubMed Central

    Schwameis, Richard; Eder, Sandra; Pietschmann, Helmut; Fischer, Bernhard; Mascher, Hermann; Tzotzos, Susan; Fischer, Hendrik; Lucas, Rudolf; Zeitlinger, Markus; Hermann, Robert

    2014-01-01

    AP301 is an activator of ENaC-mediated Na+ uptake for the treatment of pulmonary permeability edema in acute respiratory distress syndrome (ARDS). The purpose of this “first-in-man” study was to examine local and systemic safety and systemic exposure of ascending single doses of AP301, when inhaled by healthy male subjects. In a double-blind, placebo-controlled study, 48 healthy male subjects were randomized to 6 ascending dose groups (single doses up to 120 mg) of 8 subjects each (3:1 randomization of AP301: placebo). Serial assessments included spirometry, exhaled nitric oxide (eNO), vital signs, ECG, safety laboratory, adverse events (AE), and blood samples for the quantification of AP301 in plasma. Descriptive statistics was applied. All 48 subjects received treatment, and completed the study as per protocol. No serious, local (e.g., hoarseness, cough, bronchospasm), or dose-limiting AEs were noted. None of the assessments indicated notable dose or time-related alterations of safety outcomes. Observed AP301 systemic exposure levels were very low, with mean Cmax values of <2.5 ng/mL in the highest dose groups. Inhaled AP301 single doses up to 120 mg were safe and well tolerated by healthy male subjects. Distribution of inhaled AP301 was largely confined to the lung, as indicated by very low AP301 systemic exposure levels. PMID:24515273

  4. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study.

    PubMed

    Pautas, Cecile; Merabet, Fatiha; Thomas, Xavier; Raffoux, Emmanuel; Gardin, Claude; Corm, Selim; Bourhis, Jean-Henri; Reman, Oumedaly; Turlure, Pascal; Contentin, Nathalie; de Revel, Thierry; Rousselot, Philippe; Preudhomme, Claude; Bordessoule, Dominique; Fenaux, Pierre; Terré, Christine; Michallet, Mauricette; Dombret, Hervé; Chevret, Sylvie; Castaigne, Sylvie

    2010-02-10

    PURPOSE In patients with acute myeloid leukemia (AML), induction chemotherapy is based on standard doses of anthracyclines and cytarabine. High doses of cytarabine have been reported as being too toxic for patients older than age 50 years, but few studies have evaluated intensified doses of anthracyclines. PATIENTS AND METHODS In this randomized Acute Leukemia French Association 9801 (ALFA-9801) study, high doses of daunorubicin (DNR; 80 mg/m(2)/d x 3 days) or idarubicin (IDA4; 12 mg/m(2)/d x 4 days) were compared with standard doses of idarubicin (IDA3; 12 mg/m(2)/d x 3 days) for remission induction in patients age 50 to 70 years, with an event-free survival (EFS) end point. After two consolidation courses based on intermediate doses of cytarabine, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin-2 (rIL-2; 5 x 10(6) U/m(2) x 5 days each month) for a total duration of 12 months. A total of 468 patients entered the study (median age, 60 years). Results Overall complete remission rate was 77% with significant differences among the three randomization arms (83%, 78%, and 70% in the IDA3, IDA4, and DNR arms, respectively; P = .04). However, no significant differences were observed in relapse incidence, EFS, or overall survival among the three arms. In the 161 patients randomly assigned for maintenance therapy, no difference in outcome was observed between the rIL-2 and the no further treatment arms. CONCLUSION Neither intensification of anthracycline doses nor maintenance with rIL-2 showed a significant impact on AML course, at least as scheduled in this trial. PMID:20048183

  5. A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33(+) Acute Myeloid Leukemia.

    PubMed

    Zahler, Stacey; Bhatia, Monica; Ricci, Angela; Roy, Sumith; Morris, Erin; Harrison, Lauren; van de Ven, Carmella; Fabricatore, Sandra; Wolownik, Karen; Cooney-Qualter, Erin; Baxter-Lowe, Lee Ann; Luisi, Paul; Militano, Olga; Kletzel, Morris; Cairo, Mitchell S

    2016-04-01

    Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33(+) relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33(+) AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m(2) × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m(2)). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m(2) per dose), 5 at dose level 2 (6 mg/m(2) per dose), 3 at dose level 3 (7.5 mg/m(2) per dose), and 3 at dose level 4 (9 mg/m(2) per dose). Three of 14 patients received only 1 dose of GO after

  6. Pharmacokinetics of a Once-Daily Dose of Tacrolimus Early After Liver Transplantation: With Special Reference to CYP3A5 and ABCB1 Single Nucleotide Polymorphisms.

    PubMed

    Miyata, Yoichi; Akamatsu, Nobuhisa; Sugawara, Yasuhiko; Kaneko, Junichi; Yamamoto, Takehito; Suzuki, Hiroshi; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Tamura, Sumihito; Kokudo, Norihiro

    2016-01-01

    BACKGROUND The aim of the present study was to investigate the pharmacokinetics of the once-daily tacrolimus formulation (QD form) in relation to polymorphisms of the donor cytochrome P450 family 3 sub-family A polypeptide 5 (CYP3A5) gene and recipient adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1) gene. MATERIAL AND METHODS A total of 80 consecutive living-donor liver transplant (LDLT) recipients were started on the QD form of tacrolimus (day 1), and 60 patients were completely followed for 7 days early after liver transplantation in order to evaluate the pharmacokinetics. RESULTS The concentration/dose (C/D) ratio in recipients with the donor CYP3A5 *1 allele was significantly lower throughout the observation period compared with those with the CYP3A5 genotype *3/*3 (p<0.001), while no effect of single-nucleotide polymorphisms (SNPs) of ABCB1 was observed. The administered doses required to achieve the target trough level were significantly higher on day 7 than on day 1 among all groups, regardless of the differences in the SNPs, especially among those with donor CYP3A5 *1 allele. The tacrolimus concentration was kept within the targeted level all through the study regardless of SNPs. CONCLUSIONS The donor CYP3A5 *1 allele correlated with the lower C/D ratio after administration of the QD form, and higher doses of QD-form tacrolimus and careful monitoring for the trough level should be considered, especially in recipients with the donor CYP3A5 *1 allele. PMID:27503662

  7. Surgical treatment of acute myocardial ischaemia related to coronary angioplasty with special reference to use of perfusion balloon catheter and long-term outcome.

    PubMed

    Heikkinen, L; Virtanen, K; Heikkila, J; Verkkala, K; Salo, J; Jarvinen, A

    1997-04-01

    Twenty of 569 consecutive patients (3.5%) undergoing percutaneous transluminal coronary angioplasty required emergency coronary artery bypass grafting for acute closure of the dilated vessel. In seven patients an intracoronary autoperfusion balloon catheter was inserted to ensure antegrade blood flow across the injured zone of the coronary artery. The time needed for completion of the bypass grafts ranged from 100 to 399 minutes (mean 180 minutes). An average of 1.9 coronary artery bypasses was inserted. In total, 11 of the 20 patients (55%) developed new Q waves and had elevated CK-MB levels. However, the myocardial infarction rate was only 14% in those with a perfusion balloon catheter as against 77% in those without one. The insertion of a ball-out catheter permitted greater utilization of the internal mammary artery as a bypass graft. Angiographic follow-up was conducted after a mean of 28 months (19 patients). The patency rate of the bypass grafts placed in the emergency setting was relatively good (91%). Thallium tomography revealed a scar of variable size in all 17 patients studied and a reversible exercise perfusion defect requiring coronary reangioplasty in three patients. In conclusion, the insertion of a perfusion balloon catheter after abrupt coronary occlusion during coronary angioplasty solved the problems of acute myocardial ischemia and markedly lowered the definite myocardial infarction rate. This technique ensures favourable haemodynamic conditions for emergency myocardial revascularization. PMID:9201117

  8. TIME COURSE AND DOSE RESPONSE ASSESSMENT OF CHOLINESTERASE (CHE) INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL, METHOMYL, METHIOCARB, OXAMYL, OR PROPOXUR.

    EPA Science Inventory

    To compare the toxicity of 5 N-methyl carbamates, the time course and dose response profiles for ChE inhibition were established for each. For the time course comparison, adult male Long Evans rats (n=5 dose group) were dosed orally with either carbaryl (CB; 30 mg/kg in corn oi...

  9. Determination of absorbed dose in water at the reference point D(r{sub 0},{theta}{sub 0}) for an {sup 192}Ir HDR brachytherapy source using a Fricke system

    SciTech Connect

    Austerlitz, C.; Mota, H. C.; Sempau, J.; Benhabib, S. M.; Campos, D.; Allison, R.; Almeida, C. E. de; Zhu, D.; Sibata, C. H.

    2008-12-15

    A ring-shaped Fricke device was developed to measure the absolute dose on the transverse bisector of a {sup 192}Ir high dose rate (HDR) source at 1 cm from its center in water, D(r{sub 0},{theta}{sub 0}). It consists of a polymethylmethacrylate (PMMA) rod (axial axis) with a cylindrical cavity at its center to insert the {sup 192}Ir radioactive source. A ring cavity around the source with 1.5 mm thickness and 5 mm height is centered at 1 cm from the central axis of the source. This ring cavity is etched in a disk shaped base with 2.65 cm diameter and 0.90 cm thickness. The cavity has a wall around it 0.25 cm thick. This ring is filled with Fricke solution, sealed, and the whole assembly is immersed in water during irradiations. The device takes advantage of the cylindrical geometry to measure D(r{sub 0},{theta}{sub 0}). Irradiations were performed with a Nucletron microselectron HDR unit loaded with an {sup 192}Ir Alpha Omega radioactive source. A Spectronic 1001 spectrophotometer was used to measure the optical absorbance using a 1 mL quartz cuvette with 1.00 cm light pathlength. The PENELOPE Monte Carlo code (MC) was utilized to simulate the Fricke device and the {sup 192}Ir Alpha Omega source in detail to calculate the perturbation introduced by the PMMA material. A NIST traceable calibrated well type ionization chamber was used to determine the air-kerma strength, and a published dose-rate constant was used to determine the dose rate at the reference point. The time to deliver 30.00 Gy to the reference point was calculated. This absorbed dose was then compared to the absorbed dose measured by the Fricke solution. Based on MC simulation, the PMMA of the Fricke device increases the D(r{sub 0},{theta}{sub 0}) by 2.0%. Applying the corresponding correction factor, the D(r{sub 0},{theta}{sub 0}) value assessed with the Fricke device agrees within 2.0% with the expected value with a total combined uncertainty of 3.43%(k=1). The Fricke device provides a promising

  10. Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration.

    PubMed

    Towiwat, Pasarapa; Phattanarudee, Siripan; Maher, Timothy J

    2013-01-01

    Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs. PMID:23104245

  11. Study of Pre-disposing Factors of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Antibiotic Prescribing Pattern with Reference to Antibiotic Sensitivity Test.

    PubMed

    Shrestha, R; Shrestha, B; Shakya Shrestha, S; Pant, A; Prajapati, B; Karmacharya, B M

    2015-01-01

    Background Chronic Obstructive Pulmonary Disease (COPD) affects about 329 million people worldwide, which is nearly 5% of the entire global population. In the context of Nepal, COPD accounts for 43% of the non-communicable disease burden and 2.56% of hospitalizations. Various pre-disposing factors like bacterial, viral, fungal, smoking, occupational exposures and genetic factors have been proposed to precipitate COPD and its exacerbation though, the definitive pre-disposing factors and factors related to acute exacerbation have not been determined in the context of Nepal. Objective To find out the pre-disposing factors and the related causative agents for COPD. Method A cross sectional study was conducted in a tertiary care hospital. Patients of all age group who were diagnosed as COPD and admitted in the hospital were included in this study. Patients were interviewed using structured questionnaire. The sociodemographic data including personal and medical history were recorded from those participants. In addition, sputum from those patients was sent for culture to investigate the possible responsible pathogens as well as its antibiotic sensitivity pattern. Result A total of 150 patients having Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) who have admitted from either emergency or out-patient department of the hospital were included in this study. Among the total number of patients, more than half of them were female (n=82). In addition, analysis of occupations shows that most of them were either farmer (36.0%) or housewife (30.7%). In total studied patients (n=150), most of them were using traditional firewood (83%) for cooking purpose and majority of patients (91%) were smokers. Most of the sputum samples show growth of gram-positive cocci (26.7%) and gram negative bacilli (27.5%). Considering the overall sensitivity pattern, the higher sensitivity was recorded for Co-trimoxazole and Ciprofloxacin while higher rate of resistance was noted

  12. Acute toxicity of metals and reference toxicants to a freshwater ostracod, Cypris subglobosa Sowerby, 1840 and correlation to EC(50) values of other test models.

