Evaluation of Cholinergic Deficiency in Preclinical Alzheimer’s Disease Using Pupillometry

Directory of Open Access Journals (Sweden)

Shaun Frost

2017-01-01

Full Text Available Cortical cholinergic deficiency is prominent in Alzheimer’s disease (AD, and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR in AD (N=14 and cognitively normal healthy control (HC, N=115 participants, with the HC group stratified according to high (N=38 and low (N=77 neocortical amyloid burden (NAB. Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p<0.05, maximum velocity p<0.0005, average velocity p<0.005, and constriction amplitude p<0.00005. The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.

Cardiac safety implications of hNav1.5 blockade and a framework for preclinical evaluation

Directory of Open Access Journals (Sweden)

Gul eErdemli

2012-01-01

Full Text Available The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a preclinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

Preclinical Biodistribution and Safety Evaluation of a pbi-shRNA STMN1 Lipoplex after Subcutaneous Delivery.

Science.gov (United States)

Wang, Zhaohui; Jay, Christopher M; Evans, Courtney; Kumar, Padmasini; Phalon, Connor; Rao, Donald D; Senzer, Neil; Nemunaitis, John

2017-02-01

Stathmin-1 (STMN1) is a microtubule-destabilizing protein which is overexpressed in cancer. Its overexpression is associated with poor prognosis and also serves as a predictive marker to taxane therapy. We have developed a proprietary bi-functional shRNA (bi-shRNA) platform to execute RNA interference (RNAi)-mediated gene silencing and a liposome-carrier complex to systemically deliver the pbi-shRNA plasmids. In vitro and in vivo testing demonstrated efficacy and specificity of pbi-shRNA plasmid in targeting STMN1 (Phadke, A. P., Jay, C. M., Wang, Z., Chen, S., Liu, S., Haddock, C., Kumar, P., Pappen, B. O., Rao, D. D., Templeton, N. S., et al. (2011). In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein. DNA Cell Biol. 30, 715-726.). Biodistribution and toxicology studies in bio-relevant Sprague Dawley rats with pbi-shRNA STMN1 lipoplex revealed that the plasmid DNA was delivered to a broad distribution of organs after a single subcutaneous injection. Specifically, plasmid was detected within the first week using QPCR (threshold 50 copies plasmid/1 µg genomic DNA) at the injection site, lung, spleen, blood, skin, ovary (limited), lymph nodes, and liver. It was not detected in the heart, testis or bone marrow. No plasmid was detected from any organ 30 days after injection. Treatment was well tolerated. Minimal inflammation/erythema was observed at the injection site. Circulating cytokine response was also examined by ELISA. The IL-6 levels were induced within 6 h then declined to the vehicle control level 72 h after the injection. TNFα induction was transiently observed 4 days after the DNA lipoplex treatment. In summary, the pbi-shRNA STMN1 lipoplex was well tolerated and displayed broad distribution after a single subcutaneous injection. The pre-clinical data has been filed to FDA and the pbi-shRNA STMN1 lipoplex is being investigated in a phase I clinical study. © The Author 2016. Published

Safety test No. S-6, launch pad abort sequential test Phase II: solid propellant fire

International Nuclear Information System (INIS)

Snow, E.C.

1975-08-01

In preparation for the Lincoln Laboratory's LES 8/9 space mission, a series of tests was performed to evaluate the nuclear safety capability of the Multi-Hundred Watt (MHW) Radioisotope Thermoelectric Generator (RTG) to be used to supply power for the satellite. One such safety test is Test No. S-6, Launch Pad Abort Sequential Test. The objective of this test was to subject the RTG and its components to the sequential environments characteristic of a catastrophic launch pad accident to evaluate their capability to contain the 238 PuO 2 fuel. This sequence of environments was to have consisted of the blast overpressure and fragments, followed by the fireball, low velocity impact on the launch pad, and solid propellant fire. The blast overpressure and fragments were subsequently eliminated from this sequence. The procedures and results of Phase II of Test S-6, Solid Propellant Fire are presented. In this phase of the test, a simulant Fuel Sphere Assembly (FSA) and a mockup of a damaged Heat Source Assembly (HSA) were subjected to single proximity solid propellant fires of approximately 10-min duration. Steel was introduced into both tests to simulate the effects of launch pad debris and the solid rocket motor (SRM) casing that might be present in the fire zone. (TFD)

Preclinical evaluation of strontium-containing bioactive bone cement

International Nuclear Information System (INIS)

Li, Zhaoyang; Yuan, Ning; Lam, Raymond Wing Moon; Cui, Zhenduo; Yang, Xianjin; Lu, William Weijia

2013-01-01

Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC

Preclinical evaluation of strontium-containing bioactive bone cement

Energy Technology Data Exchange (ETDEWEB)

Li, Zhaoyang, E-mail: lizy@hku.hk [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Yuan, Ning [Department of Laboratory Medicine, Tianjin Chest Hospital, Tianjin 300051 (China); Lam, Raymond Wing Moon [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Cui, Zhenduo; Yang, Xianjin [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Lu, William Weijia, E-mail: wwlu@hku.hk [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China)

2013-12-01

Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC.

EC6 safety design improvements

Energy Technology Data Exchange (ETDEWEB)

Yu, S.; Lee, A.G.; Soulard, M. [Candu Energy Inc., Mississauga, ON (Canada)

2014-07-01

The Enhanced CANDU 6 (EC6) builds on the proven high performance design such as the Qinshan CANDU 6 reactor, and has made improvements to safety, operational performance, and has incorporated extensive operational feedback. Completion of all three phases of the pre-licensing design review by the Canadian Regulator - the Canadian Nuclear Safety Commission has provided a higher level of assurance that the EC6 reference design has taken modern regulatory requirements and expectations into account and further confirmed that there are no fundamental barriers to licensing the EC6 design in Canada. The EC6 design is based on the defence-in-depth principles in INSAG-10 and provides further safety features that address the lessons learned from Fukushima. With these safety features, the EC6 design has strengthened accident prevention as the first priority in the defence-in-depth strategy, as outlined in INSAG-10. As well, the EC6 design has incorporated further mitigation measures to provide additional protection of the public and the environment if the preventive measures fail. The EC6 design has an appropriate combination of inherent, passive safety characteristics, engineered features and administrative safety measures to effectively prevent and mitigate severe accident progressions. A strong contributor to the robustness and redundancy of CANDU design is the two-group separation philosophy. This ensures a high degree of independence between safety systems as well as physical separation and functional independence in how fundamental safety functions are provided. This paper will describe the following safety features based on the application of defence-in-depth and design approach to prevent beyond design basis events progressing to severe accidents and to mitigate the consequences if it occurs: Improved steam generator heat sink via a more reliable emergency heat removal system; Increased time before manual field actions are required via enhanced capacity of

40 CFR 87.6 - Aircraft safety.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Aircraft safety. 87.6 Section 87.6... POLLUTION FROM AIRCRAFT AND AIRCRAFT ENGINES General Provisions § 87.6 Aircraft safety. The provisions of... met within the specified time without creating a safety hazard. ...

Neuraxial Analgesia In Neonates And Infants: Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

Science.gov (United States)

Walker, Suellen M.; Yaksh, Tony L.

2015-01-01

Neuraxial agents provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improve analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by addition of clonidine, ketamine, neostigmine or tramadol to single shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side-effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, the second half of this review presents preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial agents with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation prior to adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

21 CFR 315.6 - Evaluation of safety.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Evaluation of safety. 315.6 Section 315.6 Food and... USE DIAGNOSTIC RADIOPHARMACEUTICALS § 315.6 Evaluation of safety. (a) Factors considered in the safety...)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA may require, among other...

A study of 6S workplace improvement in Ergonomic Laboratory

Science.gov (United States)

Sari, AD; Suryoputro, MR; Rahmillah, FI

2017-12-01

This article discusses 6S implementation in Ergonomic Laboratory, Department of Industrial Engineering, Islamic University of Indonesia. This research is improvement project of 5S implementation in Ergonomic laboratory. Referring to the 5S implementation of the previous year, there have been improvements from environmental conditions or a more organized workplace however there is still a lack of safety aspects. There are several safeties problems such as equipment arrangement, potential hazards of room dividers that cause injury several times, placement of fire extinguisher, no evacuation path and assembly point in case of fire, as well as expired hydrant condition and lack of awareness of stakeholders related to safety. Therefore, this study aims to apply the 6S kaizen method to the Ergonomic laboratory to facilitate the work process, reduce waste, improve work safety and improve staff performance. Based on the score 6S assessment increased audit results by 32 points, before implementation is 75 point while after implementation is 107 point. This has implications for better use for mitigate people in laboratory area, save time when looking for tools and materials, safe workplace, as well as improving the culture and spirit of ‘6S’ on staff due to better and safetier working environment.

The role of radiolabelled compounds in preclinical drug development

International Nuclear Information System (INIS)

Hawkins, D.R.

1988-01-01

The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

14 CFR 34.6 - Aircraft safety.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Aircraft safety. 34.6 Section 34.6... safety. (a) The provisions of this part will be revised if at any time the Administrator determines that an emission standard cannot be met within the specified time without creating a safety hazard. (b...

Preclinical, clinical, and over-the-counter postmarketing experience with a new vaginal cup: menstrual collection.

Science.gov (United States)

North, Barbara B; Oldham, Michael J

2011-02-01

Menstrual cups have been available for decades, but their use is limited by bulky design and the need for multiple sizes. The Softcup® (Instead, Inc., San Diego, CA) is a simple single-size disposable over-the-counter (OTC) menstrual cup that compresses to tampon shape to facilitate insertion and can be worn during coitus. This report describes preclinical evaluation, clinical testing, and postmarketing monitoring of the Softcup. Preclinical testing complied with U.S. Food and Drug Administration (FDA) guidelines and used standard United States Pharmacopoeia methodologies for assessment of potential toxicity. Clinical testing enrolled 406 women in seven U.S. centers. A detailed written questionnaire assessed safety, acceptability, and effectiveness for menstrual collection. Study safety parameters included pelvic examinations, Pap smears, colposcopy, urinalysis, vaginal pH, wet mounts, gram stain, and vaginal microflora cultures. Postmarketing surveillance of over 100 million Softcups has been conducted by the manufacturer and by the FDA Medwatch system. No toxicity or mutagenicity was observed in preclinical evaluations. In clinical testing, after three cycles of cup use, 37% of subjects rated the cup as better than, 29% as worse than, and 34% as equal to pads or tampons. The cup was preferred for comfort, dryness, and less odor. Cups received lower ratings for disposal and convenience. Eighty-one percent of enrolled women were able to insert and remove their first cup using only written instructions. Use difficulties resulting in study discontinuations included cramping (1%), leakage (1%), and improper fit (3%). No safety parameters were adversely affected. No significant health risks were reported during postmarketing surveillance. These results demonstrate that a single-size vaginal device has no significant health risks and is acceptable to many women without the need for fitting or other medical services.

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.

Science.gov (United States)

Walker, Suellen M; Yaksh, Tony L

2012-09-01

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high-quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, in the second half of this review, we present preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice.

Laquinimod Safety Profile

DEFF Research Database (Denmark)

Sørensen, Per Soelberg; Comi, Giancarlo; Vollmer, Timothy L

2017-01-01

the safety profile of laquinimod versus placebo. Adverse events (AEs), laboratory value changes, and potential risks identified in preclinical studies were evaluated in participants in ALLEGRO and BRAVO treated with at least one dose of laquinimod or matching placebo (1:1 random assignment). RESULTS...... laquinimod studies demonstrate a safety profile comprising benign or manageable AEs and asymptomatic laboratory findings with a clear temporal pattern. Potential risks noted in preclinical studies were not observed....

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

Energy Technology Data Exchange (ETDEWEB)

Marks, Louise, E-mail: louise.marks@astrazeneca.com [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Kirk, Sarah [Innovative Medicines, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Valentin, Jean-Pierre [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom)

2012-09-01

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. �

S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

Science.gov (United States)

Chawla, Sonam; Rahar, Babita; Saxena, Shweta

2016-05-01

Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

46 CFR 61.40-6 - Periodic safety tests.

Science.gov (United States)

2010-10-01

... 46 Shipping 2 2010-10-01 2010-10-01 false Periodic safety tests. 61.40-6 Section 61.40-6 Shipping... INSPECTIONS Design Verification and Periodic Testing of Vital System Automation § 61.40-6 Periodic safety tests. (a) Periodic Safety tests must demonstrate the proper operation of the primary and alternate...

Study partners should be required in preclinical Alzheimer's disease trials.

Science.gov (United States)

Grill, Joshua D; Karlawish, Jason

2017-12-06

In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe.

Science.gov (United States)

Field, J; Stone, S; Orsini, C; Hussain, A; Vital, S; Crothers, A; Walmsley, D

2018-05-01

Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan-European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills. A request to complete an online questionnaire, in English, was sent electronically to skills leads at all Association of Dental Education in Europe member schools. The questionnaire collected information in relation to institution and country, regulatory requirements to demonstrate safety, details of specific pre-clinical skills courses, learning materials and teaching staff. Forty-eight institutions, from 25 European countries responded. Seven countries (n=7, 28%) reported no requirement to demonstrate student operative safety prior to patient treatment. Several core and operative clinical skills are common to the majority of institutions. The most commonly taught core skills related directly to the clinical environment such as cross-infection control and hand washing. The least common were skills that indirectly related to patient care, such as communication skills and working as a team. There are clear differences within European pre-clinical dental education, and greater efforts are needed to demonstrate that all European students are fit to practice before they start treating patients. Learning outcomes, teaching activities and assessment activities of pre-clinical skills should be shared collaboratively to further standardise curricula. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Efficacy and safety of novel multi-lumen catheter for chronic total occlusions: from preclinical study to first-in-man experience.

Science.gov (United States)

Mitsutake, Yoshiaki; Ebner, Adrian; Yeung, Alan C; Taber, Mark D; Davidson, Charles J; Ikeno, Fumiaki

2015-02-15

To report our initial animal and human experience with a new multi-lumen catheter called MultiCross™ (Roxwood Medical, Inc.) in a porcine coronary model and patients with a chronic total occlusion (CTO). Preclinical safety study was done in the coronary vasculature of a porcine model. In a clinical setting, patients with a CTO of a coronary artery (n = 5) were enrolled. After an initial unsuccessful attempt using a conventional guidewire, operators could use the MultiCross system. The primary efficacy endpoint was successful recanalization (technical success) and the primary safety endpoint was serious adverse events through 30 days post-procedure. The MultiCross catheter was used for all patients after failure of the initial attempt with a guidewire. Successful recanalization was achieved in all CTOs attempted (100%). No patients reported any adverse events at 30 days post-procedure. In this first-in-man experience, the MultiCross catheter has the potential to enhance crossing of CTOs. © 2014 Wiley Periodicals, Inc.

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.

Science.gov (United States)

Andrews, Nick A; Latrémolière, Alban; Basbaum, Allan I; Mogil, Jeffrey S; Porreca, Frank; Rice, Andrew S C; Woolf, Clifford J; Currie, Gillian L; Dworkin, Robert H; Eisenach, James C; Evans, Scott; Gewandter, Jennifer S; Gover, Tony D; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P; Kennedy, Jeffrey D; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P; McMahon, Stephen B; Price, Theodore J; Ross, Sarah E; Scherrer, Grégory; Seal, Rebecca P; Sena, Emily S; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I; Turk, Dennis C; Whiteside, Garth

2016-04-01

There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues.

Intravitreal docosahexaenoic acid in a rabbit model: preclinical safety assessment.

Directory of Open Access Journals (Sweden)

Rosa Dolz-Marco

Full Text Available PURPOSE: The purpose of the present study was to evaluate the retinal toxicity of a single dose of intravitreal docosahexaenoic acid (DHA in rabbit eyes over a short-term period. METHODS: Sixteen New Zealand albino rabbits were selected for this pre-clinical study. Six concentrations of DHA (Brudy Laboratories, Barcelona, Spain were prepared: 10 mg/50 µl, 5 mg/50 µl, 2'5 mg/50 µl, 50 µg/50 µl, 25 µg/50 µl, and 5 µg/50 µl. Each concentration was injected intravitreally in the right eye of two rabbits. As a control, the vehicle solution was injected in one eye of four animals. Retinal safety was studied by slit-lamp examination, and electroretinography. All the rabbits were euthanized one week after the intravitreal injection of DHA and the eyeballs were processed to morphologic and morphometric histological examination by light microscopy. At the same time aqueous and vitreous humor samples were taken to quantify the concentration of omega-3 acids by gas chromatography. Statistical analysis was performed by SPSS 21.0. RESULTS: Slit-lamp examination revealed an important inflammatory reaction on the anterior chamber of the rabbits injected with the higher concentrations of DHA (10 mg/50 µl, 5 mg/50 µl, 2'5 mg/50 µ Lower concentrations showed no inflammation. Electroretinography and histological studies showed no significant difference between control and DHA-injected groups except for the group injected with 50 µg/50 µl. CONCLUSIONS: Our results indicate that administration of intravitreal DHA is safe in the albino rabbit model up to the maximum tolerated dose of 25 µg/50 µl. Further studies should be performed in order to evaluate the effect of intravitreal injection of DHA as a treatment, alone or in combination, of different retinal diseases.

Extended Preclinical Safety, Efficacy and Stability Testing of a Live-attenuated Chikungunya Vaccine Candidate.

Directory of Open Access Journals (Sweden)

Kenneth S Plante

Full Text Available We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV, both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from 30% and mortality (from 0 to 100%, CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality. These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing.

Initial preclinical safety of non-replicating human endogenous retrovirus envelope protein-coated baculovirus vector-based vaccines against human papillomavirus.

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Han, Su-Eun; Kim, Mi-Gyeong; Lee, Soondong; Cho, Hee-Jeong; Byun, Youngro; Kim, Sujeong; Kim, Young Bong; Choi, Yongseok; Oh, Yu-Kyoung

2013-12-01

Human endogenous retrovirus (HERV) envelope protein-coated, baculovirus vector-based HPV 16 L1 (AcHERV-HPV16L1) is a non-replicating recombinant baculoviral vaccine. Here, we report an initial evaluation of the preclinical safety of AcHERV-HPV16L1 vaccine. In an acute toxicity study, a single administration of AcHERV-HPV16L1 DNA vaccine given intramuscularly (i.m.) to mice at a dose of 1 × 10(8) plaque-forming units (PFU) did not cause significant changes in body weight compared with vehicle-treated controls. It did cause a brief increase in the weights of some organs on day 15 post-treatment, but by day 30, all organ weights were not significantly different from those in the vehicle-treated control group. No hematological changes were observed on day 30 post-treatment. In a range-finding toxicity study with three doses of 1 × 10(7) , 2 × 10(7) and 5 × 10(7) PFU once daily for 5 days, the group treated with 5 × 10(7) PFU showed a transient decrease in the body weights from day 5 to day 15 post-treatment, but recovery to the levels similar to those in the vehicle-treated control group by post-treatment day 20. Organ weights were slightly higher for lymph nodes, spleen, thymus and liver after repeated dosing with 5 × 10(7) PFU on day 15, but had normalized by day 30. Moreover, repeated administration of AcHERV-HPV16L1 did not induce myosin-specific autoantibody in serum, and did not cause immune complex deposition or tissue damage at injection sites. Taken together, these results provide preliminary evidence of the preclinical safety of AcHERV-based HPV16L1 DNA vaccines in mice. Copyright © 2012 John Wiley & Sons, Ltd.

S-HAL : safety handbook for locals.

Science.gov (United States)

2014-01-01

The Safety Handbook for Locals (S-HAL) is intended to be a comprehensive : traffic safety resource for all local communities in Missouri, be it cities or : counties. The S-HAL mirrors the national Highway Safety Manual (HSM) : (AASHTO, 2010) in using...

AVN-492, A Novel Highly Selective 5-HT6R Antagonist: Preclinical Evaluation.

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Ivachtchenko, Alexandre V; Okun, Ilya; Aladinskiy, Vladimir; Ivanenkov, Yan; Koryakova, Angela; Karapetyan, Ruben; Mitkin, Oleg; Salimov, Ramiz; Ivashchenko, Andrey

2017-01-01

Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer's disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials.

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

International Nuclear Information System (INIS)

Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

2012-01-01

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt max and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. ► Haemodynamic

Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research.

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Sandberg, Kathryn; Umans, Jason G

2015-05-01

The U.S. National Institutes of Health (NIH) announced last May that steps will be taken to address the over-reliance on male cells and animals in preclinical research. To further address this announcement, in September 2014, scientists with varying perspectives came together at Georgetown University to discuss the following questions. (1) What metrics should the NIH use to assess tangible progress on policy changes designed to address the over-reliance on male cells and animals in preclinical research? (2) How effective can education be in reducing the over-reliance on male cells and animals in preclinical research and what educational initiatives sponsored by the NIH would most likely effect change? (3) What criteria should the NIH use to determine rigorously defined exceptions to the future proposal requirement of a balance of male and female cells and animals in preclinical studies? (4) What additional strategies in addition to proposal requirements should NIH use to reduce the overreliance of male cells and animals in preclinical research? The resulting consensus presented herein includes input from researchers not only from diverse disciplines of basic and translational science including biology, cell and molecular biology, biochemistry, physiology, pharmacology, neuroscience, cardiology, endocrinology, nephrology, psychiatry, and obstetrics and gynecology, but also from recognized experts in publishing, industry, advocacy, science policy, clinical medicine, and population health. We offer our recommendations to aid the NIH as it selects, implements, monitors, and optimizes strategies to correct the over-reliance on male cells and animals in preclinical research. © FASEB.

Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer’s disease clinical trials

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Grill, Joshua; Zhou, Yan; Elashoff, David; Karlawish, Jason

2016-01-01

Preclinical Alzheimer’s disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria to enroll. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with one of two hypothetical informed consent forms (ICF) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography (PET) scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials. PMID:26923411

ABWR (K-6/7) construction experience (computer-based safety system)

International Nuclear Information System (INIS)

Yokomura, T.