    PubMed

    Khangarot, B S; Das, Sangita

    2009-12-30

    The ostracod Cypris subglobosa Sowerby, 1840 static bioassay test on the basis of a 48h of 50% of immobilization (EC(50)) has been used to measure the toxicity of 36 metals and metalloids and 12 reference toxicants. Among the 36 metals and metalloids, osmium (Os) was found to be the most toxic in the test while boron (B), the least toxic. The EC(50) values of this study revealed positive linear relationship with the established test models of cladoceran (Daphnia magna), sludge worm (Tubifex tubifex), chironomid larvae (Chironomus tentans), protozoan (Tetrahymena pyriformis), fathead minnow (Pimephales promelas), bluegill sunfish (Lepomis macrochirus), and aquatic macrophyte duckweed (Lemna minor). Correlation coefficients (r(2)) for 17 physicochemical properties of metals or metal ions and EC(50)s (as pM) were examined by linear regression analysis. The electronegativity, ionization potential, melting point, solubility product of metal sulfides (pK(sp)), softness parameter and some other physicochemical characteristics were significantly correlated with EC(50)s of metals to C. subglobosa. The reproducibility of toxicity test was determined using 12 reference toxicants. The coefficient of variability of the EC(50)s ranged from 6.95% to 55.37% and variability was comparable to that noticed for D. magna and other aquatic test models. The study demonstrated the need to include crustacean ostracods in a battery of biotests to detect the presence of hazardous chemicals in soils, sewage sludges, sediments and aquatic systems. PMID:19683870

  13. Acute Radiation Syndrome

    MedlinePlus

    ... Dictionary Radiation Emergencies & Your Health Possible Health Effects Contamination and Exposure Acute Radiation Syndrome (ARS) Cutaneous Radiation ... Decision Making in Radiation Emergencies Protective Actions Internal Contamination Clinical Reference (ICCR) Application Psychological First Aid in ...

  14. Age-related dose response of selected reproductive parameters to acute cadmium chloride exposure in the male Long-Evans rat

    EPA Science Inventory

    Groups of Long Evans rats 30, 50, or 70 days old were injected subcutaneously (s.c.) with a single dose of between 0 and 52 micromoles Cd/Kg as cadmium (CD) chloride. Sixty days post dosing and two hours prior to sacrifice the rats were injected s.c. with 100 IU of hCG to stimula...

  15. Low Dose Radiation Response Curves, Networks and Pathways in Human Lymphoblastoid Cells Exposed from 1 to 10 cGy of Acute Gamma Radiation

    SciTech Connect

    Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.; Furtado, M. R.; Bhattacharya, M. S.; Marchetti, F.; Coleman, M.A.

    2011-04-18

    We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

  16. Relationship of glucose values to sliding scale insulin (correctional insulin) dose delivery and meal time in acute care patients with diabetes mellitus.

    PubMed

    Trotter, Barbara; Conaway, Mark R; Burns, Suzanne M

    2013-01-01

    Findings of this study suggest the traditional sliding scale insulin (SSI) method does not improve target glucose values among adult medical inpatients. Timing of blood glucose (BC) measurement does affect the required SSI dose. BC measurement and insulin dose administration should be accomplished immediately prior to mealtime. PMID:23802496

  17. A randomized controlled trial to assess the efficacy and safety of doubling dose clopidogrel versus ticagrelor for the treatment of acute coronary syndrome in patients with CYP2C19*2 homozygotes

    PubMed Central

    Xiong, Ran; Liu, Wenxian; Chen, Liying; Kang, Tieduo; Ning, Shangqiu; Li, Jiang

    2015-01-01

    Background: Compared with non-reversible, indirect P2Y12 inhibitor clopidogrel, ticagrelor is a reversible, direct acting inhibitor. The CYP2C19*2 allele is a common genetic variant in individuals that need given higher clopidogrel in acute coronary syndrome patients. Objective: We aimed to assess a pharmacogenetic approach of doubling dose clopidogrel compare with standard dose of ticagrelor among carriers with the CYP2C19*2 homozygotes. Materials and methods: We compared ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) with clopidogrel (600 mg loading dose, 150 mg daily thereafter) for the prevention of cardiovascular events in CYP2C19*2 homozygotes patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. Results: After genetic test to identify carriers of the CYP2C19*2 allele from 2295 patients, 224 cases with CYP2C19*2 homozygotes were enrolled into our prospective, randomized trial. Patients were random assignment with colpidogrel group (n = 112) and ticagrelor group (n = 112). The two groups were similar in terms of baseline characteristics. After the first 600 mg loading dose of clopidogrel, patients carrying two CYP2C19*2 allele had weaker PRU inhibition (39.8±37.4 vs 27.9±12.4; P = 0.001) and more bleeding adverse events (20.5% vs. 7.1%; hazard ratio = 2.88; 95% [CI], 1.34-6.15; P = 0.001) compared to those taking standard dose of ticagrelor. Conclusions: In CYP2C19*2 carriers with ACS, ticagrlor is as effective as high clopidogrel in reducing platelet reactivity, particularly in first days. This study suggests that ticagrelor may be much better than doubling dose clopidogrel in patients with CYP2C19*2 in according to platelet reactivity monitoring. Use of ticagrelor instead of clopidogrel may eliminate the need for genetic testing and lead to less mild bleeding adverse. PMID:26550258

  18. Poznan acute Astronomical Observatory

    NASA Astrophysics Data System (ADS)

    Murdin, P.

    2000-11-01

    This Poznan acute Astronomical Observatory is a unit of the Adam Mickiewicz University, located in Poznan acute, Poland. From its foundation in 1919, it has specialized in astrometry and celestial mechanics (reference frames, dynamics of satellites and small solar system bodies). Recently, research activities have also included planetary and stellar astrophysics (asteroid photometry, catalysmic b...

  19. Effect of extended physiotherapy and high-dose vitamin D on rate of falls and hospital re-admission after acute hip fracture: a randomized controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Guidelines for post-fracture care of elderly hip fracture patients are not established despite the significant socio-economic burden of post hip fracture morbidity and mortality. Using a factorial design, we studied the effects of extended physiotherapy (supervised 1 hour per day during acute care p...

  20. Effect of rosuvastatin dose-loading on serum sLox-1, hs-CRP, and postoperative prognosis in diabetic patients with acute coronary syndromes undergoing selected percutaneous coronary intervention (PCI)

    PubMed Central

    Jiao, Yungen; Hu, Feng; Zhang, Zhengang; Gong, Kaizheng; Sun, Xiaoning; Li, Aihua; Liu, Naifeng

    2015-01-01

    Objective: To investigate the effect of rosuvastatin dose-loading on serum levels of lectin-like oxidized low-density lipoprotein receptor-1 (Lox-1) and high-sensitivity c-reactive protein (hs-CRP) and postoperative prognosis in patients with diabetes and non-ST segment elevation acute coronary syndromes (NSTEACS) undergoing selected percutaneous coronary intervention (PCI). Methods: A total of 72 patients with diabetes and NSTEACS were randomized to either the group treated with 20 mg rosuvastatin 12 hours prior to PCI with a second dose administered just before PCI (n = 33), or a control group treated with standard method according guideline (n = 39). Serum levels of sLox-1, hs-CRP, CK-MB, and cTnI were measured prior to PCI, and at 24 hours and 30 days after PCI. The 30-day incidence of major adverse cardiac events (MACE) was recorded in both groups. Results: Compared to pre-PCI, serum levels of sLox-1 and hs-CRP of the two groups were increased at 24 hours after PCI (P < 0.05); the levels of CK-MB and cTnI were also improved (P < 0.01); however, the ascended values of sLox-1, hs-CRP, CK-MB, and cTnI were significantly lower in the loading-dose rosuvastatin-treated group than in the control-treated group. Serum levels of sLox-1 and hs-CRP were higher in the loading-dose rosuvastatin-treated group than in the control-treated group at 30 days after PCI (P < 0.05); compared to pre-PCI, the levels of TC and LDL-C were not changed at 24 hours after PCI (P > 0.05) until 30 days after PCI (P < 0.05), but there were no difference between the two groups. The levels of ALT and Scr had no significant difference between the two groups before and after PCI; the 30-day incidence of MACE occurred in 6.06% of patients in the loading-dose rosuvastatin-treated group and in 23.08% of patients in the control-treated group (P < 0.05). Conclusion: The therapy of dose-loading rosuvastatin for patients with diabetes and non-ST segment elevation acute coronary syndromes undergoing

  1. Small Bowel Dose Parameters Predicting Grade ≥3 Acute Toxicity in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation: An Independent Validation Study Comparing Peritoneal Space Versus Small Bowel Loop Contouring Techniques

    SciTech Connect

    Banerjee, Robyn; Chakraborty, Santam; Nygren, Ian; Sinha, Richie

    2013-04-01

    Purpose: To determine whether volumes based on contours of the peritoneal space can be used instead of individual small bowel loops to predict for grade ≥3 acute small bowel toxicity in patients with rectal cancer treated with neoadjuvant chemoradiation therapy. Methods and Materials: A standardized contouring method was developed for the peritoneal space and retrospectively applied to the radiation treatment plans of 67 patients treated with neoadjuvant chemoradiation therapy for rectal cancer. Dose-volume histogram (DVH) data were extracted and analyzed against patient toxicity. Receiver operating characteristic analysis and logistic regression were carried out for both contouring methods. Results: Grade ≥3 small bowel toxicity occurred in 16% (11/67) of patients in the study. A highly significant dose-volume relationship between small bowel irradiation and acute small bowel toxicity was supported by the use of both small bowel loop and peritoneal space contouring techniques. Receiver operating characteristic analysis demonstrated that, for both contouring methods, the greatest sensitivity for predicting toxicity was associated with the volume receiving between 15 and 25 Gy. Conclusion: DVH analysis of peritoneal space volumes accurately predicts grade ≥3 small bowel toxicity in patients with rectal cancer receiving neoadjuvant chemoradiation therapy, suggesting that the contours of the peritoneal space provide a reasonable surrogate for the contours of individual small bowel loops. The study finds that a small bowel V15 less than 275 cc and a peritoneal space V15 less than 830 cc are associated with a less than 10% risk of grade ≥3 acute toxicity.

  2. MAMMARY GLAND DEVELOPMENT AS A SENSITIVE END-POINT FOLLOWING ACUTE PERNATAL EXPOSURE TO A LOW DOSE ATRAZINE METABOLITE MIXTURE IN FEMALE LONG EVANS RATS

    EPA Science Inventory

    In order to characterize the potential developmental effects of atrazine (ATR) metabolites at low doses, an environmentally-based mixture (EBM) of ATR and its metabolites hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine was formulated based on surv...

  3. The dose-response effect of acute intravenous transplantation of human umbilical cord blood cells on brain damage and spatial memory deficits in neonatal hypoxia-ischemia.

    PubMed

    de Paula, S; Greggio, S; Marinowic, D R; Machado, D C; DaCosta, J Costa

    2012-05-17

    Despite the beneficial effects of cell-based therapies on brain repair shown in most studies, there has not been a consensus regarding the optimal dose of human umbilical cord blood cells (HUCBC) for neonatal hypoxia-ischemia (HI). In this study, we compared the long-term effects of intravenous administration of HUCBC at three different doses on spatial memory and brain morphological changes after HI in newborn Wistar rats. In addition, we tested whether the transplanted HUCBC migrate to the injured brain after transplantation. Seven-day-old animals underwent right carotid artery occlusion and were exposed to 8% O(2) inhalation for 2 h. After 24 h, randomly selected animals were assigned to four different experimental groups: HI rats administered with vehicle (HI+vehicle), HI rats treated with 1×10(6) (HI+low-dose), 1×10(7) (HI+medium-dose), and 1×10(8) (HI+high-dose) HUCBC into the jugular vein. A control group (sham-operated) was also included in this study. After 8 weeks of transplantation, spatial memory performance was assessed using the Morris water maze (MWM), and subsequently, the animals were euthanized for brain morphological analysis using stereological methods. In addition, we performed immunofluorescence and polymerase chain reaction (PCR) analyses to identify HUCBC in the rat brain 7 days after transplantation. The MWM test showed a significant spatial memory recovery at the highest HUCBC dose compared with HI+vehicle rats (P<0.05). Furthermore, the brain atrophy was also significantly lower in the HI+medium- and high-dose groups compared with the HI+vehicle animals (P<0.01; 0.001, respectively). In addition, HUCBC were demonstrated to be localized in host brains by immunohistochemistry and PCR analyses 7 days after intravenous administration. These results revealed that HUCBC transplantation has the dose-dependent potential to promote robust tissue repair and stable cognitive improvement after HI brain injury. PMID:22441035

  4. Prediction of nonresponsiveness to medium-dose intravenous immunoglobulin (1 g/kg) treatment: an effective and safe schedule of acute treatment for Kawasaki disease

    PubMed Central

    Moon, Kyung Pil; Kim, Beom Joon; Lee, Kyu Jin; Oh, Jin Hee; Han, Ji Whan; Lee, Kyung Yil

    2016-01-01

    Purpose Medium-dose (1 g/kg) intravenous immunoglobulin (IVIG) is effective in the majority of patients with Kawasaki disease (KD) but some patients who do not respond to medium-dose IVIG are at high risk for the development of coronary artery lesions (CALs). The purpose of this study was to identify the clinical predictors associated with unresponsiveness to medium-dose IVIG and the development of CALs. Methods A retrospective study was performed in 91 children with KD who were treated with medium-dose IVIG at our institution from January 2004 to December 2013. We classified the patients into responders (group 1; n=68) and nonresponders (group 2; n=23). We compared demographic, laboratory, and echocardiographic data between the 2 groups. Results Multivariate logistic regression analysis identified 6 variables as predictors for resistance to medium-dose IVIG. We generated a predictive scoring system assigning 1 point each for percentage of neutrophils ≥65%, C-reactive protein≥100 mg/L, aspartate aminotransferase≥100 IU/L, and alanine aminotransferase≥100 IU/L, as well as 2 points for less than 5 days of illness, and serum sodium level≤136 mmol/L. Using a cutoff point of ≥4 with this scoring system, we could predict nonresponsiveness to medium-dose IVIG with 74% sensitivity and 71% specificity. Conclusion If a patient has a low-risk score in this system, medium-dose IVIG can be recommended as the initial treatment. Through this process, we can minimize the adverse effects of high-dose IVIG and incidence of CALs. PMID:27186228

  5. Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.

    PubMed

    Strunk, Ann-Kathrin; Ciesek, Sandra; Schmidt, Julius J; Kühn, Christian; Hoeper, Marius M; Welte, Tobias; Kielstein, Jan T

    2016-01-01

    The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis. PMID:26518065

  6. RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

    SciTech Connect

    Kachnic, Lisa A.; Winter, Kathryn; Myerson, Robert J.; Goodyear, Michael D.; Willins, John; Esthappan, Jacqueline; Haddock, Michael G.; Rotman, Marvin; Parikh, Parag J.; Safran, Howard; Willett, Christopher G.

    2013-05-01

    Purpose: A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. Methods and Materials: T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤3 cm or 54 Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigator’s ability to perform DP-IMRT. Results: Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. Conclusions: Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.

  7. Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD.

    PubMed

    Cazzola, Mario; Santus, Pierachille; D'Adda, Alice; Pizzolato, Silvia; Di Marco, Fabiano; Centanni, Stefano

    2009-06-01

    Knowledge on the effects of the additive bronchodilatory effects of short-acting agents on the top of the effect of long-acting bronchodilators is limited. In this trial, we examined the influence of higher than conventional doses of the short-acting inhaled beta(2)-adrenergic agent salbutamol and the short-acting anticholinergic drug ipratropium bromide on bronchodilation induced by a regular treatment with the long-acting anticholinergic drug tiotropium 18 microg/day in 30 patients with stable COPD. On 3 separate days, a dose-response curve to inhaled salbutamol (100 microg puff-1), ipratropium bromide (20 microg puff-1) or placebo was constructed 3h after inhalation of the last dose of tiotropium, using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg salbutamol or 120 microg ipratropium bromide. Doses were given at 30-min intervals and measurements made 15 min after each dose. At the highest cumulative dose, salbutamol showed a trend to be more effective than ipratropium bromide in improving FEV(1) (0.157 L vs 0.125 L), and reducing sRaw (-4.52 kPa/s vs 3.57 kPa/s), although the differences between the two treatments were always not significant (p>0.05), whereas there was no substantial difference between the two drugs in changing FVC (0.179 L vs 0.168 L), IC (0.254 L vs 0.240 L), TGV (-0.444 L vs -0.441 L), TLC (-0.334 L vs -0.318 L) and RV (-0.467 L vs -0.498 L). Both drugs did not affect heart rate and SpO2. Our results indicate that there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium bromide to tiotropium in patients with stable COPD. Effective improvement of the pulmonary function may be achieved in such a type of patients by adding salbutamol 600 microg or ipratropium bromide 120 microg to regular tiotropium. These is an interesting finding mainly for those COPD patients suffering from cardiovascular co-morbidities that are at highest risk of

  8. Sinusitis (acute)

    PubMed Central

    2008-01-01

    Introduction Acute sinusitis is defined pathologically, by transient inflammation of the mucosal lining of the paranasal sinuses lasting less than 4 weeks. Clinically, it is characterised by nasal congestion, rhinorrhoea, facial pain, hyposmia, sneezing, and, if more severe, additional malaise and fever. It affects 1−5% of the adult population each year in Europe. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with clinically diagnosed acute sinusitis, and with radiologically or bacteriologically confirmed acute sinusitis? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin, co-amoxiclav, doxycycline, cephalosporins, macrolides, different doses [amoxicillin, co-amoxiclav, doxycycline, cephalosporins, macrolides], long-course regimens), antihistamines, cephalosporins or macrolides, decongestants (xylometazoline, phenylephrine, pseudoephedrine), doxycycline, saline nasal washes, steam inhalation, and topical corticosteroids (intra-nasal). PMID:19450327

  9. Sinusitis (acute)

    PubMed Central

    2011-01-01

    Introduction Acute sinusitis is defined pathologically, by transient inflammation of the mucosal lining of the paranasal sinuses lasting less than 4 weeks. Clinically, it is characterised by nasal congestion, rhinorrhoea, facial pain, hyposmia, sneezing, and, if more severe, additional malaise and fever. It affects 1% to 5% of the adult population each year in Europe. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with clinically diagnosed acute sinusitis, and in people with radiologically or bacteriologically confirmed acute sinusitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin, amoxicillin–clavulanic acid [co-amoxiclav], doxycycline, cephalosporins, macrolides; different doses, long-course regimens), antihistamines, decongestants (xylometazoline, phenylephrine, pseudoephedrine), saline nasal washes, steam inhalation, and topical corticosteroids (intranasal). PMID:22189346

  10. [Clinical usefulness of 201Tl/99mTc-PYP dual myocardial quantitative gated SPECT program using low-dose dobutamine loading in assessment of myocardial viability in patient with acute myocardial infarction--a case report].

    PubMed

    Irie, Hidekazu; Ito, Kazuki; Koide, Masahiro; Taniguchi, Takuya; Yokoi, Hirokazu; Nakamura, Reo; Kinoshita, Noriyuki; Hashimoto, Tetsuo; Tamaki, Shunichi; Sawada, Takahisa; Azuma, Akihiro; Matsubara, Hiroaki

    2006-05-01

    An 86-year-old man with chest pain was admitted to our hospital. Coronary angiography revealed 99% stenosis of the mid segment of the left anterior descending coronary artery, therefore, a coronary stent was implanted. Immediately after the stent implantation, 99% stenosis occurred at the proximal site of the 1st diagonal artery because of stent jeal. On the 4th hospital day, ECG-gated 201TL/99mTc-PYP dual myocardial quantitative gated SPECT was performed at rest and during low-dose dobutamine loading. The 201Tl scintigraphy revealed moderately reduced uptake in the anterior, septal and apical walls, and 99mTc-PYP uptake was observed in the mid-anterior wall. A three-dimensional surface display of gated 201Tl SPECT images showed severe hypokinesis in the anterior, septal and apical walls at rest. On the other hand, during low-dose dobutamine loading, improved wall motion was observed in the basal anterior and septal walls, while no change was observed in the midanterior and apical wall movements. Three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images revealed similar patterns of wall motion as those of gated 201Tl SPECT images at rest. During low-dose dobutamine loading, on the other hand, a three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images revealed improved wall motion in the basal anterior, septal and apical walls, but worsened wall motion of the mid-anterior wall. After 6 months, a follow-up coronary angiography revealed no re-stenosis of the stent, but 99% stenosis at the proximal aspect of the 1st diagonal artery. Left ventriculography revealed improved wall motion in the apex and akinesis of the mid-anterior wall. These wall motion findings were similar to those visualized in the three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images during low-dose dobutamine loading in the acute phase. These results suggest that 201Tl/99mTc-PYP dual myocardial quantitative gated SPECT using low-dose

  11. Intracoronary versus intravenous high-dose bolus plus maintenance administration of tirofiban in patients undergoing primary percutaneous coronary intervention for acute ST elevation myocardial infarction.

    PubMed

    Candemir, Basar; Kilickap, Mustafa; Ozcan, Ozgur Ulas; Kaya, Cansin Tulunay; Gerede, Menekse; Ozdemir, Aydan Ongun; Ozdol, Cagdas; Kumbasar, Deniz; Erol, Cetin

    2012-07-01

    We aimed to examine whether intracoronary high-dose bolus of tirofiban plus maintenance would result in improved clinical outcome in STEMI patients undergoing primary PCI in this pilot trial. A total of 56 patients were enrolled to receive either intracoronary high-dose bolus plus maintenance (n = 34) or intravenous high-dose bolus plus maintenance (n = 22) of tirofiban. Pre and post intervention TIMI flow grades, myocardial blush grades, peak CKMB and troponin levels, time to peak CKMB and troponin, time to 50% ST resolution and major composite adverse cardiac event rates at 30 days were recorded. Although incidence of major adverse cardiac events was not different, post intervention TIMI flow and TIMI blush grades, peak CKMB and troponin levels, and time to peak CKMB and time to peak troponin were significantly different, favoring intracoronary strategy. In conclusion, this regimen improved myocardial reperfusion and coronary flow, and reduced myocardial necrosis, but failed to improve clinical outcomes at 30 days. PMID:22252901

  12. Effect of folate status and methylenetetrahydrofolate reductase genotypes on the complications and outcome of high dose methotrexate chemotherapy in north Indian children with acute lymphoblastic leukemia

    PubMed Central

    Moulik, Nirmalya Roy; Kumar, Archana; Agrawal, Suraksha; Mahdi, Abbas Ali; Kumar, Ashutosh

    2016-01-01

    Purpose: The genes of the folate metabolic pathway have been associated with toxicities during high dose methotrexate therapy for childhood ALL, however, the importance of intrinsic folate status in this regard is unclear. Methods: In the present study the effect of precourse folate levels and MTHFR genotypes on the complications during high dose methotrexate chemotherapy in children with ALL were examined. Results: Twenty-one children were studied. Folate deficiency was associated with higher incidence of neutropenia (P = 0.03) and longer duration of chemotherapy interruption (P = 0.009). Children with MTHFR1298 mutations needed more red cell transfusion (P = 0.03). All 3 deaths encountered were seen in folate deficient children. Conclusions: Folate deficiency was associated with higher complications during high dose methotrexate therapy, the implications of which are important especially in resource poor settings with high prevalence of folate deficiency. PMID:27168705

  13. A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

    PubMed

    Buckley, Sarah A; Mawad, Raya; Gooley, Ted A; Becker, Pamela S; Sandhu, Vicky; Hendrie, Paul; Scott, Bart L; Wood, Brent L; Walter, Roland B; Smith, Kelly; Dean, Carol; Estey, Elihu H; Pagel, John M

    2015-08-01

    Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low-dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high-risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment-related grade 3-4 non-haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18-50%] and 6.8 months overall and 38% [95% CI, 19-57%] and 7.2 months at the MTD. The median disease-free survival was 7.4 months. Fifty-two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients. PMID:25854284

  14. REFERENCE DOSE FOR METHYLMERCURY (EXTERNAL REVIEW DRAFT)

    EPA Science Inventory

    In 1997, U.S. EPA issued the Mercury Study Report to Congress (MSRC). Among the assessments in the MSRC was a state-of-the-science evaluation of the health effects of methylmercury. There has been considerable discussion within the scientific community regarding the level of e...

  15. DEVELOPING AN EXPOSURE-DOSE-RESPONSE MODEL FOR THE ACUTE NEUROTOXICITY OF ORGANIC SOLVENTS: OVERVIEW AND PROGRESS ON IN VITRO MODELS AND DOSIMETRY.

    EPA Science Inventory

    This article provides an overview of the current status of an exposure-dose-response (EDR) model for the volatile organic compound toluene. This model is being developed as a vehicle for understanding the neurotoxicity of organic solvents and will be used to support risk assessme...

  16. Assessment of hepatic function, oxidant/antioxidant status, and histopathological changes in rats treated with atorvastatin: Effect of dose and acute intoxication with acetaminophen.

    PubMed

    Farag, M M; Mohamed, M B; Youssef, E A

    2015-08-01

    A major disadvantage that may occur in association with atorvastatin (ATV) therapy is elevation of serum transaminases. This study was designed to evaluate the effects of treatment of rats with various doses of ATV (2, 5, and 10 mg/kg/day) on liver function, oxidative stress, and histology and on the severity of acetaminophen (APAP) hepatotoxicity. ATV administration for 21 days resulted in a dose-dependent significant rise in serum activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Only ATV at 10 mg/kg/day decreased reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity, increased malondialdehyde (MDA) levels, and elicited histopathological changes in the liver. In rats challenged with APAP (500 mg/kg), the livers showed centrilobular necrosis with evident oxidative stress and liver dysfunction after 24 h. Rats challenged with APAP after pretreatment with ATV 2 or 5 mg/kg/day showed significantly lower activities of serum enzymes, higher hepatic GSH levels and SOD activities, lower MDA levels and milder histopathological changes compared with rats challenged with APAP after pretreatment with ATV 10 mg/kg/day or without drug pretreatment. In conclusion, the effect of ATV on the liver is dose dependent. Our results showed that ATV, at the highest dose used, induced hepatic lipid peroxidation and injury, suggesting a role for oxidative stress in ATV-induced hepatotoxicity. However, lower doses of ATV attenuated APAP-induced hepatotoxicity via a mechanism related, at least in part, to a reduction of APAP-induced hepatic oxidative stress. These results are of practical interest as both drugs may be used concurrently in clinical practice. PMID:25425547

  17. Decitabine Compared with Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia: A Pilot Study of Safety, Efficacy, and Cost-Effectiveness

    PubMed Central

    Jacob, Linu A.; Aparna, S.; Lakshmaiah, K. C.; Lokanatha, D.; Babu, Govind; Babu, Suresh; Appachu, Sandhya

    2015-01-01

    Introduction. The incidence of Acute Myeloid Leukemia (AML) increases progressively with age and its treatment is challenging. This prospective case control study was undertaken to compare the safety, efficacy, and cost-effectiveness of decitabine with those of cytarabine in older patients with newly diagnosed AML who are not fit for intensive chemotherapy. Materials and Methods. 30 eligible patients above 60 years old with newly diagnosed AML were assigned to receive decitabine or cytarabine. The primary end point was overall survival (OS). The secondary objective was to compare adverse events and cost-effectiveness of therapy in the two study groups. Results. In this study, 15 patients received decitabine and 15 patients received cytarabine. The median OS was 5.5 months for each of the treatment groups. The hazard ratio between the treatment groups was 0.811 with 95% CI of 0.390 to 1.687. Toxicity profile was similar in both groups. Cost per cycle of chemotherapy in INR was 24,200 for decitabine and 1,600 for low-dose cytarabine group. Median of simplified cost-effectiveness ratio was 0.00022 for decitabine group and 0.0034 for low-dose cytarabine group. Conclusions. For elderly patients with AML, decitabine and low-dose cytarabine should be chosen based on the patient's choice and affordability. Our study has shown that both of these agents have similar OS and toxicity. Low-dose cytarabine scores over decitabine in developing countries as it is more cost-effective. PMID:26617639

  18. A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial

    PubMed Central

    Sierra, Jorge; Szer, Jeffrey; Kassis, Jeannine; Herrmann, Richard; Lazzarino, Mario; Thomas, Xavier; Noga, Stephen J; Baker, Nigel; Dansey, Roger; Bosi, Alberto

    2008-01-01

    Background Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics. Methods Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy. Results The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim. Conclusion These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics. Trial registration Clinicaltrials.gov NCT00114764 PMID:18616811

  19. Low-Dose Interleukin-2 Immunotherapy Does Not Improve Outcome of Patients Age 60 Years and Older With Acute Myeloid Leukemia in First Complete Remission: Cancer and Leukemia Group B Study 9720

    PubMed Central

    Baer, Maria R.; George, Stephen L.; Caligiuri, Michael A.; Sanford, Ben L.; Bothun, Sandra M.; Mrózek, Krzysztof; Kolitz, Jonathan E.; Powell, Bayard L.; Moore, Joseph O.; Stone, Richard M.; Anastasi, John; Bloomfield, Clara D.; Larson, Richard A.