1998-01-01

TEPCO applied a digital safety system to Kashiwazaki-Kariwa Nuclear Power Station Unit Nos. 6 and 7, the world's first ABWR plant. Although this was the first time to apply a digital safety logic system in Japan, we were able to complete construction of K-6/7 very successfully and without any delay. TEPCO took a approach of developing a substantial amount of experience in digital non- safety systems before undertaking the design of the safety protection system. This paper describes the history, techniques and experience behind achieving a highly reliable digital safety system. (author)

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

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Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

2017-05-09

To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Making safety an integral part of 5S in healthcare.

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Ikuma, Laura H; Nahmens, Isabelina

2014-01-01

Healthcare faces major challenges with provider safety and rising costs, and many organizations are using Lean to instigate change. One Lean tool, 5S, is becoming popular for improving efficiency of physical work environments, and it can also improve safety. This paper demonstrates that safety is an integral part of 5S by examining five specific 5S events in acute care facilities. We provide two arguments for how safety is linked to 5S:1. Safety is affected by 5S events, regardless of whether safety is a specific goal and 2. Safety can and should permeate all five S's as part of a comprehensive plan for system improvement. Reports of 5S events from five departments in one health system were used to evaluate how changes made at each step of the 5S impacted safety. Safety was affected positively in each step of the 5S through initial safety goals and side effects of other changes. The case studies show that 5S can be a mechanism for improving safety. Practitioners may reap additional safety benefits by incorporating safety into 5S events through a safety analysis before the 5S, safety goals and considerations during the 5S, and follow-up safety analysis.

CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

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Kosovec, Juliann E; Zaidi, Ali H; Omstead, Ashten N; Matsui, Daisuke; Biedka, Mark J; Cox, Erin J; Campbell, Patrick T; Biederman, Robert W W; Kelly, Ronan J; Jobe, Blair A

2017-11-21

Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

Technological Advances in Cardiovascular Safety Assessment Decrease Preclinical Animal Use and Improve Clinical Relevance.

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Berridge, Brian R; Schultze, A Eric; Heyen, Jon R; Searfoss, George H; Sarazan, R Dustan

2016-12-01

Cardiovascular (CV) safety liabilities are significant concerns for drug developers and preclinical animal studies are predominately where those liabilities are characterized before patient exposures. Steady progress in technology and laboratory capabilities is enabling a more refined and informative use of animals in those studies. The application of surgically implantable and telemetered instrumentation in the acute assessment of drug effects on CV function has significantly improved historical approaches that involved anesthetized or restrained animals. More chronically instrumented animals and application of common clinical imaging assessments like echocardiography and MRI extend functional and in-life structural assessments into the repeat-dose setting. A growing portfolio of circulating CV biomarkers is allowing longitudinal and repeated measures of cardiac and vascular injury and dysfunction better informing an understanding of temporal pathogenesis and allowing earlier detection of undesirable effects. In vitro modeling systems of the past were limited by their lack of biological relevance to the in vivo human condition. Advances in stem cell technology and more complex in vitro modeling platforms are quickly creating more opportunity to supplant animals in our earliest assessments for liabilities. Continuing improvement in our capabilities in both animal and nonanimal modeling should support a steady decrease in animal use for primary liability identification and optimize the translational relevance of the animal studies we continue to do. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Trends in safety pharmacology: posters presented at the annual meetings of the Safety Pharmacology Society 2001-2010.

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Redfern, William S; Valentin, Jean-Pierre

2011-01-01

The inaugural meeting of the Safety Pharmacology Society (SPS) was in 2001, soon after ICH S7A had been adopted. The 10th anniversary is an appropriate milestone at which to analyse trends in the science and themes of safety pharmacology, as reflected in posters presented at the annual meetings. The source information was the poster abstract booklets from each of the first ten annual meetings. The number of posters rose steadily from 34 in 2001 to 201 in 2010. The proportion of posters containing in vitro data has remained constant throughout the decade at ~30%. In terms of organ functions, themes relating to the cardiovascular system (CVS) have always generated the majority of posters, remaining above 60% of the total for the last 9years. The dominant theme has been around 'QT liability'. This peaked in 2003 at 68% of all posters presented, around the time of the ICHS7B discussions, and has remained above 30% thereafter. Apart from 2003 (dipping to 4%), CNS-related posters have remained steady at 11-17% throughout the decade. Respiratory-related posters have remained at 5-8% over the last 5years. Gastrointestinal (GI)-related posters have contributed 2-6% throughout the decade, and renal-related posters 1-3%. Posters on combined organ assessments have appeared in recent years. The relative emphasis on the different organ functions is broadly proportional to the causes of candidate drug attrition preclinically, whereas both CNS and GI are under-represented when considering their contribution to significant adverse effects during clinical development. Trends are either regulatory-driven (e.g. increase in posters on abuse-dependence liability since EMEA/CHMP/SWP/94227/2004), technology-driven (e.g. automated hERG assay; left ventricular function; non-invasive CVS measurements; stem cells, etc.), or relate to the predictive ability of safety pharmacology data (e.g. clinical translation initiatives; concordance between in vitro and in vivo preclinical data; integrated

Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

International Nuclear Information System (INIS)

Liang, Li-Ping; Huang, Jie; Fulton, Ruth; Pearson-Smith, Jennifer N.; Day, Brian J.; Patel, Manisha

2017-01-01

Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD. - Highlights: • A series of metalloporphyrins were optimized in a mouse model of parkinsonism. • Two novel orally active, brain permeable antioxidant metalloporphyrins were identified. • The identified metalloporphyrins were well tolerated.

Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

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Liang, Li-Ping [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Huang, Jie [Department of Medicine, National Jewish Health, Denver, CO (United States); Fulton, Ruth; Pearson-Smith, Jennifer N. [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Day, Brian J. [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Department of Medicine, National Jewish Health, Denver, CO (United States); Patel, Manisha, E-mail: manisha.patel@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States)

2017-07-01

Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD. - Highlights: • A series of metalloporphyrins were optimized in a mouse model of parkinsonism. • Two novel orally active, brain permeable antioxidant metalloporphyrins were identified. • The identified metalloporphyrins were well tolerated.

Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies.

Science.gov (United States)

Jans, Verna; Dondorp, Wybo; Goossens, Ellen; Mertes, Heidi; Pennings, Guido; de Wert, Guido

2018-02-07

In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R's (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research.

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

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Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.

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Serabian, M A; Pilaro, A M

1999-01-01

Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Directory of Open Access Journals (Sweden)

Ghosh Anamitra

2012-10-01

Full Text Available Abstract Background Parkinson’s disease (PD is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of PD. Methods Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1, glial fibrillary acidic protein (GFAP, gp91phox and inducible nitric oxide synthase (iNOS, were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT, 4-hydroxynonenal (4-HNE and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. Results Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN. MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in

A phase i study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas

NARCIS (Netherlands)

Infante, Jeffrey R.; Cassier, Philippe A.; Gerecitano, John F.; Witteveen, Petronella O.; Chugh, Rashmi; Ribrag, Vincent; Chakraborty, Abhijit; Matano, Alessandro; Dobson, Jason R.; Crystal, Adam S.; Parasuraman, Sudha; Shapiro, Geoffrey I.

2016-01-01

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity,

Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura.

Science.gov (United States)

Kopić, A; Benamara, K; Piskernik, C; Plaimauer, B; Horling, F; Höbarth, G; Ruthsatz, T; Dietrich, B; Muchitsch, E-M; Scheiflinger, F; Turecek, M; Höllriegl, W

2016-07-01

Essentials ADAMTS-13-deficiency is a cause of thrombotic thrombocytopenic purpura (TTP). Preclinical safety of recombinant human ADAMTS-13 (BAX930) was shown in animal models. Preclinical efficacy of BAX930 was shown in a mouse model of TTP. BAX930 showed advantageous efficacy over fresh frozen plasma, the current standard of care. Click to hear Dr Cataland and Prof. Lämmle present a seminar on Thrombotic Thrombocytopenic Purpura (TTP): new Insights in Pathogenesis and Treatment Modalities. Background Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by microthrombosis in small blood vessels of the body, resulting in a low platelet count. Baxalta has developed a new recombinant ADAMTS-13 (rADAMTS-13) product (BAX930) for on-demand and prophylactic treatment of patients with hereditary TTP (hTTP). Objectives To evaluate the pharmacokinetics, efficacy and safety of BAX930 in different species, by use of an extensive preclinical program. Methods The prophylactic and therapeutic efficacies of BAX930 were tested in a previously established TTP mouse model. Pharmacokinetics were evaluated after single intravenous bolus injection in mice and rats, and after repeated dosing in cynomolgus monkeys. Toxicity was assessed in rats and monkeys, safety pharmacology in monkeys, and local tolerance in rabbits. Results BAX930 was shown to be efficacious, as demonstrated by a stabilized platelet count in ADAMTS-13 knockout mice that were thrombocytopenic when treated. Prophylactic efficacy was dose-dependent and comparable with that achieved by treatment with fresh frozen plasma, the mainstay of hTTP treatment. Therapeutic efficacy was treatment interval-dependent. Safety pharmacology evaluation did not show any deleterious effects of BAX930 on cardiovascular and respiratory functions in monkeys. The compound's pharmacokinetics were similar and dose-proportional in mice, rats, and monkeys. BAX930 was well tolerated in rats, monkeys, and rabbits, even

The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers

Science.gov (United States)

Ayutyanont, Napatkamon; Langbaum, Jessica B.; Hendrix, Suzanne B.; Chen, Kewei; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

2014-01-01

Objective There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials. Method We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains. Results This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05). Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most

Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

Directory of Open Access Journals (Sweden)

Maximilian Richter

2016-01-01

Full Text Available Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs. The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with

U.S. Nuclear Regulatory Commission Safety Culture Oversight

International Nuclear Information System (INIS)

Sieracki, D. J.

2016-01-01

The NRC recognises that it is important for all organizations performing or overseeing regulated activities to establish and maintain a positive safety culture commensurate with the safety and security significance of their activities and the nature and complexity of their organizations and functions. The NRC’s approach to safety culture is based on the premise that licencees bear the primary responsibility for safety. The NRC provides oversight of safety culture through expectations detailed in policy statements, safety culture assessor training for NRC inspectors, the oversight process, and the Allegations and Enforcement Programs. The NRC’s Safety Culture Policy Statement (SCPS) sets forth the Commission’s expectation that individuals and organizations establish and maintain a positive safety culture commensurate with the safety and security significance of their activities and the nature and complexity of their organizations and functions. The SCPS is not a regulation. It applies to all licencees, certificate holders, permit holders, authorisation holders, holders of quality assurance program approvals, vendors and suppliers of safety-related components, and applicants for a licence, certificate, permit, authorisation, or quality assurance program approval, subject to NRC authority.

A Scholarly Pathway in Quality Improvement and Patient Safety.