    2008-01-01

    Purpose Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML). Patients and Methods AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis. Results A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival. Conclusion Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients. PMID:18591543

  20. Efficacy and safety of flexibly dosed paliperidone palmitate in Chinese patients with acute schizophrenia: an open-label, single-arm, prospective, interventional study

    PubMed Central

    Si, Tianmei; Zhang, Kerang; Tang, Jisheng; Fang, Maosheng; Li, Keqing; Zhuo, Jianmin; Feng, Yu

    2015-01-01

    This open-label, single-arm, multicenter, 13-week, prospective study explored the efficacy, safety, and tolerability of paliperidone palmitate (150 milligram equivalents [mg eq] [day 1], 100 mg eq [day 8], both deltoid injections; 75–150 mg eq, deltoid/gluteal injection) in Chinese patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score ≥70), who previously had unsatisfactory therapeutic effect following oral antipsychotic treatment (without washout period). Primary efficacy endpoint was percentage of patients with ≥30% improvement in the PANSS total score at the end of 13 weeks. Secondary efficacy endpoints included change from baseline to end of week 13 in PANSS total score, PANSS subscale scores, Marder factor scores, Clinical Global Impressions–Severity score, and Personal and Social Performance Scale scores. Overall, 477/610 enrolled patients (full analysis set, 78.2%) completed the study (men: 55.1%; women: 44.9%; mean age: 31.5 years). Total, 443/610 (72.6%, full analysis set) patients achieved primary endpoint (mean [standard deviation] change from baseline: –30.9 [19.51]). All secondary endpoints demonstrated significant improvement at the end of 13 weeks. One death occurred during this acute phase. The most common (>5%) treatment-emergent adverse events were extrapyramidal disorders (8.4%). The efficacy and safety data are consistent with other short-term, placebo-controlled studies of paliperidone palmitate conducted in similar populations. PMID:26150719

  1. Life-span exposure to sinusoidal-50 Hz magnetic field and acute low-dose γ radiation induce carcinogenic effects in Sprague-Dawley rats.

    PubMed

    Soffritti, Morando; Tibaldi, Eva; Padovani, Michela; Hoel, David G; Giuliani, Livio; Bua, Luciano; Lauriola, Michelina; Falcioni, Laura; Manservigi, Marco; Manservisi, Fabiana; Panzacchi, Simona; Belpoggi, Fiorella

    2016-01-01

    Background In 2002 the International Agency for Research on Cancer classified extremely low frequency magnetic fields (ELFMF) as a possible carcinogen on the basis of epidemiological evidence. Experimental bioassays on rats and mice performed up to now on ELFMF alone or in association with known carcinogens have failed to provide conclusive confirmation. Objectives To study the carcinogenic effects of combined exposure to sinusoidal-50 Hz (S-50 Hz) magnetic fields and acute γ radiation in Sprague-Dawley rats. Methods We studied groups of male and female Sprague-Dawley rats exposed from prenatal life until natural death to 20 or 1000 μT S-50 Hz MF and also to 0.1 Gy γ radiation delivered as a single acute exposure at 6 weeks of age. Results The results of the study showed significant carcinogenic effects for the mammary gland in males and females and a significant increased incidence of malignant schwannomas of the heart as well as increased incidence of lymphomas/leukemias in males. Conclusions These results call for a re-evaluation of the safety of non-ionizing radiation. PMID:26894944

  2. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood.

    PubMed Central

    Nysom, K.; Holm, K.; Olsen, J. H.; Hertz, H.; Hesse, B.

    1998-01-01

    The aim of this study was to examine pulmonary function after acute lymphoblastic leukaemia in childhood and identify risk factors for reduced pulmonary function. We studied a population-based cohort of 94 survivors of acute lymphoblastic leukaemia in childhood who were in first remission after treatment without spinal irradiation or bone marrow transplantation. Pulmonary function test results were compared with reference values for our laboratory, based on 348 healthy subjects who had never smoked from a local population study. A median of 8 years after cessation of therapy (range 1-18 years) the participants had a slight, subclinical, restrictive ventilatory insufficiency and reduced transfer factor and transfer coefficient. The changes in lung function were related to younger age at treatment and to more dose-intensive treatment protocols that specified more use of cranial irradiation and higher cumulative doses of anthracyclines, cytosine arabinoside and intravenous cyclophosphamide than previous protocols. We conclude that, 8 years after treatment without bone marrow transplantation or spinal irradiation, survivors of childhood acute lymphoblastic leukaemia in first remission were without pulmonary symptoms but had signs of slight restrictive pulmonary disease including reduced transfer factor. The increased dose intensity of many recent protocols for childhood acute lymphoblastic leukaemia may lead to increased late pulmonary toxicity. PMID:9662245

  3. Reference Assessment

    ERIC Educational Resources Information Center

    Bivens-Tatum, Wayne

    2006-01-01

    This article presents interesting articles that explore several different areas of reference assessment, including practical case studies and theoretical articles that address a range of issues such as librarian behavior, patron satisfaction, virtual reference, or evaluation design. They include: (1) "Evaluating the Quality of a Chat Service"…

  4. Reference Services.

    ERIC Educational Resources Information Center

    Bunge, Charles A.

    1999-01-01

    Discusses library reference services. Topics include the historical development of reference services; instruction in library use, particularly in college and university libraries; guidance; information and referral services and how they differ from traditional question-answering service; and future concerns, including user fees and the planning…

  5. Age-related dose response of selected reproductive parameters to acute cadmium chloride exposure in the male Long-Evans rat

    SciTech Connect

    Laskey, J.W.; Rehnberg, G.L.; Laws, S.C.; Hein, J.F.

    1986-01-01

    Groups of male Long-Evans rats 30, 50, or 70 d old were injected subcutaneously (sc) with a single dose of 0, 5.5, 11.5, or 24.6 ..mu..mol Cd/kg as cadmium chloride. All animals were killed 60 d after treatment. At 2 h prior to sacrifice, the rats were injected sc with 100 IU human chlorionic gonadotrophin (hCG) to maximally stimulate serum testosterone concentrations. After sacrifice the testes, epididymides and seminal vesicles were removed and weighed. Cardiac blood was taken, and serum concentrations of testosterone (sT) and follicle-stimulating hormone (sFSH) were determined. Sperm concentration in luminal fluid collected from the vas deferens was determined. Significant (p < 0.01) dose-dependent effects for all measured reproductive parameters were noted in the 70-d-old animals, while no effects were seen in the 30- to 50-d-old rats in either seminal vesicles weight or hCG-stimulated sT concentration. In the absence of significant (p > 0.05) changes in body weight gain, effects were seen in testes and epididymides weight, sperm concentration, and sFSH in the 70-d-old rats at Cd doses that were lower than those necessary to bring about similar changes in the 30- or 50-d-old animals.

  6. Effects of an acute dose of gamma radiation exposure on stem diameter growth, carbon gain, and biomass partitioning in Helianthus annuus

    SciTech Connect

    Thiede, M.E.

    1988-05-25

    Nineteen-day-old dwarf sunflower plants (Helianthus annuus, variety NK894) received a variable dose (0-40 Gy) from a cobalt-60 gamma source. A very sensitive stem monitoring device, developed at Battelle's Pacific Northwest Laboratories, Richland, Washington was used to measure real-time changes in stem diameter. Exposure of plants caused a significant reduction in stem growth and root biomass. Doses as low as 5 Gy resulted in a significant increase in leaf density, suggesting that nonreversible morphological growth changes could be induced by very low doses of radiation. Carbohydrate analysis of 40-Gy irradiated plants demonstrated significantly more starch content in leaves and significantly less starch content in stems 18 days after exposure than did control plants. In contrast, the carbohydrate content in roots of 40-Gy irradiated plants were not significantly different from unirradiated plants 18 days after exposure. These results indicate that radiation either decreased phloem transport or reduced the availability of sugar reducing enzymes in irradiated plants. 44 refs., 12 figs.

  7. Dose-dependent antioxidant responses and pathological changes in tenca (Tinca tinca) after acute oral exposure to Microcystis under laboratory conditions.

    PubMed

    Atencio, L; Moreno, I; Jos, A; Pichardo, S; Moyano, R; Blanco, A; Cameán, A M

    2008-07-01

    The effects of cyanobacterial cells containing microcystins (MCs), toxins from cyanobacteria, on oxidative stress biomarkers from liver and kidney of Tenca fish (Tinca tinca) were investigated under laboratory conditions. Moreover, a histopathological study of liver, kidney, heart and intestine tissues was performed. Fish were orally exposed to cyanobacterial cells dosing 0, 5, 11, 25 and 55 microg MC-LR/fish mixed with the food. Results showed a dose-dependent decrease of superoxide dismutase (SOD) activity, and also of catalase (CAT) in the liver. Glutathione levels and protein oxidation, however, were not altered by the exposure to the cyanobacterial material. The microscopic study revealed tissue alterations even at the lower cyanobacterial cells doses. Onion-like hepatocytes in the liver, glomerulopathy in the kidney, loss of myofibrils in the heart and vacuolated enterocytes in the gastrointestinal tract were the main changes observed. These findings suggest that this fresh water fish can be adversely affected by cyanobacterial blooms in their natural habitats. PMID:18588906

  8. Targeted Therapy for Acute Lymphocytic Leukemia

    MedlinePlus

    ... Monoclonal antibodies to treat acute lymphocytic leukemia Targeted therapy for acute lymphocytic leukemia In recent years, new ... These drugs are often referred to as targeted therapy. Some of these drugs can be useful in ...

  9. Correlation Between Radiation Dose to {sup 18}F-FDG-PET Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

    SciTech Connect

    Rose, Brent S.; Liang Yun; Lau, Steven K.; Jensen, Lindsay G.; Yashar, Catheryn M.; Hoh, Carl K.; Mell, Loren K.

    2012-07-15

    Purpose: To test the hypothesis that radiation dose to {sup 18}F-fluorodeoxyglucose positron emission tomography ({sup 18}F-FDG-PET)-defined active bone marrow (BM{sub ACT}) subregions is correlated with hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Methods and Materials: The conditions of 26 women with cervical cancer who underwent {sup 18}F-FDG-PET before treatment with concurrent cisplatin and intensity-modulated radiation therapy were analyzed. BM{sub ACT} was defined as the subregion of total bone marrow (BM{sub TOT}) with a standardized uptake value (SUV) equal to or above the mean for that individual. Inactive bone marrow (BM{sub INACT}) was defined as BM{sub TOT} - BM{sub ACT}. Generalized linear modeling was used to test the correlation between BM{sub ACT} and BM{sub INACT} dose-volume metrics and hematologic nadirs, particularly white blood cell count (WBC) and absolute neutrophil count (ANC). Results: Increased BM{sub ACT} mean dose was significantly associated with decreased log(WBC) nadir ({beta} = -0.04; 95% CI, -0.07to -0.01; p = 0.009), decreased log(ANC) nadir ({beta} = -0.05; 95% CI, -0.08 to -0.02; p = 0.006), decreased hemoglobin nadir ({beta} = -0.16; 95% CI, -0.27 to -0.05; p = 0.010), and decreased platelet nadir ({beta} = -6.16; 95% CI, -9.37 to -2.96; p < 0.001). By contrast, there was no association between BM{sub INACT} mean dose and log(WBC) nadir ({beta} = -0.01; 95% CI, -0.06 to 0.05; p = 0.84), log(ANC) nadir ({beta} = -0.03; 95% CI, -0.10 to 0.04; p = 0.40), hemoglobin nadir ({beta} = -0.09; 95% CI, -0.31 to 0.14; p = 0.452), or platelet nadir ({beta} = -3.47; 95% CI, -10.44 to 3.50; p = 0.339). Conclusions: Irradiation of BM subregions with higher {sup 18}F-FDG-PET activity was associated with hematologic toxicity, supporting the hypothesis that reducing dose to BM{sub ACT} subregions could mitigate hematologic toxicity. Future investigation should seek to confirm these findings and to identify

  10. The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum

    PubMed Central

    Sirima, Sodiomon B; Tiono, Alfred B; Gansané, Adama; Diarra, Amidou; Ouédraogo, Amidou; Konaté, Amadou T; Kiechel, Jean René; Morgan, Caroline C; Olliaro, Piero L; Taylor, Walter RJ

    2009-01-01

    Background Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested. Methods A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety. Results Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7–94.7) vs. AS+AQ = 313/340 (95% CI: 88.6–94.7). Non-inferiority was demonstrated at two-sided α = 0.05: Δ (AS+AQ – AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Δ = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances. Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients

  11. Reference frames and reference networks

    NASA Astrophysics Data System (ADS)

    Bosy, Jaroslaw; Krynski, Jan

    2015-12-01

    The summary of research activities concerning reference frames and reference networks performed in Poland in a period of 2011-2014 is presented. It contains the results of research on implementation of IUGG2011 and IAU2012 resolutions on reference systems, implementation of the ETRS89 in Poland, operational work of permanent IGS/ EUREF stations in Poland, operational work of ILRS laser ranging station in Poland, active GNSS station networks in Poland, maintenance of vertical control in Poland, maintenance and modernization of gravity control, and maintenance of magnetic control in Poland. The bibliography of the related works is given in references.

  12. Application of the hybrid approach to the benchmark dose of urinary cadmium as the reference level for renal effects in cadmium polluted and non-polluted areas in Japan

    SciTech Connect

    Suwazono, Yasushi; Nogawa, Kazuhiro; Uetani, Mirei; Nakada, Satoru; Kido, Teruhiko; Nakagawa, Hideaki

    2011-02-15

    Objectives: The aim of this study was to evaluate the reference level of urinary cadmium (Cd) that caused renal effects. An updated hybrid approach was used to estimate the benchmark doses (BMDs) and their 95% lower confidence limits (BMDL) in subjects with a wide range of exposure to Cd. Methods: The total number of subjects was 1509 (650 men and 859 women) in non-polluted areas and 3103 (1397 men and 1706 women) in the environmentally exposed Kakehashi river basin. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and {beta}2-microglobulin ({beta}2-MG) as a marker of renal effects. The BMD and BMDL that corresponded to an additional risk (BMR) of 5% were calculated with background risk at zero exposure set at 5%. Results: The U-Cd BMDL for {beta}2-MG was 3.5 {mu}g/g creatinine in men and 3.7 {mu}g/g creatinine in women. Conclusions: The BMDL values for a wide range of U-Cd were generally within the range of values measured in non-polluted areas in Japan. This indicated that the hybrid approach is a robust method for different ranges of cadmium exposure. The present results may contribute further to recent discussions on health risk assessment of Cd exposure.

  13. Acute administration of high doses of taurine does not substantially improve high-intensity running performance and the effect on maximal accumulated oxygen deficit is unclear.

    PubMed

    Milioni, Fabio; Malta, Elvis de Souza; Rocha, Leandro George Spinola do Amaral; Mesquita, Camila Angélica Asahi; de Freitas, Ellen Cristini; Zagatto, Alessandro Moura

    2016-05-01

    The aim of the present study was to investigate the effects of acute administration of taurine overload on time to exhaustion (TTE) of high-intensity running performance and alternative maximal accumulated oxygen deficit (MAODALT). The study design was a randomized, placebo-controlled, crossover design. Seventeen healthy male volunteers (age: 25 ± 6 years; maximal oxygen uptake: 50.5 ± 7.6 mL·kg(-1)·min(-1)) performed an incremental treadmill-running test until voluntary exhaustion to determine maximal oxygen uptake and exercise intensity at maximal oxygen uptake. Subsequently, participants completed randomly 2 bouts of supramaximal treadmill-running at 110% exercise intensity at maximal oxygen uptake until exhaustion (placebo (6 g dextrose) or taurine (6 g) supplementation), separated by 1 week. MAODALT was determined using a single supramaximal effort by summating the contribution of the phosphagen and glycolytic pathways. When comparing the results of the supramaximal trials (i.e., placebo and taurine conditions) no differences were observed for high-intensity running TTE (237.70 ± 66.00 and 277.30 ± 40.64 s; p = 0.44) and MAODALT (55.77 ± 8.22 and 55.06 ± 7.89 mL·kg(-1); p = 0.61), which seem to indicate trivial and unclear differences using the magnitude-based inferences approach, respectively. In conclusion, acute 6 g taurine supplementation before exercise did not substantially improve high-intensity running performance and showed an unclear effect on MAODALT. PMID:27109264

  14. Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats.

    PubMed

    Zhang, Wenhui; Zhi, Jianming; Cui, Yongyao; Zhang, Fan; Habyarimana, Adélite; Cambier, Carole; Gustin, Pascal

    2014-01-01

    The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases. PMID:25313925

  15. Potentiated Interaction between Ineffective Doses of Budesonide and Formoterol to Control the Inhaled Cadmium-Induced Up-Regulation of Metalloproteinases and Acute Pulmonary Inflammation in Rats

    PubMed Central

    Zhang, Wenhui; Zhi, Jianming; Cui, Yongyao; Zhang, Fan; Habyarimana, Adélite; Cambier, Carole; Gustin, Pascal

    2014-01-01

    The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases. PMID:25313925

  16. Notes on the effect of dose uncertainty

    SciTech Connect

    Morris, M.D.

    1987-01-01

    The apparent dose-response relationship between amount of exposure to acute radiation and level of mortality in humans is affected by uncertainties in the dose values. It is apparent that one of the greatest concerns regarding the human data from Hiroshima and Nagasaki is the unexpectedly shallow slope of the dose response curve. This may be partially explained by uncertainty in the dose estimates. Some potential effects of dose uncertainty on the apparent dose-response relationship are demonstrated.

  17. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. International Multicentre Hirudin Study Group.

    PubMed

    Schiele, F; Lindgaerde, F; Eriksson, H; Bassand, J P; Wallmark, A; Hansson, P O; Grollier, G; Sjo, M; Moia, M; Camez, A; Smyth, V; Walker, M

    1997-05-01

    The aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous recombinant hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 +/- 1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Day 1 and Day 5 +/- 1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients. PMID:9184388

  18. High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

    PubMed

    Takahashi, Hiroyuki; Watanabe, Tomoyuki; Kinoshita, Akitoshi; Yuza, Yuki; Moritake, Hiroshi; Terui, Kiminori; Iwamoto, Shotaro; Nakayama, Hideki; Shimada, Akira; Kudo, Kazuko; Taki, Tomohiko; Yabe, Miharu; Matsushita, Hiromichi; Yamashita, Yuka; Koike, Kazutoshi; Ogawa, Atsushi; Kosaka, Yoshiyuki; Tomizawa, Daisuke; Taga, Takashi; Saito, Akiko M; Horibe, Keizo; Nakahata, Tatsutoshi; Miyachi, Hayato; Tawa, Akio; Adachi, Souichi

    2016-08-01

    We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered. PMID:27029412

  19. Ready Reference.

    ERIC Educational Resources Information Center

    Koltay, Emery

    1999-01-01

    Includes the following ready reference information: "Publishers' Toll-Free Telephone Numbers"; "How to Obtain an ISBN (International Standard Book Number)"; "How to Obtain an ISSN (International Standard Serial Number)"; and "How to Obtain an SAN (Standard Address Number)". (AEF)

  20. Short Term Efficacy and Safety of Low Dose Tolvaptan in Patients with Acute Decompensated Heart Failure with Hyponatremia: A Prospective Observational Pilot Study from a Single Center in South India

    PubMed Central

    Patra, Soumya; Kumar, Basant; Harlalka, Kaushal K.; Jain, Apoorva; Bhanuprakash, H. M.; Sadananda, K. S.; Basappa, Harsha; Santhosh, K.; Rajith, K. S.; Bharathi, K. S.; Manjunath, C. N.

    2014-01-01

    Background: In acute decompensated heart failure (ADHF), diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. Vasopressin mediates fluid retention in heart failure. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function. Hyponatremia (serum sodium concentration, <135 mEq/L) is a predictor of death among patients with heart failure. Objective: We prospectively observed the short term efficacy and safety of low dose (15 mg) tolvaptan in admitted patients with hyponatremia and ADHF in Indian population. Methodology: A total of 40 patients with ADHF along with hyponatremia (<125 mEq/L) on standard therapy were treated with 15 mg of tolvaptan at a single oral dose for 7 days. Results: Serum sodium concentrations increased significantly after treatment with tolvaptan from baseline (P < 0.02). There was a significant improvement in symptoms and New York Heart Association (NYHA) class after starting tolvaptan (P ≤ 0.05). Total diuretic dose and mean body weight was reduced non-significantly at 7th day from the baseline. Side-effects associated with tolvaptan included increased thirst, dry mouth and increased urination. Few patients had worsening renal function. However, several patients developed hypernatremia. Conclusion: In this small observational study, tolvaptan initiation in patients with ADHF with hyponatremia in addition to standard therapy may hold promise in improvement in NYHA class and serum sodium. At the same time, we observed that serious adverse events such as renal function deterioration and hypernatremia developed after tolvaptan treatment, which needs to be addressed in future by randomized study with larger sample size. PMID:24949180

  1. In vivo flow cytometric Pig-a and micronucleus assays: highly sensitive discrimination of the carcinogen/noncarcinogen pair benzo(a)pyrene and pyrene using acute and repeated-dose designs.

    PubMed

    Torous, Dorothea K; Phonethepswath, Souk; Avlasevich, Svetlana L; Mereness, Jared; Bryce, Steven M; Bemis, Jeffrey C; Weller, Pamela; Bell, Sara; Gleason, Carol; Custer, Laura L; MacGregor, James T; Dertinger, Stephen D

    2012-07-01

    frequencies were observed with BP, whereas Pyr had no effect. These results demonstrate that Pig-a and micronucleus endpoints discriminate between these structurally related carcinogenic and noncarcinogenic agents. Furthermore, the high sensitivity demonstrated with the enrichment protocol indicates that the Pig-a endpoint is suitable for both repeated-dose and acute studies, allowing integration of mutagenic and clastogenic endpoints into on-going toxicology studies, and use as a short-term assay that provides efficient screening and mechanistic information in vivo. PMID:22730284

  2. Acute Bronchitis

    MedlinePlus

    ... or though physical contact (for example, on unwashed hands). Being exposed to tobacco smoke, air pollution, dusts, vapors, and fumes can also cause acute bronchitis. Less often, bacteria can also cause acute bronchitis. To diagnose acute ...

  3. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... control. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  4. Naproxen Twice Daily Versus as Needed (PRN) Dosing: Efficacy and Tolerability for Treatment of Acute Ankle Sprain, a Randomized Clinical Trial

    PubMed Central

    Hajimaghsoudi, Majid; Jalili, Mohammad; Mokhtari, Mehdi; Nejati, Amir; Mesbahi, Javad; Paydary, Koosha

    2013-01-01

    Purpose This study was conducted to compare the efficacy and safety of naproxen 500 mg twice daily (BID) versus naproxen 500 mg as needed (PRN) for treatment of ankle sprain. Methods In this seven-day, randomized, parallel group trial, 135 patients with ankle sprain occurring less than 48 hours prior to the first dose of study medication were randomized to receive naproxen 500 mg BID (67 patients) and naproxen 500 mg as needed (PRN) (68 patients). The ankle pain was assessed at rest and on full weight bearing using Numeric Rating Scale (NRS) from 0 (no pain) to 10 (the worst imaginable pain). Ankle swelling was assessed as a 4-point scale ranging from 0 (no swelling) to 3 (severe swelling) rated by the investigator. The primary efficacy end point was the patient's assessment of ankle pain via NRS and the degree of swelling on day seven. Results Results showed a significant decrease in pain on weight bearing, pain at rest and the extent of swelling (P<0.001) in both groups, but there was no substantial difference between the two groups (P>0.05) after seven days. Assessing the safety profile of the two different dosing, 13.3% of the naproxen BID group and 6.7% of the as needed group had adverse events, showing that the as needed regimen was safer (P<0.001). Conclusion Results showed that naproxen as needed may reduce the pain and edema of the sprained ankle with no significant difference compared to the BID regimen, while it possesses better safety profile and lower total drug use. PMID:24799999

  5. Computer-aided detection of therapy-induced leukoencephalopathy in pediatric acute lymphoblastic leukemia patients treated with intravenous high-dose methotrexate.