Science.gov (United States)

Ferguson, Catherine C; Lamb, Geoffrey

2015-10-01

There are several challenges to teaching quality improvement (QI) and patient safety material to medical students, as successful programs should combine didactic and experiential teaching methods, integrate the material into the preclinical and clinical years, and tailor the material to the schools' existing curriculum. The authors describe the development, implementation, and assessment of the Quality Improvement and Patient Safety (QuIPS) Scholarly Pathway-a faculty-mentored, three-year experience for students interested in gaining exposure to QI and patient safety concepts at the Medical College of Wisconsin (MCW). The QuIPS pathway capitalized on the existing structure of scholarly pathways for MCW medical students, allowing QI and patient safety to be incorporated into the existing curriculum using didactic and experiential instruction and spanning preclinical and clinical education. Student reaction to the QuIPS pathway has been favorable. Preliminary data demonstrate that student knowledge as measured by the Quality Improvement Knowledge Assessment Tool significantly increased after the first year of implementation. A novel curriculum such as the QuIPS pathway provides an important opportunity to develop and test new assessment tools for curricula in systems-based practice and practice-based learning and improvement. The authors also hope that by bringing together local QI and patient safety experts and stakeholders during the curricular development process, they have laid the groundwork for the creation of a more pervasive curriculum that will reach all MCW students in the future. The model may be generalizable to other U.S. medical schools with scholarly pathways as well.

Development of computational small animal models and their applications in preclinical imaging and therapy research

NARCIS (Netherlands)

Xie, Tianwu; Zaidi, Habib

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal

Changing the S and MA [Safety and Mission Assurance] Paradigm

Science.gov (United States)

Malone, Roy W., Jr.

2010-01-01

Objectives: 1) Optimize S&MA organization to best facilitate Shuttle transition in 2010, successfully support Ares developmental responsibilities, and minimize the impacts of the gap between last Shuttle flight and start of Ares V Project. 2) Improve leveraging of critical skills and experience between Shuttle and Ares. 3) Split technical and supervisory functions to facilitate technical penetration. 4) Create Chief Safety and Mission Assurance Officer (CSO) stand-alone position for successfully implementation of S&MA Technical Authority. 5) Minimize disruption to customers. 6) Provide early involvement of S&MA leadership team and frequent/open communications with S&MA team members and steak-holders.

Outsource Power, Import Safety? Challenges and Opportunities of the U.S.-China Food Safety Regulatory Cooperation.

Science.gov (United States)

Lin, Ching-Fu

The United States has a high stake in China’s serious food safety problem, as food products of Chinese origin have dominated the U.S. food market in numerous areas and continue to grow. The conclusion of the U.S.-China Food Safety Agreement (“the Agreement”) has allowed FDA to strengthen regulatory cooperation with its Chinese counterpart in various aspects. The Agreement also paves the way for the implementation of the new regulatory tools incorporated in FSMA, especially in the cross-border context. However, both the Agreement and FSMA have certain crucial limitations that may create future hurdles to effective implementation in the U.S.-China cooperation. This paper therefore endeavors to first examine China’s governance challenges over food safety, with a focus on the 2009 Food Safety Law, the 2015 Amendment, and the fundamental problem of “thin” rule of law. This paper moves to analyze the U.S.-China Food Safety Agreement, reviewing the agreement’s strengths and weaknesses. It further assesses FSMA’s innovative institutional design to regulate imported food products and its limitations. However, both the U.S.-China Food Safety Agreement and FSMA arguably create a regulatory dilemma for FDA when addressing imported food safety, due to structural mismatch between the broad scope of power granted to FDA and the long chain of power outsourcing to governments or private companies as primary “regulators.” Neither the Agreement nor FSMA give FDA adequate capacity to closely oversee such “agents” along the chain of power outsourcing. Framing the U.S.-China food safety cooperation as a multilayer structure that “outsources power” to “import safety,” this paper concludes by stressing the need for a robust accountability and effective mechanism for U.S.-China food safety cooperation.

Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of ["1"8F]fluorocholine in mice

International Nuclear Information System (INIS)

Silveira, Marina B.; Ferreira, Soraya M.Z.M.D.; Nascimento, Leonardo T.C.; Costa, Flávia M.; Mendes, Bruno M.; Ferreira, Andrea V.; Malamut, Carlos; Silva, Juliana B.; Mamede, Marcelo

2016-01-01

["1"8F]Fluorocholine (["1"8F]FCH) has been proven to be effective in prostate cancer. Since ["1"8F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of ["1"8F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. - Highlights: • Data demonstrated the high quality, safety and effectiveness of ["1"8F]FCH. • ["1"8F]FCH preclinical profile is in accordance with previously published. • Toxicity, distribution, kinetics and radiation dosimetry were well characterized. • The results are important for regulatory issues in Brazil and other countries.

Safety-Culture Exploration in Taiwan’s Metal Industries: Identifying the Workers’ Background Influence on Safety Climate

Directory of Open Access Journals (Sweden)

Shu-Chiang Lin

2017-10-01

Full Text Available The present study aims to assess the safety-climate level in Taiwan’s metal industries, as well as to identify the influence of workers’ backgrounds on the safety climate. An earlier report showed that a poor safety culture was related to the cause of accidents in Taiwan’s traditional manufacturing industries. This study surveyed a total of 839 workers who voluntarily participated and completed the safety-culture questionnaires. These workers were from a Taiwanese metal company and its five satellite companies. Three safety-climate factors, namely safety perception, safety communication and safety-management systems, were assessed. Confirmatory factor analysis (CFA was conducted by developing structural equation modeling to ensure the questionnaire’s validity. The influence of workers’ backgrounds on the safety climate was identified by using one-way ANOVA. The reliability result of the questionnaire was above the acceptable level. The overall safety-climate score was 4.22 out of a five-point scale for safety perception, 4.23 for safety-management systems and 3.97 for safety communication. The scores indicate a good level of safety climate, with room for improvement in safety communication. Additionally, the influence of workers’ backgrounds on the safety climate was confirmed. Based on the validity test, it was also found that the questionnaire could be improved by reconstructing its questions in its development process in order to increase the safety-climate model’s reliability and validity, as well as its model fit.

An olfactory ‘stress test’ may detect preclinical Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Schofield Peter W

2012-05-01

Full Text Available Abstract Background The olfactory bulb (OB receives extensive cholinergic input from the basal forebrain and is affected very early in Alzheimer’s disease (AD. We speculated that an olfactory ‘stress test’ (OST, targeting the OB, might be used to unmask incipient AD. We investigated if change in olfactory performance following intranasal atropine was associated with several known antecedents or biomarkers of AD. Methods We measured change in performance on the University of Pennsylvania Smell Identification Test (UPSIT in the left nostril before (20-items and after (remaining 20-items intranasal administration of 1 mg of atropine. We administered cognitive tests, measured hippocampal volume from MRI scans and recorded Apolipoprotein E genotype as indices relevant to underlying AD. Results In a convenience sample of 56 elderly individuals (14 probable AD, 13 cognitive impairment no dementia, 29 cognitively intact the change in UPSIT score after atropine (‘atropine effect’ = AE correlated significantly with demographically scaled episodic memory score (r = 0.57, p Conclusions The OST using atropine as an olfactory probe holds promise as a simple, inexpensive screen for early and preclinical AD and further work, including longitudinal studies, is needed to explore this possibility.

High dose-per-pulse electron beam dosimetry: Commissioning of the Oriatron eRT6 prototype linear accelerator for preclinical use.

Science.gov (United States)

Jaccard, Maud; Durán, Maria Teresa; Petersson, Kristoffer; Germond, Jean-François; Liger, Philippe; Vozenin, Marie-Catherine; Bourhis, Jean; Bochud, François; Bailat, Claude

2018-02-01

The Oriatron eRT6 is an experimental high dose-per-pulse linear accelerator (linac) which was designed to deliver an electron beam with variable dose-rates, ranging from a few Gy/min up to hundreds of Gy/s. It was built to study the radiobiological effects of high dose-per-pulse/dose-rate electron beam irradiation, in the context of preclinical and cognitive studies. In this work, we report on the commissioning and beam monitoring of the Oriatron eRT6 prototype linac. The beam was characterized in different steps. The output stability was studied by performing repeated measurements over a period of 20 months. The relative output variations caused by changing beam parameters, such as the temporal electron pulse width, the pulse repetition frequency and the pulse amplitude were also analyzed. Finally, depth dose curves and field sizes were measured for two different beam settings, resulting in one beam with a conventional radiotherapy dose-rate and one with a much higher dose-rate. Measurements were performed with Gafchromic EBT3 films and with a PTW Advanced Markus ionization chamber. In addition, we developed a beam current monitoring system based on the signals from an induction torus positioned at the beam exit of the waveguide and from a graphite beam collimator. The stability of the output over repeated measurements was found to be good, with a standard deviation smaller than 1%. However, non-negligible day-to-day variations of the beam output were observed. Those output variations showed different trends depending on the dose-rate. The analysis of the relative output variation as a function of various beam parameters showed that in a given configuration, the dose-rate could be reliably varied over three orders of magnitude. Interdependence effects on the output variation between the parameters were also observed. The beam energy and field size were found to be slightly dose-rate-dependent and suitable mainly for small animal irradiation. The beam monitoring

U.S. ALMR safety approach and licensing status

International Nuclear Information System (INIS)

Herczeg, J.W.; Hardy, R.W.; Gyorey, G.L.

1992-01-01

The Advanced Liquid Metal Cooled Reactor (ALMR) in the United States is based on the Power Reactor Innovative Small Module (PRISM) concept originated by the General Electric Company (GE). This concept features a compact modular system suitable for factory fabrication, and a high degree of passive and natural safety characteristics. The safety approach emphasizes accident prevention, backed up by accident mitigation. First-round safety evaluations by U.S. regulators have found that the design provides passive, natural, and other desirable features enhancing the safety of the power plant. A Preapplication Safety Evaluation Report (PSER) from the U.S. Nuclear Regulatory Commission (NRC) is anticipated in early 1993. (author)

METHODOLOGICAL APPROACHES TO EXPERT EVALUATION OF PRECLINICAL AND CLINICAL TRIALS OF HUMAN IMMUNOGLOBULIN PRODUCTS

Directory of Open Access Journals (Sweden)

V. B. Ivanov

2017-01-01

Full Text Available The article considers the experience of Russian and leading foreign regulatory agencies in organisation and conduction of preclinical and clinical trials of human immunoglobulin products. The authors suggest a classification of human immunoglobulins and provide updated information on authorization of these products in Russia. The article summarizes methodological approaches, basic scientific principles and criteria relating to expert evaluation of preclinical and clinical trials of blood products. The authors further define the expert body’s requirements for data on preclinical and clinical trials of human normal immuniglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases which are submitted as part of applications for marketing authorization or marketing authorization variation. The article suggests programs of preclinical and clinical trials for human normal immunoglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases that are aligned with the Russian legislation and Eurasian Economic Union’s regulations on medicines circulation, and have been elaborated with respect to the guidelines of the European Medicines Agency.

A patient safety course for preclinical medical students.