    PubMed

    Glass, John O; Reddick, Wilburn E; Li, Chin-Shang; Laningham, Fred H; Helton, Kathleen J; Pui, Ching-Hon

    2006-07-01

    The purpose of this study was to use objective quantitative magnetic resonance imaging (MRI) methods to develop a computer-aided detection (CAD) tool to differentiate white matter (WM) hyperintensities into either leukoencephalopathy (LE) induced by chemotherapy or normal maturational processes in children treated for acute lymphoblastic leukemia without irradiation. A combined MRI set consisting of T1-weighted, T2-weighted, proton-density-weighted and fluid-attenuated inversion recovery images and WM, gray matter and cerebrospinal fluid proportional volume maps from a spatially normalized atlas were analyzed with a neural network segmentation based on a Kohonen self-organizing map (SOM). Segmented maps were manually classified to identify the most hyperintense WM region and the normal-appearing genu region. Signal intensity differences normalized to the genu within each examination were generated for four time points in 228 children. A second Kohonen SOM was trained on the first examination data and divided the WM into normal-appearing or LE groups. Reviewing labels from the CAD tool revealed a consistency measure of 89.8% (167 of 186) within patients. The overall agreement between the CAD tool and the consensus reading of two trained observers was 84.1% (535 of 636), with 84.2% (170 of 202) agreement in the training set and 84.1% (365 of 434) agreement in the testing set. These results suggest that subtle therapy-induced LE can be objectively and reproducibly detected in children treated for cancer using this CAD approach based on relative differences in quantitative signal intensity measures normalized within each examination. PMID:16824973

  6. Dose-enhanced combined priming regimens for refractory acute myeloid leukemia and middle-and-high-risk myelodysplastic syndrome: a single-center, retrospective cohort study

    PubMed Central

    Ma, Xiaorong; Wang, Jin; Xu, Yan; Zhang, Wanggang; Liu, Jie; Cao, Xingmei; He, Aili; Wang, Fangxia; Gu, Liufang; Lei, Bo; Wang, Jianli

    2016-01-01

    Objective To assess chemotherapeutic regimens for refractory acute myeloid leukemia (AML) and middle-and-high-risk myelodysplastic syndrome (MDS). Methods Between 2004 and 2014, 44 patients with refractory AML and 36 patients with MDS were treated with new priming regimens (CHAG, CHTG, CHMG, or CTMG), and 77 patients with refractory AML and 52 patients with MDS were treated with conventional priming regimens (CHG or CAG). This was a single-center retrospective analysis of remission, adverse event, mortality, and survival. The capacity of clinical features (including the expression of co-stimulatory molecule B7.1 on tumor cells) to influence survival was assessed by multivariate Cox regression. Results Complete and partial remission rates (RRs) were significantly higher in AML patients treated with new regimens compared to conventional ones (68.2% vs 13.6%, P<0.05). Complete and partial remission were also significantly higher in patients with MDS treated with new regimens (55.6% vs 19.4%, P<0.05). However, although survival advantages were observed in the first year, the new regimens did not significantly improve 3-year overall survival (P>0.05). Patients administered the new regimens experienced more severe and sustained myelosuppression (P<0.05), but no severe adverse events or treatment-related deaths were observed. The rate of non-hematological side effects did not differ significantly between treatment regimens (P>0.05). Both RR and B7.1 expression were significantly higher in patients with AML-M2 and M5 (P<0.05). Conclusion The new priming regimens improved the RR, lowered the recurrence rate, and improved survival in AML and middle-and-high-risk MDS, without significantly increasing adverse events. PMID:27382304

  7. Acute radiation risk models

    NASA Astrophysics Data System (ADS)

    Smirnova, Olga

    Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

  8. Effects of Korean White Ginseng (Panax Ginseng C.A. Meyer) on Vascular and Glycemic Health in Type 2 Diabetes: Results of a Randomized, Double Blind, Placebo-controlled, Multiple-crossover, Acute Dose Escalation Trial

    PubMed Central

    Shishtar, Esra'; Jovanovski, Elena; Jenkins, Alexandra

    2014-01-01

    Korean red ginseng (steam treated Panax ginseng C.A. Meyer), among most prized traditional herbal remedies, has been clinically shown to improve cardiovascular disease (CVD) risk factors. Whether this holds true for the dried non-steamed variety, known as Korean white ginseng (KWG) is unclear. This study therefore, investigated the efficacy and safety of escalating doses of KWG on vascular and glycemic parameters in type 2 diabetes (T2DM). Using an acute, randomized, placebo-controlled, double-blind, crossover design, 25 participants with well-controlled T2DM (12-males: 13-females, age: 63 ± 9 years, A1c: 6.9 ± 0.7%, BMI: 29.3 ± 4.3 kg/m2) underwent five visits during which they received 1 g, 3 g, or 6 g KWG or 3 g wheat-bran control (twice) together with 50 g-glucose load. For the duration of 240 minutes, augmentation index (AI), and central blood pressure were measured at baseline and at 60 min-intervals, and ambulatory blood pressure was assessed at baseline and at 10 min-intervals. Additionally, capillary blood was collected at time zero and at 15, 30, 45, 60, 90, 120, and 180 minutes post-treatment. A symptoms questionnaire was used to assess safety and adverse events. Two-way ANOVA demonstrated a significant time-treatment interaction effect on AI (p = 0.01) with one-way ANOVA showing significant reductions in AI with 3 g KWG relative to control (p = 0.04). Compared to control, acute administration of KWG appeared to be safe, but did not affect any other postprandial, vascular or glycemic parameters. KWG might have a beneficial effect on AI, a cumulative indicator of arterial health. However, these results are preliminary and highlight the need for long-term investigation with a focus on its accountable components. Clinical Trial Registration: NCT01699074 PMID:25136536

  9. Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

    PubMed Central

    Hütter-Krönke, Marie-Luise; Benner, Axel; Döhner, Konstanze; Krauter, Jürgen; Weber, Daniela; Moessner, Margit; Köhne, Claus-Henning; Horst, Heinz A.; Schmidt-Wolf, Ingo G.H.; Rummel, Mathias; Götze, Katharina; Koller, Elisabeth; Petzer, Andreas L.; Salwender, Hans; Fiedler, Walter; Kirchen, Heinz; Haase, Detlef; Kremers, Stephan; Theobald, Matthias; Matzdorff, Axel C.; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F.

    2016-01-01

    Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m2 intravenously on day 1), all-trans retinoic acid (45 mg/m2 orally on days 4–6 and 15 mg/m2 orally on days 7–28), high-dose cytarabine (3 g/m2/12 h intravenously on days 1–3) and mitoxantrone (12 mg/m2 intravenously on days 2–3) in 93 patients aged 18–60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975) PMID:27036160

  10. To compare the efficacy and safety of fixed dose combination of thiocolchicoside and aceclofenac versus chlorzoxazone, aceclofenac and paracetamol in patients with acute lower backache associated with muscle spasm

    PubMed Central

    Kumar, Sanjeev; Rani, Seema; Siwach, Ramchander; Verma, Prem

    2014-01-01

    Background: The fixed dose combinations (FDCs) of muscle relaxants, non-steroidal anti-inflammatory drugs and paracetamol are commonly prescribed in the treatment of acute lower backache. Aim: The present study was undertaken with the aim of comparing the efficacy and safety of FDCs of thiocolchicoside and aceclofenac versus chlorzoxazone, aceclofenac and paracetamol in patients with acute lower backache associated with muscle spasm. Materials and Methods: A total of 100 patients between ages range from 18 and 55 years having low back pain of ≤7 days duration were randomly divided into two groups. Group A was prescribed thiocolchicoside (4 mg) + aceclofenac (100 mg) while Group B was prescribed chlorzoxazone (500 mg) + aceclofenac (100 mg) + paracetamol (325 mg) orally twice daily for 7 days. Severity of pain at rest and on movement was recorded using visual analogue scale. Muscle spasm was evaluated by hand-to-floor distance and Lasegue's maneuver. Readings were noted on day 1 (baseline), day 3 and day 7. Results: There was statistically significant reduction in severity of pain and muscle spasm on day 3 and day 7 in both groups. There was no statistically significant difference in pain relief and muscle spasm among the treatment groups but clinically showed better improvement in the Group A. The adverse drug reactions occurring during study showed a statistically significant better safety profile in the Group A than Group B. Conclusion: These findings confirm that FDC of thiocolchicoside and aceclofenac is a preferred option for patients with lower backache pain associated with muscle spasm. PMID:25143885

  11. Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy.

    PubMed

    Hütter-Krönke, Marie-Luise; Benner, Axel; Döhner, Konstanze; Krauter, Jürgen; Weber, Daniela; Moessner, Margit; Köhne, Claus-Henning; Horst, Heinz A; Schmidt-Wolf, Ingo G H; Rummel, Mathias; Götze, Katharina; Koller, Elisabeth; Petzer, Andreas L; Salwender, Hans; Fiedler, Walter; Kirchen, Heinz; Haase, Detlef; Kremers, Stephan; Theobald, Matthias; Matzdorff, Axel C; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F

    2016-07-01

    Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975). PMID:27036160

  12. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial.

    PubMed

    Burnett, Alan; Cavenagh, Jamie; Russell, Nigel; Hills, Robert; Kell, Jonathan; Jones, Gail; Nielsen, Ove Juul; Khwaja, Asim; Thomas, Ian; Clark, Richard

    2016-06-01

    Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535). PMID:26921360

  13. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial

    PubMed Central

    Burnett, Alan; Cavenagh, Jamie; Russell, Nigel; Hills, Robert; Kell, Jonathan; Jones, Gail; Nielsen, Ove Juul; Khwaja, Asim; Thomas, Ian; Clark, Richard

    2016-01-01

    Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m2 or 6 mg/m2. In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m2 or 6 mg/m2 with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m2 [82% vs. 76%; odds ratio 1.46 (1.04–2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m2 treatment (10% vs. 7%) resulting in similar overall response rate [89% vs. 86%; hazard ratio 1.34 (0.88–2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs. 54%; hazard ratio 1.17 (0.94–1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90–1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m2 recipients: 7% versus 3%; hazard ratio 2.07 (1.11–3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17–3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs. 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m2 of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m2 dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535.) PMID:26921360

  14. Estimation of the Dose and Dose Rate Effectiveness Factor

    NASA Technical Reports Server (NTRS)

    Chappell, L.; Cucinotta, F. A.

    2013-01-01

    Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

  15. A perspective of pesticide residue variability and acute dietary risk assessment.

    PubMed

    Walsh, M

    2000-07-01

    The question of the variability of pesticide residues and acute risk assessment has arisen in the context of the work of the European Commission's Scientific Committee for Plants (SCP). A brief outline is presented of European Community legislation on pesticide residues and the authorization of plant protection products. It is stated that although chronic risk assessment is systematically carried out in connection with the fixing of Community MRLs, the same has not applied for acute risk assessment. The reasons for this situation have been the absence of an agreed methodology, acute reference dose (RfD) and adequate dietary and residue data. It is stated that in the opinion of the Scientific Committee for Plants an acute risk assessment should be considered on a routine basis and that steps should be taken to ensure the availability of the necessary data. Possible implications for risk communication and the authorization of plant protection products in the EC are also discussed. PMID:10983589

  16. Ready Reference.

    ERIC Educational Resources Information Center

    Koltay, Emery

    2001-01-01

    Includes four articles that relate to ready reference, including a list of publishers' toll-free telephone numbers and Web sites; how to obtain an ISBN (International Standard Book Number) and an ISSN (International Standard Serial Number); and how to obtain an SAN (Standard Address Number), for organizations that are involved in the book…

  17. Poroelastic references

    SciTech Connect

    Morency, Christina

    2014-12-12

    This file contains a list of relevant references on the Biot theory (forward and inverse approaches), the double-porosity and dual-permeability theory, and seismic wave propagation in fracture porous media, in RIS format, to approach seismic monitoring in a complex fractured porous medium such as Brady?s Geothermal Field.

  18. Effect of different doses of GLP-2 (Teduglutide) on acute esophageal lesion due to acid-pepsin perfusion in male rats.

    PubMed

    Moloudi, Rohallah; Nabavizadeh, Fatemeh; Nahrevanian, Hossein; Hassanzadeh, Gholamreza

    2011-10-01

    Gastro-esophageal reflux currently is widespread disorders with dangerous complications. GLP-2 is a peptide that has trophic and anti-inflammatory effects on gastrointestinal mucosa. The aim of this study was to evaluate the protective role of GLP-2 in esophageal mucosa lesion due to perfusion acid-pepsin. Thirty-six male rats were used in this study and divided into six groups. They were control, acid-pepsin, GLP-2 20 μg, GLP-2 30 μg, GLP-2 40 μg and GLP-2 50 μg/kg groups. Esophageal blood flow, plasma NO metabolite, esophageal tissue NO metabolites and histological study of esophagus were performed as indicators of esophageal damage following acid-pepsin perfusion. Results showed that GLP-2 significantly increased plasma and tissue NO metabolites in comparison to acid-pepsin group. Also histological study showed significantly fewer lesions in the most effective dose GLP-2 30 μg in comparison to acid-pepsin group, our results show that GLP-2 could be useful for the treatment of esophageal in animal model. PMID:21930171

  19. An autopsy case of acute multiple sclerosis (Marburg's type) during pregnancy.

    PubMed

    Letournel, F; Cassereau, J; Scherer-Gagou, C; Bernard, I; Mercat, A; Gray, F; Tanguy, J Y; Richard-Crémieux, I; Jeanfaivre, Th; Barthelaix, A; Dubas, F

    2008-05-01

    We report a case of a 9-month pregnant woman who presented acute psychiatric and neurological symptoms with extensive involvement of the white matter on MRI and no oligoclonal bands on CSF examination. Despite high doses of intravenous steroids, plasmapheresis and immunosuppressive drugs, a fatal outcome (coma) was noted 8 months later. Neuropathological examination confirmed the diagnosis of Marburg's type of multiple sclerosis showing sharp-edged lesions of demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation. We discuss the definition and limits of the Marburg entity with reference to acute disseminated encephalomyelitis, impact of pregnancy, unusual MRI features, neuropathology and treatment. PMID:18342435

  20. Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

    ClinicalTrials.gov

    2015-11-16

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  1. Acute paraquat exposure determines dose-dependent oxidative injury of multiple organs and metabolic dysfunction in rats: impact on exercise tolerance.

    PubMed

    Novaes, Rômulo D; Gonçalves, Reggiani V; Cupertino, Marli C; Santos, Eliziária C; Bigonha, Solange M; Fernandes, Geraldo J M; Maldonado, Izabel R S C; Natali, Antônio J

    2016-04-01

    This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose-dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes. PMID:27277193

  2. Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-resistant B-precursor Acute Lymphoblastic Leukemia in Mice☆

    PubMed Central

    Uckun, Fatih M.; Myers, Dorothea E.; Ma, Hong; Rose, Rebecca; Qazi, Sanjive

    2015-01-01

    In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after the use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high “minimal residual disease” (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand × soluble TRAIL (“CD19L–sTRAIL”) fusion protein. CD19L–sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. Low dose total body irradiation (TBI) combined with CD19L–sTRAIL was highly effective against (1) xenografted CD19+ radiochemotherapy-resistant human BPL in NOD/SCID (NS) mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2) radiation-resistant advanced stage CD19+ murine BPL with lymphomatous features in CD22ΔE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L–sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT. PMID:26097891

  3. Impact of Cytochrome P450 2C19* 2 and * 3 on Clopidogrel Loading Dose in Saudi Patients with Acute Coronary Syndrome

    PubMed Central

    Khalaf, Hassan; AlMeman, Ahmad AbdulRahman; Rasool, Seemab

    2016-01-01

    Background: Emerging evidence shows that clopidogrel is greatly affected by non-functioning alleles measured by P2Y12 or platelet reactivity units (PRU). Cardiac events during short in-hospital stays have been inconclusively suggested as the main causes of discrepancies. Objectives: Evaluate the impact of CYP2C19 allele * 2 and allele * 3 on PRU and the potential clinical consequences of such interaction. To establish a rough estimation for the safe PRU limits for short in-hospital stay following PCI. Method: A short-term experimental study was conducted with 90 patients who underwent coronary angioplasty with drug eluting stents at the Prince Sultan Cardiac Center, Buraidah. All the patients received an initial loading dose of 300 mg clopidogrel, followed by 75 mg daily. Blood samples were used for DNA extraction for cytochrome P450 (CYP) and real-time polymerase chain reaction (PCR) was used for genotyping. PRU and inhibition rate were tested by Verifynow®. All in-hospital cardiac events were recorded until patients were discharged. Results: Genotypes 1/1, 2/2, and 1/2 were expressed by 60, 28, and two patients (67, 32, and 3%), respectively. The 
PRU of the female patients was significantly higher than that of the male patients was (255.6 ± 68.8 and 177.7 ± 66.6, 
p = 0.000, respectively). There was no significant difference in PRUs (193 ± 79 and 212 ±55.4, respectively, p = 0.349), nor inhibition (17.9 ± 18.80 and 13.88 ± 11.5, p = 0.135) in wild and resistant variants, respectively. We only reported one cardiac in-thrombosis events. Conclusion: Genotype differences may not explain variations in the PRU of patients during short-term in-hospital stays. Although it is difficult to confirm, 117–267 units may be a safe PRU range for such patients, with emphasis on attaining higher PRU values in females.

  4. Low Dose Cytosine Arabinoside and Azacitidine Combination in Elderly Patients with Acute Myeloid Leukemia and Refractory Anemia with Excess Blasts (MDS-RAEB2).

    PubMed

    Atalay, Figen; Ateşoğlu, Elif Birtaş

    2016-03-01

    Only one-third of elderly (>60 years) AML and MDS-RAEB2 patients may receive intensive chemotherapy treatment alternatives that are limited in this patient group due to the potential of severe toxicity. Previous studies have shown that azacitidine and low dose cytarabine treatments may be a beneficial treatment option for these patients. In this study, we aimed to good results with low toxicity in elderly patients. We retrospectively analyzed the AML and MDS-RAEB2 patients who received azacitidine monotherapy and azacitidine and LDL-ara-c combination therapy for a comparison of their response to therapy, survival rates, and toxicity rates and for determining the factors that could affect their overall survival. A total of 27 patients who were diagnosed with de novo AML and MDS-RAEB2 and who received at least four cycles of chemotherapy were included in the study, and the data were evaluated retrospectively. When monotherapy and combination therapy groups were compared, the pretreatment bone marrow blast count was observed to be greater in the combination therapy group. A statistically significant difference was not detected between the groups regarding the response to therapy ratios (p = 0.161) (42.9 and 57.1 %, respectively). No difference was detected between the groups regarding therapy-related toxicity. Infections were the most common complication. Progression-free survival was 30.3 % for the azacitidine monotherapy group and 66.7 % for the combination (azacitidine + LD-ara-c) group. The factors influencing the overall survival rate were determined based on the response to the first-line therapies, more than a grade 2 infection, fever, and relapse in a multi-variance analysis. The combination therapy may be a well-tolerated treatment option for the elderly, vulnerable AML patients whose blast count is high in response to therapy rates, overall survival rates, and toxicities are not different, although the pre-treatment bone marrow blast count was

  5. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    SciTech Connect

    Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, B. M.; Matthews, D. C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, P. J.; Storb, R.; Press, Oliver W.; Appelbaum, Frederick R.

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of I-131-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of I-131-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

  6. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222

    PubMed Central

    Moore, Joseph O.; George, Stephen L.; Dodge, Richard K.; Amrein, Philip C.; Powell, Bayard L.; Kolitz, Jonathan E.; Baer, Maria R.; Davey, Frederick R.; Bloomfield, Clara D.; Larson, Richard A.; Schiffer, Charles A.

    2005-01-01

    The Cancer and Leukemia Group B (CALGB) study 9222 tested the hypothesis that treatment intensification of acute myeloid leukemia (AML) in first remission with multiple chemotherapy agents is superior to high-dose cytarabine (HiDAC) alone. We enrolled 474 patients younger than 60 years old with untreated de novo AML. Daunorubicin and cytarabine resulted in complete remission (CR) in 342 patients (72%), and 309 of these patients were randomized to receive one of 2 different intensification regimens. The first regimen consisted of 3 courses of HiDAC. The second regimen consisted of one course of HiDAC, a second course with etoposide and cyclophosphamide, and a third course with diaziquone and mitoxantrone. After a median follow-up time of 8.3 years, the median survival for all randomized patients was 2.8 years (95% CI, 1.9-6.8 years). There was no difference in disease-free survival (DFS) between the 2 regimens (P = .66). The median DFS was 1.1 years (95% CI, 0.9-1.7 years) for patients receiving HiDAC and 1.0 year (95% CI, 0.9-1.3 years) for those receiving multiagent chemotherapy. Cytogenetics was the only pretreatment characteristic prognostic for DFS, but there was no evidence of a differential treatment effect within cytogenetic risk groups. Toxicity was greater with multiagent chemotherapy. These 2 postremission regimens produced similar outcomes. PMID:15572587

  7. A low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus a daunorubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia: A propensity score analysis.

    PubMed

    Minakata, Daisuke; Fujiwara, Shin-Ichiro; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Nakano, Hirofumi; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamasaki, Ryoko; Yamamoto, Chihiro; Ashizawa, Masahiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

    2016-03-01

    This retrospective analysis compared the efficacy of intensive induction therapy consisting of daunorubicin and cytarabine (DNR-AraC) to that of less-intensive therapy including low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming (CAG). Patients aged 60 years or older who were newly diagnosed as acute myeloid leukemia (AML) were analyzed. Sixty-four and 48 patients were treated with DNR-AraC and CAG, respectively. The complete remission rates, 3-year overall survival and event-free survival in the DNR-AraC group were significantly superior to those in the CAG group (65.6% vs. 29.2%, p<0.001, 38.4% vs. 12.3%, p=0.0033, and 20.3% vs. 7.8%, p=0.0030, respectively), although these differences were not statistically significant in multivariate analyses. Next, we calculated a propensity score for selecting the CAG regimen from six factors. The DNR-AraC regimen was associated with better survival than the CAG regimen in a low propensity score group, but there was no difference in survival between regimens in a high propensity score group. Intensive therapy should be performed for patients with sufficient general and comorbid conditions, but less-intensive therapy may be sufficient for patients with higher age, myelodysplasia-related changes, and lower white blood cell counts, which were relevant factors in the propensity score calculation. PMID:26790727

  8. Circulating Myeloid‐Related Protein–8/14 is Related to Thromboxane‐Dependent Platelet Activation in Patients With Acute Coronary Syndrome, With and Without Ongoing Low‐Dose Aspirin Treatment

    PubMed Central

    Santilli, Francesca; Paloscia, Leonardo; Liani, Rossella; Di Nicola, Marta; Di Marco, Massimo; Lattanzio, Stefano; La Barba, Sara; Pascale, Silvia; Mascellanti, Marco; Davì, Giovanni

    2014-01-01

    Background Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low‐dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11‐dehydro‐TXB2) is predictive of vascular events in high‐risk patients. Myeloid‐related protein (MRP)‐8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP‐14 has emerged as a powerful predictor of ACS. Methods and Results We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP‐8/14 release in the circulation is related to TX‐dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low‐dose aspirin–treated ACS patients. In ACS patients, plasma MRP‐8/14 and urinary 11‐dehydro‐TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin‐treated ACS patients, MRP‐8/14 and 11‐dehydro‐TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11‐dehydro‐TXB2 significantly predicted higher MRP‐8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R2=0.463 and adj R2=0.497) after multivariable adjustment. Conversely, plasma MRP‐8/14 (P<0.001) and higher urinary 8‐iso‐prostaglandin F2α (P=0.050) levels were significant predictors of residual, on‐aspirin, TX biosynthesis in ACS (adjusted R2=0.384). Conclusions Circulating MRP‐8/14 is associated with TX‐dependent platelet activation in ACS, even during low‐dose aspirin treatment, suggesting a contribution of residual TX to MRP‐8/14 shedding, which may further amplify platelet activation. Circulating MRP‐8/14 may be a target to test different antiplatelet

  9. Acute genital ulcers

    PubMed Central

    Delgado-García, Silvia; Palacios-Marqués, Ana; Martínez-Escoriza, Juan Carlos; Martín-Bayón, Tina-Aurora

    2014-01-01

    Acute genital ulcers, also known as acute vulvar ulcers, ulcus vulvae acutum or Lipschütz ulcers, refer to an ulceration of the vulva or lower vagina of non-venereal origin that usually presents in young women, predominantly virgins. Although its incidence is unknown, it seems a rare entity, with few cases reported in the literature. Their aetiology and pathogenesis are still unknown. The disease is characterised by an acute onset of flu-like symptoms with single or multiple painful ulcers on the vulva. Diagnosis is mainly clinical, after exclusion of other causes of vulvar ulcers. The treatment is mainly symptomatic, with spontaneous resolution in 2 weeks and without recurrences in most cases. We present a case report of a 13-year-old girl with two episodes of acute ulcers that fit the clinical criteria for Lipschütz ulcers. PMID:24473429

  10. The influence of dose, dose-rate and particle fragmentation on cataract induction by energetic iron ions

    NASA Technical Reports Server (NTRS)

    Medvedovsky, C.; Worgul, B. V.; Huang, Y.; Brenner, D. J.; Tao, F.; Miller, J.; Zeitlin, C.; Ainsworth, E. J.

    1994-01-01

    Because activities in space necessarily involve chronic exposure to a heterogeneous charged particle radiation field it is important to assess the influence of dose-rate and the possible modulating role of heavy particle fragmentation on biological systems. Using the well-studied cataract model, mice were exposed to plateau 600 MeV/amu Fe-56 ions either as acute or fractionated exposures at total doses of 5-504 cGy. Additional groups of mice received 20, 360 and 504 cGy behind 50 mm of polyethylene, which simulates body shielding. The reference radiation consisted of Co-60 gamma radiation. The animals were examined by slit lamp biomicroscopy over their three year life spans. In accordance with our previous observations with heavy particles, the cataractogenic potential of the 600 MeV/amu Fe-56 ions was greater than for low-Linear Energy Transfer (LET) radiation and increased with decreasing dose relative to gamma rays. Fractionation of a given dose of Fe-56 ions did not reduce the cataractogenicity of the radiation compared to the acute regimen. Fragmentation of the beam in the polyethylene did not alter the cataractotoxicity of the ions, either when administered singly or in fractions.

  11. The influence of dose, dose-rate and particle fragmentation on cataract induction by energetic iron ions

    NASA Astrophysics Data System (ADS)

    Medvedovsky, C.; Worgul, B. V.; Huang, Y.; Brenner, D. J.; Tao, F.; Miller, J.; Zeitlin, C.; Ainsworth, E. J.

    1994-10-01

    Because activities in space necessarily involve chronic exposure to a heterogeneous charged particle radiation field it is important to assess the influence of dose-rate and the possible modulating role of heavy particle fragmentation on biological systems. Using the well-studied cataract model, mice were exposed to plateau 600 MeV/amu 56Fe ions either as acute or fractionated exposures at total doses of 5 - 504 cGy. Additional groups of mice received 20, 360 and 504 cGy behind 50 mm of polyethylene, which simulates body shielding. The reference radiation consisted of 60Co γ radiation. The animals were examined by slit lamp biomicroscopy over their three year life spans. In accordance with our previous observations with heavy particles, the cataractogenic potential of the 600 MeV/amu 56Fe ions was greater than for low-LET radiation and increased with decreasing dose relative to γ-rays. Fractionation of a given dose of 56Fe ions did not reduce the cataractogenicity of the radiation compared to the acute regimen. Fragmentation of the beam in the polyethylene did not alter the cataractotoxicity of the ions, either when administered singly or in fractions.