Science.gov (United States)

Shekhter, Ilya; Rosen, Lisa; Sanko, Jill; Everett-Thomas, Ruth; Fitzpatrick, Maureen; Birnbach, David

2012-12-01

We developed a course to introduce incoming third-year medical students to the subject of patient safety, to focus their attention on teamwork and communication, and to create an awareness of patient-safe practices that will positively impact their performance as clinicians. The course, held prior to the start of clinical rotations, consisted of lectures, web-based didactic materials, small group activities and simulation exercises, with an emphasis on experiential learning. First, students inspected a 'room of horrors', which is a simulated clinical environment riddled with errors. Second, we used lenticular puzzles in small groups to elicit teamwork behaviours that parallel real-life interactions in health care. Each team was given 8 minutes to complete a 48-piece puzzle, with five pieces removed at random and given to other teams. The salient teaching point of this exercise is that for a team to complete the task, team members must communicate with members of their own team as well as with other teams. Last, simulation scenarios provided a clinical context to reinforce the skills introduced through the puzzle exercise and lectures. The students were split into groups of six or seven members and challenged with two scenarios. Both scenarios focused on a 56-year-old man in respiratory distress. The teams were debriefed on both clinical management and teamwork. The vast majority of the students (93%) agreed that the course improved their patient safety knowledge and skills. The positive response from students to the introductory course is an important step in fostering a culture of patient safety. © Blackwell Publishing Ltd 2012.

Preclinical animal research on therapy dosimetry with dual isotopes

International Nuclear Information System (INIS)

Konijnenberg, Mark W.; Jong, Marion de

2011-01-01

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Preclinical animal research on therapy dosimetry with dual isotopes

Energy Technology Data Exchange (ETDEWEB)

Konijnenberg, Mark W.; Jong, Marion de [Nuclear Medicine Department, Erasmus MC, Rotterdam (Netherlands)

2011-06-15

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Safety and effectiveness considerations for clinical studies of visual prosthetic devices

Science.gov (United States)

Cohen, Ethan D.

2007-03-01

With the advent of new designs of visual prostheses for the blind, FDA is faced with developing guidance for evaluating their engineering, safety and patient performance. Visual prostheses are considered significant risk medical devices, and their use in human clinical trials must be approved by FDA under an investigation device exemption (IDE). This paper contains a series of test topics and design issues that sponsors should consider in order to assess the safety and efficacy of their device. The IDE application includes a series of pre-clinical and clinical data sections. The pre-clinical section documents laboratory, animal and bench top performance tests of visual prostheses safety and reliability to support a human clinical trial. The materials used in constructing the implant should be biocompatible, sterile, corrosion resistant, and able to withstand any forces exerted on it during normal patient use. The clinical data section is composed of items related to patient-related evaluation of device performance. This section documents the implantation procedure, trial design, statistical analysis and how visual performance is assessed. Similar to cochlear implants, a visual prosthesis is expected to last in the body for many years, and good pre-clinical and clinical testing will help ensure its safety, durability and effectiveness.

Investigative safety science as a competitive advantage for Pharma.

Science.gov (United States)

Moggs, Jonathan; Moulin, Pierre; Pognan, Francois; Brees, Dominique; Leonard, Michele; Busch, Steve; Cordier, Andre; Heard, David J; Kammüller, Michael; Merz, Michael; Bouchard, Page; Chibout, Salah-Dine

2012-09-01

Following a US National Academy of Sciences report in 2007 entitled "Toxicity Testing of the 21st Century: a Vision and a Strategy," significant advances within translational drug safety sciences promise to revolutionize drug discovery and development. The purpose of this review is to outline why investigative safety science is a competitive advantage for the pharmaceutical industry. The article discusses the essential goals for modern investigative toxicologists including: cross-species target biology; molecular pathways of toxicity; and development of predictive tools, models and biomarkers that allow discovery researchers and clinicians to anticipate safety problems and plan ways to address them, earlier than ever before. Furthermore, the article emphasizes the importance of investigating unanticipated clinical safety signals through a combination of mechanistic preclinical studies and/or molecular characterization of clinical samples from affected organs. The traditional boundaries between pharma industry teams focusing on safety/efficacy and preclinical/clinical development are rapidly disappearing in favor of translational safety science-centric organizations with a vision of bringing more effective medicines forward safely and quickly. Comparative biology and mechanistic toxicology approaches facilitate: i) identifying translational safety biomarkers; ii) identifying new drug targets/indications; and iii) mitigating off-target toxicities. These value-adding safety science contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

Mutagenic and cytotoxic properties of 6-thioguanine, S6-methylthioguanine, and guanine-S6-sulfonic acid.

Science.gov (United States)

Yuan, Bifeng; Wang, Yinsheng

2008-08-29

Thiopurine drugs, including 6-thioguanine ((S)G), 6-mercaptopurine, and azathioprine, are widely employed anticancer agents and immunosuppressants. The formation of (S)G nucleotides from the thiopurine prodrugs and their subsequent incorporation into nucleic acids are important for the drugs to exert their cytotoxic effects. (S)G in DNA can be methylated by S-adenosyl-l-methionine to give S(6)-methylthioguanine (S(6)mG) and oxidized by UVA light to render guanine-S(6)-sulfonic acid ((SO3H)G). Here, we constructed single-stranded M13 shuttle vectors carrying a (S)G, S(6)mG, or (SO3H)G at a unique site and allowed the vectors to propagate in wild-type and bypass polymerase-deficient Escherichia coli cells. Analysis of the replication products by using the competitive replication and adduct bypass and a slightly modified restriction enzyme digestion and post-labeling assays revealed that, although none of the three thionucleosides considerably blocked DNA replication in all transfected E. coli cells, both S(6)mG and (SO3H)G were highly mutagenic, which resulted in G-->A mutation at frequencies of 94 and 77%, respectively, in wild-type E. coli cells. Deficiency in bypass polymerases does not result in alteration of mutation frequencies of these two lesions. In contrast to what was found from previous steady-state kinetic analysis, our data demonstrated that 6-thioguanine is mutagenic, with G-->A transition occurring at a frequency of approximately 10%. The mutagenic properties of 6-thioguanine and its derivatives revealed in the present study offered important knowledge about the biological implications of these thionucleosides.

Monochromatic minibeam radiotherapy: theoretical and experimental dosimetry for preclinical treatment plans

Energy Technology Data Exchange (ETDEWEB)

Deman, P; Vautrin, M; Stupar, V; Barbier, E L; Elleaume, H; Esteve, F; Adam, J F, E-mail: adam@esrf.fr [INSERM, U836, BP 170, Grenoble Cedex 9, F-38042 (France)

2011-07-21

Monochromatic x-ray minibeam radiotherapy is a new radiosurgery approach based on arrays of submillimetric interlaced planar x-ray beams. The aim of this study was to characterize the dose distributions obtained with this new modality when being used for preclinical trials. Monte Carlo simulations were performed in water phantoms. Percentage depth-dose curves and dose profiles were computed for single incidences and interleaved incidences of 80 keV planar x-ray minibeam (0.6 x 5 mm) arrays. Peak to valley dose ratios were also computed at various depths for an increasing number of minibeams. 3D experimental polymer gel (nPAG) dosimetry measurements were performed using MRI devices designed for small animal imaging. These very high spatial resolution (50 {mu}m) dose maps were compared to the simulations. Preclinical minibeams dose distributions were fully characterized. Experimental dosimetry correlated well with Monte Carlo calculations (Student t-tests: p > 0.1). F98 tumor-bearing rats were also irradiated with interleaved minibeams (80 keV, prescribed dose: 25 Gy). This associated preclinical trial serves as a proof of principle of the technique. The mean survival time of irradiated glioma-bearing rats increased significantly, when compared to the untreated animals (59.6 {+-} 2.8 days versus 28.25 {+-} 0.75 days, p < 0.001).

Introduction to South Africa's safety classification

Energy Technology Data Exchange (ETDEWEB)

Kang, Kyung Jun; Wu, Sang Ik; Yoon, Juh Yeon [KAERI, Daejeon (Korea, Republic of)

2012-10-15

The safety functions of nuclear reactor facilities such as research reactors have to be maintained for all initiating events, incidents and accidents. From the position of licensee, it is a very important issue and design challenge to meet the licensing requirements for the final goal of proper safety functions from nuclear regulator. This paper intends to introduce and understand South Africa's licensing requirements and processing for safety classification of SSCs. South Africa's licensing requirements are shown in Table 1. Three categories A, B and C are categorized based on the occurrence frequency and the dose limitation of worker and public exposure. The Defense in Depth (DiD) and ALARA principle are forced to apply to a nuclear reactor facility design. Also, South Africa's safety and quality class compare with that of ANSI 51.1.

Mutagenic and Cytotoxic Properties of 6-Thioguanine, S6-Methylthioguanine, and Guanine-S6-sulfonic Acid*S⃞

OpenAIRE

Yuan, Bifeng; Wang, Yinsheng

2008-01-01

Thiopurine drugs, including 6-thioguanine (SG), 6-mercaptopurine, and azathioprine, are widely employed anticancer agents and immunosuppressants. The formation of SG nucleotides from the thiopurine prodrugs and their subsequent incorporation into nucleic acids are important for the drugs to exert their cytotoxic effects. SG in DNA can be methylated by S-adenosyl-l-methionine to give S6-methylthioguanine (S6mG) and oxidized by UVA light to render guanine-S6-sulfonic acid ...

Precision Pulse Capsulotomy: Preclinical Safety and Performance of a New Capsulotomy Technology.

Science.gov (United States)

Chang, David F; Mamalis, Nick; Werner, Liliana

2016-02-01

To assess the preclinical safety and performance of a new precision pulse capsulotomy (PPC) method. Human cadaver eye studies and surgical, slit-lamp, and histopathologic evaluation in a consecutive series of 20 live rabbits. Human cadaver eyes and New Zealand white rabbits. Precision pulse capsulotomy uses a highly focused, fast, multipulse, low-energy discharge to produce a perfectly round anterior capsulotomy instantaneously and simultaneously along all 360°. Capsulotomies are performed using a disposable handpiece with a soft collapsible tip and circular nitinol cutting element. Miyake-Apple imaging and scanning electron microscopy (SEM) of PPC were conducted in human cadaver eyes. Surgical, postoperative slit-lamp, and histopathologic assessments of PPC were performed in 20 live rabbits and were compared with manual continuous curvilinear capsulorrhexis (CCC) in the fellow eye. Anterior chamber (AC) thermocouple temperature measurements were evaluated in a subset of rabbit eyes. Capsulotomy edge circularity, SEM morphologic features and zonular movement with PPC in human cadaver eyes. Anterior chamber temperature during PPC and grading of ocular inflammation, corneal endothelial damage, anterior capsular opacification (ACO), and posterior capsular opacification (PCO). Miyake-Apple imaging showed minimal zonular stress, and thermocouple measurements demonstrated negligible AC temperature changes during PPC. Precision pulse capsulotomy produced round, complete capsulotomies in all 20 rabbit eyes, leading to successful in-the-bag intraocular lens (IOL) implantation. Slit-lamp examinations at 3 days and 1, 2, and 4 weeks after surgery showed no significant differences between PPC and CCC in corneal edema, AC inflammatory reaction, capsular fibrosis, ACO, and PCO. Postmortem studies showed no difference in the corneal endothelium between PPC and CCC eyes. All IOLs were well centered in PPC eyes, and histopathologic analysis showed no greater inflammatory

Safety, Security and Safeguards (3S) Culture

International Nuclear Information System (INIS)

Mladineo, S.V.; Frazar, S.