  12. Acute liver failure and self-medication

    PubMed Central

    de OLIVEIRA, André Vitorio Câmara; ROCHA, Frederico Theobaldo Ramos; ABREU, Sílvio Romero de Oliveira

    2014-01-01

    Introduction Not responsible self-medication refers to drug use in high doses without rational indication and often associated with alcohol abuse. It can lead to liver damage and drug interactions, and may cause liver failure. Aim To warn about how the practice of self-medication can be responsible for acute liver failure. Method Were used the Medline via PubMed, Cochrane Library, SciELO and Lilacs, and additional information on institutional sites of interest crossing the headings acute liver failure [tiab] AND acetaminophen [tiab]; self-medication [tiab] AND acetaminophen [tiab]; acute liver failure [tiab] AND dietary supplements [tiab]; self-medication [tiab] AND liver failure [tiab] and self-medication [tiab] AND green tea [tiab]. In Lilacs and SciELO used the descriptor self medication in Portuguese and Spanish. From total surveyed were selected 27 articles and five sites specifically related to the purpose of this review. Conclusions Legislation and supervision disabled and information inaccessible to people, favors the emergence of cases of liver failure drug in many countries. In the list of released drugs that deserve more attention and care, are some herbal medicines used for the purpose of weight loss, and acetaminophen. It is recommended that institutes of health intensify supervision and better orient their populations on drug seemingly harmless, limiting the sale of products or requiring a prescription for release them. PMID:25626943

  13. Lamotrigine for acute and chronic pain

    PubMed Central

    Wiffen, Philip J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background This is an update of the original Cochrane review published in Issue 2, 2007. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review adds five new additional studies looking at evidence for Lamotrigine as an effective treatment for acute and chronic pain. Objectives To assess analgesic efficacy and adverse effects of the antiepileptic drug lamotrigine in acute and chronic pain. Search methods Randomised controlled trials (RCTs) of lamotrigine in acute, and chronic pain (including cancer pain) were identified from MEDLINE, EMBASE and CENTRAL up to January 2011. Additional studies were sought from the reference list of the retrieved papers. Selection criteria RCTs investigating the use of lamotrigine (any dose, by any route, and for any study duration) for the treatment of acute or chronic pain. Assessment of pain intensity or pain relief, or both, using validated scales. Participants were adults aged 18 and over. Only full journal publication articles were included. Data collection and analysis Dichotomous data (ideally for the outcome of at least 50% pain relief) were used to calculate relative risk with 95% confidence intervals. Meta-analysis was undertaken using a fixed-effect model. Numbers needed to treat to benefit (NNTs) were calculated as the reciprocal of the absolute risk reduction. For unwanted effects, the NNT becomes the number needed to harm (NNH) and was calculated. Main results Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post stroke pain (1), chemotherapy induced neuropathic pain (1), diabetic neuropathy (4), HIV related neuropathy (2), mixed neuropathic pain (2), spinal cord injury related pain (1), and trigeminal neuralgia (1); none investigated lamotrigine in acute pain. The update had five additional studies (1111 additional participants). Participants were aged between 26 and 77 years. Study duration

  14. A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

    PubMed

    Weinstein, A; Brickner, O; Lerman, H; Greemland, M; Bloch, M; Lester, H; Chisin, R; Sarne, Y; Mechoulam, R; Bar-Hamburger, R; Freedman, N; Even-Sapir, E

    2008-06-01

    Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana. PMID:18635724

  15. Acute Bronchitis

    MedlinePlus

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis ...

  16. Intermediate dose 5-fluorouracil-induced encephalopathy.

    PubMed

    Kim, Yeon-A; Chung, Hyun Cheol; Choi, Hye Jin; Rha, Sun Young; Seong, Jin Sil; Jeung, Hei-Cheul

    2006-01-01

    As an acute neurotoxicity, high dose 5-fluorouracil (5-FU)-induced encephalopathy is well-known, but encephalopathy associated with lower dose is rarely reported. Here, we report a case of a male with anal cancer who was treated with 5-FU 1000 mg/m(2), continuous infusion for 5 days q4 weeks. At the second and the fourth cycles of chemotherapy, sudden confusion, cognitive dysfunction and disorientation occurred during 5-FU infusion. They were accompanied by hyperammonemia in the absence of focal neurological deficits or structural abnormalities. These symptoms completely disappeared and the serum ammonia level returned to normal after discontinuation of 5-FU and conservative care. In order to investigate a possible deficit of dihydropyrimidine dehydrogenase (DPD), we checked its mRNA level before and after treatment using real-time PCR. The patient's pre-treatment level was 80% compared with reference group, and it was elevated up to 187% of initial after 5-FU treatment, implying that that his encephalopathy may be 5-FU catabolite type rather than DPD deficiency. In conclusion, we report that encephalopathy can develop even with the dose of 5-FU lower than ever reported, and it should be considered as a differential diagnosis for proper management. PMID:16436463

  17. Acute bronchial asthma.

    PubMed

    Grover, Sudhanshu; Jindal, Atul; Bansal, Arun; Singhi, Sunit C

    2011-11-01

    Acute asthma is the third commonest cause of pediatric emergency visits at PGIMER. Typically, it presents with acute onset respiratory distress and wheeze in a patient with past or family history of similar episodes. The severity of the acute episode of asthma is judged clinically and categorized as mild, moderate and severe. The initial therapy consists of oxygen, inhaled beta-2 agonists (salbutamol or terbutaline), inhaled budesonide (three doses over 1 h, at 20 min interval) in all and ipratropium bromide and systemic steroids (hydrocortisone or methylprednisolone) in acute severe asthma. Other causes of acute onset wheeze and breathing difficulty such as pneumonia, foreign body, cardiac failure etc. should be ruled out with help of chest radiography and appropriate laboratory investigations in first time wheezers and those not responding to 1 h of inhaled therapy. In case of inadequate response or worsening, intravenous infusion of magnesium sulphate, terbutaline or aminophylline may be used. Magnesium sulphate is the safest and most effective alternative among these. Severe cases may need ICU care and rarely, ventilatory support. PMID:21769523

  18. Acute nephritic syndrome

    MedlinePlus

    Glomerulonephritis - acute; Acute glomerulonephritis; Nephritis syndrome - acute ... Acute nephritic syndrome is often caused by an immune response triggered by an infection or other disease. Common causes ...

  19. Nuclear-weapon-effect research at PSR (Pacific-Sierra Research Corporation) - 1983. Volume 10. Symptomatology of acute radiation effects in humans after exposure to doses of 75 to 4500 rads (cGy) free-in-air. Final technical report, 27 October 1982-30 November 1983

    SciTech Connect

    Baum, S.J.; Young, R.W.; Anno, G.H.; Withers, H.R.

    1984-08-31

    This report distills from available data descriptions of typical human symptoms in reaction to prompt ionizing radiation in the dose range 75 to 4500 rads (cGy) free-in-air. The descriptions correlate symptoms with dose and time over the acute post-exposure period of six weeks. Their purpose is to provide an empirical base for estimating combat troop performance after a nuclear weapon attack. The dose range of interest is subdivided into eight subranges associated with important pathophysiological events. For each subrange, the signs and symptoms manifested by an exposed population are estimated--symptom onset, severity, duration, and incidence. The early or prodromal phase of radiation sickness begins about 2 to 4 hrs after doses of 300 to 530 rads (cGy). Onset time diminishes with dose, occurring within minutes of exposure to 4500 rads (cGy). Characteristic prodromal symptoms are nausea, vomiting, anorexia, and diarrhea. The prodromal phase lasts from several days to a matter of hours, depending on dose. Symptoms of the hemopoietic syndrome are bleeding, fever, infection, and ulceration. Symptoms of the gastrointestinal syndrome are fluid loss, electrolyte imbalance, severe diarrhea, and septicemia.

  20. The Dose Makes the Poison.

    ERIC Educational Resources Information Center

    Ottoboni, Alice

    1992-01-01

    A Toxicologist discusses common misconception that all chemicals are poisonous to people and the environment and how these misconceptions are perpetuated. Describes what makes a chemical toxic. Defines related concepts including dose, acute and chronic toxicity, and natural verses synthetic chemicals. (MCO)

  1. Patient dose measurements in diagnostic radiology procedures in Korea.

    PubMed

    Kim, You-hyun; Choi, Jong-hak; Kim, Chang-kyun; Kim, Jung-min; Kim, Sung-soo; Oh, Yu-whan; Lee, Chang-yeap; Kang, Dae-hyun; Lee, Young-bae; Cho, Pyong-kon; Kim, Hyung-chul; Kim, Chel-min

    2007-01-01

    This study is the first nationwide investigation aimed at estimating the patient dose for radiographic examinations in Korea including gastrointestinal studies, computed tomography and mammography. The survey data from 161 hospitals and the dose data from 32 hospitals were analysed. The third quartile entrance surface dose, dose area product (DAP), weighted CT dose index (CTDIw) and mean glandular dose (MGD) were reported. All the estimated doses were less than the stated International Atomic Energy Agency (IAEA) reference levels for radiographic examinations. However, DAPs for the fluoroscopic examinations had higher dose values than the IAEA reference levels. In addition, the CTDIw and MGD were lower than the IAEA reference levels. PMID:17223642

  2. Acute sacroiliitis.

    PubMed

    Slobodin, Gleb; Rimar, Doron; Boulman, Nina; Kaly, Lisa; Rozenbaum, Michael; Rosner, Itzhak; Odeh, Majed

    2016-04-01

    The purpose of this study was to review the data on the etiology, risk factors, clinical presentations, and diagnosis of acute sacroiliitis. A Pubmed search utilizing the indexing term "acute sacroiliitis" was conducted and the data pertinent to the aim of the review was extracted and organized in accordance with the preplanned structure of the manuscript. The diagnosis of acute sacroiliitis is often challenging because of both the relative rarity of this presentation and diverse character of acute sacroiliac pain, frequently mimicking other, more prevalent disorders. Technetium bone scintigraphy can localize the disease process to the sacroiliac joint, while computed tomography or magnetic resonance imaging can be used for the detailed characterization and the extent of the disease as well as the diagnosis of complications. Pyogenic sacroiliitis is by far the most common cause of acute sacroiliitis. Brucellosis, acute sacroiliitis in the course of reactive arthritis, and crystalline-induced sacroiliitis frequently imitate pyogenic sacroiliitis. Acute sacroiliitis can rarely be also related to hematological malignancies or treatment with isotretinoin. Awareness to the possibility of acute sacroiliitis and a thorough physical examination are the necessary prerequisites to its timely diagnosis, while the appropriate laboratory and imaging studies should confirm the precise diagnosis and direct the appropriate treatment strategy. PMID:26847855

  3. Library Reference Services.

    ERIC Educational Resources Information Center

    Miller, Constance; And Others

    1985-01-01

    Seven articles on library reference services highlight reference obsolescence in academic libraries, major studies of unobtrusive reference tests, methods for evaluating reference desk performance, reference interview evaluation, problems of reference desk control, online searching by end users, and reference collection development in…

  4. Determination of absorbed dose to water in reference conditions for radiotherapy kilovoltage x-rays between 10 and 300 kV: a comparison of the data in the IAEA, IPEMB, DIN and NCS dosimetry protocols

    NASA Astrophysics Data System (ADS)

    Peixoto, J. G. P.; Andreo, P.

    2000-03-01

    A comparison of four of the most commonly used dosimetry protocols for the determination of absorbed dose to water in therapeutic kilovoltage x-rays using an ionization chamber (IAEA TRS-277, IPEMB, DIN and NCS) has been carried out. Owing to the different energy ranges and HVLs recommended by each protocol, backscatter factors, water-to-air mass energy absorption coefficient ratios and perturbation correction factors have been recast to a common quality range that all protocols satisfy individually to make a comparison possible. The results of the comparison show that in the sometimes reduced quality range originally included by the different protocols, determinations of absorbed dose to water at all beam qualities agree to within ±1.0% with that obtained using the second edition of the IAEA TRS-277 code of practice (1997). The extrapolation of data to a common beam quality range practically preserves the agreement for all the protocols except for that issued by the NCS at the extremes of the range, where differences of up to 1.8% and 1.4% have been found for low and medium energies respectively. In all cases the DIN protocol yields very good agreement with TRS-277.

  5. Health physics research reactor reference dosimetry

    SciTech Connect

    Sims, C.S.; Ragan, G.E.

    1987-06-01

    Reference neutron dosimetry is developed for the Health Physics Research Reactor (HPRR) in the new operational configuration directly above its storage pit. This operational change was physically made early in CY 1985. The new reference dosimetry considered in this document is referred to as the 1986 HPRR reference dosimetry and it replaces any and all HPRR reference documents or papers issued prior to 1986. Reference dosimetry is developed for the unshielded HPRR as well as for the reactor with each of five different shield types and configurations. The reference dosimetry is presented in terms of three different dose and six different dose equivalent reporting conventions. These reporting conventions cover most of those in current use by dosimetrists worldwide. In addition to the reference neutron dosimetry, this document contains other useful dosimetry-related data for the HPRR in its new configuration. These data include dose-distance measurements and calculations, gamma dose measurements, neutron-to-gamma ratios, ''9-to-3 inch'' ratios, threshold detector unit measurements, 56-group neutron energy spectra, sulfur fluence measurements, and details concerning HPRR shields. 26 refs., 11 figs., 31 tabs.

  6. Reference Frames and Relativity.

    ERIC Educational Resources Information Center

    Swartz, Clifford

    1989-01-01

    Stresses the importance of a reference frame in mechanics. Shows the Galilean transformation in terms of relativity theory. Discusses accelerated reference frames and noninertial reference frames. Provides examples of reference frames with diagrams. (YP)

  7. Acute malocclusion.

    PubMed

    Dupont, John S

    2006-01-01

    Acute malocclusion can result from disturbances in the maxillary/mandibular tooth relationship. These alterations in the occlusal position can result from high fillings, sinus problems, abscesses, periodontal disease, and moving or erupting teeth. Conditions seen less frequently include acute malocclusions secondary to an event (such as trauma) that make a stable dental relationship an unstable one. Patients can demonstrate any of a number of clinical conditions that interfere with their comfort and ability to function. This art