2013-01-01

A meaningful discussion of Safety, Security, and Safeguards (3S) Culture requires a review of the concepts related to the culture of the three components. The concept of culture can be confusing, and so careful use of terminology is needed to enable a focused and constructive dialogue. To this end, this paper will use the concept of organizational culture as a backdrop for a broader discussion about how the three subcultures of safety, security and safeguards come together to enhance the mission of an organization. Since the accidents at Three Mile Island and Chernobyl, the nuclear industry has embraced the concept of safety culture. The work on safety culture has been used to develop programs and concepts in the culture of Material Protection, Control, and Accounting and Nuclear Security Culture. More recently, some work has been done on defining an International Safeguards Culture. Others have spoken about a 3S Culture, but there has been little rigorous consideration of the concept. This paper attempts to address 3S Culture, to begin to evaluate the merit of the concept, and to propose a definition. The paper is followed by the slides of the presentation. (authors)

Efficacy and Safety of Human Retinal Progenitor Cells

Science.gov (United States)

Semo, Ma'ayan; Haamedi, Nasrin; Stevanato, Lara; Carter, David; Brooke, Gary; Young, Michael; Coffey, Peter; Sinden, John; Patel, Sara; Vugler, Anthony

2016-01-01

Purpose We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. Methods Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. Results The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and βIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. Conclusions Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. Translational Relevance Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies. PMID:27486556

Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

Energy Technology Data Exchange (ETDEWEB)

Teipel, Stefan [University of Rostock, Department of Psychosomatic Medicine, Rostock (Germany); DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States); Grothe, Michel J. [DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States)

2016-03-15

Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

International Nuclear Information System (INIS)

Teipel, Stefan; Grothe, Michel J.

2016-01-01

Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

New C$_{6}$D$_{6}$ detectors: reduced neutron sensitivity and improved safety

CERN Document Server

Mastinu, Pierfrancesco; Berthoumieux, Eric; Cano-Ott, Daniel; Gramegna, F; Guerrero, Carlos; Massimi, Cristian; Milazzo, Paolo Maria; Mingrone, Federica; Praena, Javier; Prete, G; García, Aczel Regino

2013-01-01

During the 2011 data measurement campaign at n_TOF, the liquid scintillator detectors developed at FZK-Karlsruhe (hereafter named K6D6, [1]) and used with success along 10 years have shown ageing problems, mainly related to liquid leakage. The mould used to produce the carbon fiber structure, containing the liquid and the detection elements, was not available anymore and the technician involved in its construction was retired. Once decided to proceed to the production of new detectors (L6D6 in the following) two major items have been identified: - The detector setup must be able to work in the new class A experimental area (safety requirements advise to avoid the use of the old K6D6 in this area). - If possible, it is useful to reduce the neutron sensitivity, with the aim to have a liquid scintillator detector with very low neutron sensitivity (improving the already high performing K6D6). [1] R.Plag et al., NIM A496 (2003) 425

29 CFR 1902.6 - Consultation with the National Institute for Occupational Safety and Health.

Science.gov (United States)

2010-07-01

... Safety and Health. 1902.6 Section 1902.6 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL... Occupational Safety and Health. The Assistant Secretary will consult, as appropriate, with the Director of the National Institute for Occupational Safety and Health with regard to plans submitted by the States under...

A review of the safety features of 6M packagings for DOE programs

International Nuclear Information System (INIS)

1988-12-01

This report, prepared by a US Department of Energy (DOE) Task Force and organized for clarity into two-page modules, argues that the US Department of Transportation (DOT) Specification-6M packagings (hereafter referred to as 6M packaging, or simply 6M) merit continued DOE use and, if necessary, DOE certification. This report is designed to address the specific requirements of a Safety Analysis Report for Packaging (SARP). While not a SARP, this report constitutes a compilation of all available documentation on 6M packagings. The authors individually, and the Task Force collectively, believe their investigation provides justification for the continued use of 6M packagings because they meet criteria for quality assurance and for safety under normal and accident conditions as defined by the US Nuclear Regulatory Commission (NRC) regulations. This report may be used by DOE managers to assist in deliberations on future requirements for 6M packagings as they are required to support DOE programs. For the purpose of ready evaluation, this report includes categorical topics found in Nuclear Regulatory Guide 7.9, the topical guideline for SARPs. The format, however, will (it is hoped) pleasantly surprise customary reader expectations. For, while maintaining categorical headings and subheadings found in SARPs as a skeleton, the Task Force chose to adopt the document design principles developed by Hughes Aircraft in the 1960s, ''Sequential Thematic Organization of Publications'' (STOP). 37 figs

Legacy data sharing to improve drug safety assessment: the eTOX project

DEFF Research Database (Denmark)

Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas

2017-01-01

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through...

Criticality safety enhancements for SCALE 6.2 and beyond

International Nuclear Information System (INIS)

Rearden, Bradley T.; Bekar, Kursat B.; Celik, Cihangir; Clarno, Kevin T.; Dunn, Michael E.; Hart, Shane W.; Ibrahim, Ahmad M.; Johnson, Seth R.; Langley, Brandon R.; Lefebvre, Jordan P.; Lefebvre, Robert A.; Marshall, William J.; Mertyurek, Ugur; Mueller, Don; Peplow, Douglas E.; Perfetti, Christopher M.; Petrie Jr, Lester M.; Thompson, Adam B.; Wiarda, Dorothea; Wieselquist, William A.; Williams, Mark L.

2015-01-01

SCALE is a widely used suite of tools for nuclear systems modeling and simulation that provides comprehensive, verified and validated, user-friendly capabilities for criticality safety, reactor physics, radiation shielding, and sensitivity and uncertainty analysis. Since 1980, regulators, industry, and research institutions around the world have relied on SCALE for nuclear safety analysis and design. SCALE 6.2 provides several new capabilities and significant improvements in many existing features for criticality safety analysis. Enhancements are realized for nuclear data; multigroup resonance self-shielding; continuous-energy Monte Carlo analysis for sensitivity/uncertainty analysis, radiation shielding, and depletion; and graphical user interfaces. An overview of these capabilities is provided in this paper, and additional details are provided in several companion papers.

BP's driving safety strategy

Energy Technology Data Exchange (ETDEWEB)

Herman, B. [BP Canada Energy Company, Calgary, AB (Canada)

2006-07-01

This presentation focused on why it is important to drive safely. It addressed driver fatigue as well as BP's global driving standard. The Standard applies to all BP employees and contractors that drive any vehicle on BP business and consists of 10 mandatory elements focusing on safety of the driver, the safety of the journey, and the safety of the vehicle. The driving standards focus on several themes, including skill and competency of the driver, safety of the journey, and safety of the vehicle. Fatigue causes more than 20 per cent of motorway accidents and is the most frequent cause of accidental death of truck drivers. The presentation also discussed vehicle data recorders, driving immersion, and Driving Safety Program results. Journey management, driver training, vehicle inspections and policies, and statistics on vehicle incidents were also provided. The presentation revealed that a lack of pre-trip journey management, inadequate training or recall of training, and not following safe driving practices were major contributors to incident occurrences. It also revealed that traveling on gravel or ice and avoiding wildlife were factors in many vehicle incidents. 1 tab., 1 fig.

Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

Science.gov (United States)

2014-01-01

Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical

Preclinical models in radiation oncology

Directory of Open Access Journals (Sweden)

Kahn Jenna

2012-12-01

Full Text Available Abstract As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.

Verification of MCNP6.2 for Nuclear Criticality Safety Applications

Energy Technology Data Exchange (ETDEWEB)

Brown, Forrest B. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Rising, Michael Evan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Alwin, Jennifer Louise [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2017-05-10

Several suites of verification/validation benchmark problems were run in early 2017 to verify that the new production release of MCNP6.2 performs correctly for nuclear criticality safety applications (NCS). MCNP6.2 results for several NCS validation suites were compared to the results from MCNP6.1 [1] and MCNP6.1.1 [2]. MCNP6.1 is the production version of MCNP® released in 2013, and MCNP6.1.1 is the update released in 2014. MCNP6.2 includes all of the standard features for NCS calculations that have been available for the past 15 years, along with new features for sensitivity-uncertainty based methods for NCS validation [3]. Results from the benchmark suites were compared with results from previous verification testing [4-8]. Criticality safety analysts should consider testing MCNP6.2 on their particular problems and validation suites. No further development of MCNP5 is planned. MCNP6.1 is now 4 years old, and MCNP6.1.1 is now 3 years old. In general, released versions of MCNP are supported only for about 5 years, due to resource limitations. All future MCNP improvements, bug fixes, user support, and new capabilities are targeted only to MCNP6.2 and beyond.

Cognitive reserve and lifestyle: moving towards preclinical Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Eider M Arenaza-Urquijo

2015-08-01

Full Text Available The large majority of neuroimaging studies in Alzheimer’s disease (AD patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis. This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e. through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older people that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. Here, we review current findings on the effects of lifestyle factors on AD neuroimaging biomarkers in cognitively normal older people. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory pathways. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory pathways in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage.

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

Science.gov (United States)

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

Second-generation magnesium scaffold Magmaris: device design and preclinical evaluation in a porcine coronary artery model.

Science.gov (United States)

Waksman, Ron; Zumstein, Philine; Pritsch, Martin; Wittchow, Eric; Haude, Michael; Lapointe-Corriveau, Capucine; Leclerc, Guy; Joner, Michael

2017-07-20

The second-generation drug-eluting absorbable magnesium scaffold Magmaris, recently introduced for the treatment of obstructive coronary atherosclerotic lesions, suggests a good safety profile, but preclinical assessment is important for predicting clinical performance. The aim of the present study was to assess subacute and long-term safety as well as pharmacokinetic properties of the Magmaris compared with a current-generation metallic DES and an approved BRS in porcine and rabbit animal models. Ninety Magmaris scaffolds were implanted into non-diseased porcine and rabbit models. A bioresorbable vascular scaffold (Absorb) and a permanent drug-eluting stent (XIENCE Xpedition) served as controls. Scanning electron microscopy showed increased endothelialisation and decreased thrombus formation at three and 28 days in the Magmaris group compared with the Absorb group. In the XIENCE group, inflammation exceeded the level in the Magmaris group at 365 and 730 days. Neointimal growth was greater in the Magmaris group than in the XIENCE group. Late lumen loss decreased over time in both groups. Optical coherence tomography (OCT) showed stable luminal dimensions in both the Magmaris and XIENCE groups. Pharmacokinetic studies demonstrated a retarded elution profile in the Magmaris group with 69.4% of sirolimus released at 90 days. Preclinical results suggest that the Magmaris has a favourable safety profile with advanced healing relative to benchmark, low acute thrombogenicity, and absence of excessive lumen loss up to two years. These results support clinical application of Magmaris for human use.

ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

Directory of Open Access Journals (Sweden)

F. Noël

Full Text Available This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity. LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min. LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s, indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min, and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

Evaluation of focused multipolar stimulation for cochlear implants: a preclinical safety study

Science.gov (United States)

Shepherd, Robert K.; Wise, Andrew K.; Enke, Ya Lang; Carter, Paul M.; Fallon, James B.

2017-08-01

Objective. Cochlear implants (CIs) have a limited number of independent stimulation channels due to the highly conductive nature of the fluid-filled cochlea. Attempts to develop highly focused stimulation to improve speech perception in CI users includes the use of simultaneous stimulation via multiple current sources. Focused multipolar (FMP) stimulation is an example of this approach and has been shown to reduce interaction between stimulating channels. However, compared with conventional biphasic current pulses generated from a single current source, FMP is a complex stimulus that includes extended periods of stimulation before charge recovery is achieved, raising questions on whether chronic stimulation with this strategy is safe. The present study evaluated the long-term safety of intracochlear stimulation using FMP in a preclinical animal model of profound deafness. Approach. Six cats were bilaterally implanted with scala tympani electrode arrays two months after deafening, and received continuous unilateral FMP stimulation at levels that evoked a behavioural response for periods of up to 182 d. Electrode impedance, electrically-evoked compound action potentials (ECAPs) and auditory brainstem responses (EABRs) were monitored periodically over the course of the stimulation program from both the stimulated and contralateral control cochleae. On completion of the stimulation program cochleae were examined histologically and the electrode arrays were evaluated for evidence of platinum (Pt) corrosion. Main results. There was no significant difference in electrode impedance between control and chronically stimulated electrodes following long-term FMP stimulation. Moreover, there was no significant difference between ECAP and EABR thresholds evoked from control or stimulated cochleae at either the onset of stimulation or at completion of the stimulation program. Chronic FMP stimulation had no effect on spiral ganglion neuron (SGN) survival when compared with

Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

Science.gov (United States)

Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

2015-10-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. ©2015 American Association for Cancer Research.

Challenges for Preclinical Investigations of Human Biofield Modalities

Science.gov (United States)

Gronowicz, Gloria; Bengston, William

2015-01-01

Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

U.S. ALMR safety approach and licensing status

International Nuclear Information System (INIS)

Hardy, R.W.; Gyorey, G.L.

1991-01-01

The Advanced Liquid Metal Cooled Reactor in the United States is based on the PRISM concept originated by General Electric. This concept features a compact modular system suitable for factory fabrication, and a high degree of passive and natural safety characteristics. The safety approach emphasizes accident prevention, backed up by accident mitigation as required. First-round safety evaluations by the U.S. regulators have found that the design provides passive, natural and other desirable features enhancing the safety of the power plant. Licensing review continuing. (author)

Preclinical evaluation of BAY 1075553, a novel 18F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer

International Nuclear Information System (INIS)

Lesche, Ralf; Kettschau, Georg; Gromov, Alexey V.; Boehnke, Niels; Borkowski, Sandra; Moenning, Ursula; Doehr, Olaf; Graham, Keith; Hegele-Hartung, Christa; Dinkelborg, Ludger M.

2014-01-01

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[ 18 F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel 18 F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor. The 18 F-radiolabelled stereoisomers of 2-[ 18 F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl ]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553. BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non

SKI's and SSI's review of SKB's safety report SR-Can

Energy Technology Data Exchange (ETDEWEB)

Dverstorp, Bjoern; Stroemberg, Bo (and others)

2008-03-15

This report summarises SKI's and SSI's joint review of the Swedish Nuclear Fuel and Waste Management Co's (SKB) safety report SR-Can (SKB TR-06-09). SR-Can is the first assessment of post-closure safety for a KBS-3 spent nuclear fuel repository at the candidate sites Forsmark and Laxemar, respectively. The analysis builds on data from the initial stage of SKB's surface-based site investigations and on data from full-scale manufacturing and testing of buffer and copper canisters. SR-Can can be regarded as a preliminary version of the safety report that will be required in connection with SKB's planned licence application for a final repository in late 2009. The main purpose of the authorities' review is to provide feedback to SKB on their safety reporting as part of the pre-licensing consultation process. However, SR-Can is not part of the formal licensing process. In support of the authorities' review three international peer review teams were set up to make independent reviews of SR-Can from three perspectives, namely integration of site data, representation of the engineered barriers and safety assessment methodology, respectively. Further, several external experts and consultants have been engaged to review detailed technical and scientific issues in SR-Can. The municipalities of Oesthammar and Oskarshamn where SKB is conducting site investigations, as well NGOs involved in SKB's programme, have been invited to provide their views on SR-Can as input to the authorities' review. Finally, the authorities themselves, and with the help of consultants, have used independent models to reproduce part of SKB's calculations and to make complementary calculations. All supporting review documents are published in SKI's and SSI's report series. The main findings of the review are: -SKB's safety assessment methodology is overall in accordance with applicable regulations, but part of the methodology needs to be

Nuclear criticality safety aspects of gaseous uranium hexafluoride (UF6) in the diffusion cascade

International Nuclear Information System (INIS)

Huffer, J.E.

1997-04-01

This paper determines the nuclear safety of gaseous UF 6 in the current Gaseous Diffusion Cascade and auxiliary systems. The actual plant safety system settings for pressure trip points are used to determine the maximum amount of HF moderation in the process gas, as well as the corresponding atomic number densities. These inputs are used in KENO V.a criticality safety models which are sized to the actual plant equipment. The ENO V.a calculation results confirm nuclear safety of gaseous UF 6 in plant operations

Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Science.gov (United States)

Wood, Michael R; Noetzel, Meredith J; Melancon, Bruce J; Poslusney, Michael S; Nance, Kellie D; Hurtado, Miguel A; Luscombe, Vincent B; Weiner, Rebecca L; Rodriguez, Alice L; Lamsal, Atin; Chang, Sichen; Bubser, Michael; Blobaum, Anna L; Engers, Darren W; Niswender, Colleen M; Jones, Carrie K; Brandon, Nicholas J; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

2017-02-09

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M 4 ) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M 4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Preclinical evaluation of [{sup 18}F]2FNQ1P as the first fluorinated serotonin 5-HT{sub 6} radioligand for PET imaging

Energy Technology Data Exchange (ETDEWEB)

Becker, Guillaume [Universite Claude Bernard Lyon 1, CNRS INSERM, Lyon Neuroscience Research Center, Lyon (France); Hospices Civils de Lyon, Lyon (France); Colomb, Julie [Universite Claude Bernard Lyon 1, CNRS, Institute of Chemistry and Biochemistry, Villeurbanne (France); Sgambato-Faure, Veronique; Tremblay, Leon [Universite Claude Bernard Lyon 1, CNRS, Cognitive Neuroscience Center, Bron (France); Billard, Thierry [Universite Claude Bernard Lyon 1, CNRS, Institute of Chemistry and Biochemistry, Villeurbanne (France); CERMEP-Imaging Platform, Groupement Hospitalier Est, Lyon (France); Zimmer, Luc [Universite Claude Bernard Lyon 1, CNRS INSERM, Lyon Neuroscience Research Center, Lyon (France); Hospices Civils de Lyon, Lyon (France); CERMEP-Imaging Platform, Groupement Hospitalier Est, Lyon (France)

2014-10-21

Brain serotonin 6 receptor (5-HT{sub 6}) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HT{sub 6} {sup 18}F-labelled radiotracer. 2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT{sub 6} affinity and selectivity and was radiolabelled by {sup 18}F nucleophilic substitution. The cerebral distribution of [{sup 18}F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys. The chemical and radiochemical purities of [{sup 18}F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT{sub 6} antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [{sup 18}F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT{sub 6} receptor antagonist, SB258585. 2FNQ1P was initially selected because of its suitable characteristics for 5-HT{sub 6} receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [{sup 18}F]2FNQ1P appeared to be a suitable 5-HT{sub 6} PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT{sub 6} PET radiotracer. (orig.)

Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

Directory of Open Access Journals (Sweden)

Susanne Krasemann

Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

The Inspector General's report on Nuclear Safety and Radiation Protection 2013

International Nuclear Information System (INIS)

2014-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's view of 2013 2 - Safety in operation: good standing of results; 3 - Management of safety priority; 4 - Occupational safety: managers mobilization is necessary in France; 5 - Radiation protection: a new dynamics to initiate; 6 - Maintenance: regaining the essentials for the great careening; 7 - Fostering occupations to improve safety; 8 - A new momentum to the EPRs; 9 - Nuclear fuel, a major contribution to safety; 10 - Research-development: a lever to anticipate; 11 - Japan: safety under reconstruction; 12 - Noteworthy operational events; 13- Appendices: Results for the nuclear fleets (EDF SA, EDF Energy; Maps of the nuclear power plants(EDF SA, EDF Energy); Key dates for the nuclear units (EDF SA, EDF Energy); Abbreviations

The application of a "6S Lean" initiative to improve workflow for emergency eye examination rooms.

Science.gov (United States)

Nazarali, Samir; Rayat, Jaspreet; Salmonson, Hilary; Moss, Theodora; Mathura, Pamela; Damji, Karim F

2017-10-01

Ophthalmology residents on call at the Royal Alexandra Hospital identified workplace disorganization and lack of standardization in emergency eye examination rooms as an impediment to efficient patient treatment. The aim of the study was to use the "6S Lean" model to improve workflow in eye examination rooms at the Royal Alexandra Hospital. With the assistance of quality improvement consultants, the "6S Lean" model was applied to the current operation of the emergency eye clinic examination rooms. This model, considering 8 waste categories, was then used to recommend and implement changes to the examination rooms and to workplace protocols to enhance efficiency and safety. Eye examination rooms were improved with regards to setup, organization of supplies, inventory control, and maintenance. All targets were achieved, and the 5S audit checklist score increased by 33 points from 44 to 77. Implementation of the 6S methodology is a simple approach that removes inefficiencies from the workplace. The ophthalmology clinic removed waste from all 8 waste categories, increased audit results, mitigated patient and resident safety risks, and ultimately redirected resident time back to patient care delivery. Copyright © 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Preclinical evaluation of BAY 1075553, a novel {sup 18}F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Lesche, Ralf; Kettschau, Georg; Gromov, Alexey V.; Boehnke, Niels; Borkowski, Sandra; Moenning, Ursula; Doehr, Olaf; Graham, Keith [Global Drug Discovery, Bayer Healthcare, Berlin, Germany, Berlin (Germany); Hegele-Hartung, Christa [Global Drug Discovery, Bayer Healthcare, Wuppertal, Germany, Wuppertal (Germany); Dinkelborg, Ludger M. [Global Drug Discovery, Bayer Healthcare, Berlin, Germany, Berlin (Germany); Piramal Imaging GmbH, Berlin (Germany)

2014-01-15

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[{sup 18}F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel {sup 18}F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor. The {sup 18}F-radiolabelled stereoisomers of 2-[{sup 18}F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl ]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553. BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 m

Reload safety evaluation report for Ulchin nuclear power plant unit 1, cycle 6

Energy Technology Data Exchange (ETDEWEB)

Lee, Won Jae; Kim, Yong Rae; Kim, Oh Hwan; Kwon, Hyuk Sung; Yoon, Han Young; Choi, Han Rim; Ku, Dong Uk [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

1993-11-01

This report presents a reload safety evaluation for Ulchin 1, cycle 6 and demonstrates that the reactor core being fully composed of KOFA as described in this report will not adversely affect the safety of the public and the plant. All of the accidents comprising the licensing bases which could potentially be affected by the fuel reload have been reviewed for the cycle 6 core and results are described in this report. (Author) 1 ref., 5 figs., 6 tabs.

Reload safety evaluation report for Ulchin nuclear power plant unit 1, cycle 6

International Nuclear Information System (INIS)

Lee, Won Jae; Kim, Yong Rae; Kim, Oh Hwan; Kwon, Hyuk Sung; Yoon, Han Young; Choi, Han Rim; Ku, Dong Uk

1993-11-01

This report presents a reload safety evaluation for Ulchin 1, cycle 6 and demonstrates that the reactor core being fully composed of KOFA as described in this report will not adversely affect the safety of the public and the plant. All of the accidents comprising the licensing bases which could potentially be affected by the fuel reload have been reviewed for the cycle 6 core and results are described in this report. (Author) 1 ref., 5 figs., 6 tabs

Index to Nuclear Safety. A technical progress review by chronology, permuted title, and author. Vol. 11, No. 1 through Vol. 15, No. 6

International Nuclear Information System (INIS)

Cottrell, W.B.; Klein, A.

1975-04-01

This issue of the Index to Nuclear Safety covers only articles included in Nuclear Safety, Vol. 11, No. 1, through Vol. 15, No. 6. This index is presented in three sections as follows: Chronological List of Articles by Volume; Permuted Title (KWIC) Index; and Author Index. (U.S.)

Safety measure S 05 'Sump clogging risk'

International Nuclear Information System (INIS)

Murani, J.

1997-01-01

This paper dealt with the safety measure S 05 'Sump clogging risk'. Problem specification contains: (1) to determine the effective strainer surface needed to be available in order to assure sufficient coolant volumes for a reliable operation of emergency systems; (2) to determine quantity and structure of insulation material which can be dislodged and can induce strained clogging; (3) to verify properties of insulation material with regard to its thermal degradation as a result of a long-term reactor unit operation; (4) to design and erect strainers so to assure sufficient congestion of emergency pump intake lines in post-accident regimes; (5) to design seismically resistant strainers with a capability to resist dynamic impacts from adjacent piping; (6) to assure monitoring of the strainer condition in real time with signals sent to the main control room

Preclinical safety, toxicology, and biodistribution study of adenoviral gene therapy with sVEGFR-2 and sVEGFR-3 combined with chemotherapy for ovarian cancer.

Science.gov (United States)

Tuppurainen, Laura; Sallinen, Hanna; Kokki, Emmi; Koponen, Jonna; Anttila, Maarit; Pulkkinen, Kati; Heikura, Tommi; Toivanen, Pyry; Hämäläinen, Kirsi; Kosma, Veli-Matti; Heinonen, Seppo; Alitalo, Kari; Ylä-Herttuala, Seppo

2013-03-01

Abstract Antiangiogenic and antilymphangiogenic gene therapy with soluble vascular endothelial growth factor receptor-2 (VEGFR-2) and soluble VEGFR-3 in combination with chemotherapy is a potential new treatment for ovarian carcinoma. We evaluated the safety, toxicology, and biodistribution of intravenous AdsVEGFR-2 and AdsVEGFR-3 combined with chemotherapy in healthy rats (n=90) before entering a clinical setting. The study groups were: AdLacZ and AdLacZ with chemotherapy as control groups, low dose AdsVEGFR-2 and AdsVEGFR-3, high dose AdsVEGFR-2 and AdsVEGFR-3, combination of low dose AdsVEGFR-2 and AdsVEGFR-3 with chemotherapy, combination of high dose AdsVEGFR-2 and AdVEGFR-3 with chemotherapy, and chemotherapy only. The follow-up time was 4 weeks. Safety and toxicology were assessed by monitoring the clinical status of the animals and by histological, hematological, and clinical chemistry parameters. For the biodistribution studies, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used. Low dose (2×10(10) vp) AdsVEGFR-2 and AdsVEGFR-3 gene therapy was well tolerated, even when gene therapy was combined with chemotherapy. Notably, only transient elevation of liver enzymes and mild regenerative changes were seen in liver after the gene transfer in the groups that received high doses (2×10(11) vp) of AdsVEGFR-2 and AdsVEGFR-3 with or without chemotherapy. No life-threatening adverse effects were noticed in any of the treatment groups. The highest protein concentration of soluble VEGFR-2 (sVEGFR-2) in circulation was seen 1 week after the gene transfer. The combination of chemotherapy to gene therapy seemed to prolong the time of detectable transgene protein at least 1 week in the circulation. The expression of AdsVEGFR-2 and AdsVEGFR-3 transgenes was mainly seen in the liver and spleen as detected by qRT-PCR. According to these results, AdsVEGFR-2 and AdsVEGFR-3 gene therapy combined with

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.

Science.gov (United States)

Tiphaine, Adam de Beaumais; Hjalgrim, Lisa Lynqsie; Nersting, Jacob; Breitkreutz, Joerg; Nelken, Brigitte; Schrappe, Martin; Stanulla, Martin; Thomas, Caroline; Bertrand, Yves; Leverger, Guy; Baruchel, André; Schmiegelow, Kjeld; Jacqz-Aigrain, Evelyne

2016-02-15

6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination. The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred. Pharmacokinetic, palatability and safety data support the use of Loulla in children. Copyright © 2015 Elsevier B.V. All rights reserved.

Proceedings of the 6. Argentine congress on radiation protection and nuclear safety

International Nuclear Information System (INIS)

1998-01-01

The 6th Argentine Congress on Radiation Protection and Nuclear Safety was organized by the Radioprotection Argentine Society, in Buenos Aires, between the 22 and 24 of september of 1998. In this event, were presented almost 66 papers in the following sessions, about these subjects: 1.- Safety in nuclear installations. 2.- Control of nuclear material and physical protection of nuclear installations. 3.- Programs of quality assurance. 4.- Training, technical information and public information. 5.- Physical dosimetry. 6.- Physical dosimetry and occupational radiation protection. 7.- Exposure of the natural radiation. 8.- Environmental radiological safety. 9.- Biological effects of the ionizing radiations and biological dosimetry. 10.- Radiological protection of the medical practice and the radiological emergencies. 11.- Radioactive wastes management. 12.- Transport of radioactive materials

Quantitative angiographic anatomy of the renal arteries and adjacent aorta in the swine for preclinical studies of intravascular catheterization devices.

Science.gov (United States)

Sakaoka, Atsushi; Koshimizu, Masafumi; Nakamura, Shintaro; Matsumura, Kiyoshi

2018-05-10

Swine are the most common animal model in preclinical studies of cardiovascular devices. Because of the recent trend for development of new devices for percutaneous catheterization, especially for the renal arteries (RAs), we examined the quantitative anatomical dimensions of the RAs and adjacent aorta in swine. Angiographic images were analyzed in 66 female Yorkshire/Landrace crossbred swine. The diameter of both the right and left main RA was 5.4 ± 0.6 mm. The length of the right main RA was significantly longer than that of the left (29.8 ± 7.5 mm vs. 20.6 ± 5.4 mm, respectively; Pswine are an appropriate animal model for assessing the safety of, and determining optimal design of, catheter devices for RAs in simulated clinical use. However, there were species differences in the branching angle and adjacent aorta diameter, suggesting that swine models alone are inadequate to assess the delivery performance of catheter devices for RAs.

Preclinical electrogastrography in experimental pigs

Science.gov (United States)

Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

2010-01-01

Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

Economics of the specification 6M safety re-evaluation and regulatory requirements

International Nuclear Information System (INIS)

Hopper, C.M.

1985-01-01

The objective of this work was to examine the potential economic impact of the DOT Specification 6M criticality safety re-evaluation and regulatory requirements. The examination was based upon comparative analyses of current authorized fissile material load limits for the 6M, current Federal regulations (and interpretations) limiting the contents of Type B fissile material packages, limiting aggregates of fissile material packages, and recent proposed fissile material mass limits derived from specialized criticality safety analyses of the 6M package. The work examines influences on cost in transportation, handling, and storage of fissile materials. Depending upon facility throughput requirements (and assumed incremental costs of fissile material packaging, storage, and transport), operating, facility storage capacity, and transportation costs can be reduced significantly. As an example of the pricing algorithm application based upon reasonable cost influences, the magnitude of the first year cost reductions could extend beyond four times the cost of the packaging nuclear criticality safety re-evaluation. 1 tab

Changing the Safety and Mission Assurance (S and MA) Paradigm

Science.gov (United States)

Malone, Roy W.; Safie, Fayssal M.

2010-01-01

This slide presentation reviews the change in the work and impact of the Safety and Mission Assurance directorate at Marshall Space Flight Center. It reviews the background and the reasons given for a strong Safety & Mission Assurance presence in all planning for space flight. This was pointed out by the Rogers Commission Report after the Space Challenger accident, by the Columbia Accident Investigation Board (CAIB) and by a 2006 NASA Exploration Safety Study (NESS) Team. The overall objective of the work in this area was to improve and maintain S&MA expertise and skills. Training for this work was improved and the S&MA organization was reorganized. This has resulted in a paradigm shift for NASA's safety efforts, which is described. The presentation then reviews the impact of the new S&MA work in the Ares I design and development.

The Inspector General's report on Nuclear Safety and Radiation Protection 2016

International Nuclear Information System (INIS)

2017-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's view of 2016; 2 - Operational safety: encouraging results; 3 - High-profile focus on safety; 4 - Risk prevention: effort must be intensified; 5 - Team skills and commitment; 6 - Simplification; 7 - Maintenance quality; 8 - Nuclear fuel; 9 - New build; 10 - Protection against site security threats; 11 - Appendices

Safety report on WWR-S reactor

International Nuclear Information System (INIS)

Horyna, J.; Kaisler, L.; Listik, E.

1981-04-01

The present Safety Report of the WWR-S reactor summarizes findings obtained during the trial and partially also permanent operation of the reactor after two stages of its reconstruction implemented between 1974 and 1976. Most data are presented necessary for assessing probable risks of possible accident conditions whose consequences pose health hazards to individuals of the population, radiation personnel and the facilities themselves. Attention is devoted to the description of the locality, to components and systems, heat removal from the core, design aspects, the quality of new and old parts of the technological circuits, the systems of protection and control, the emergency core cooling system, the problems of radiation safety, and to the safety analyses of the abnormal states envisaged. The Report was compiled with regard to IAEA and CMEA recommendations concerning safe operation of research reactors and to the recommendations and binding decisions of the Czechoslovak Atomic Energy Commission. (author)

Using Rose’s metal alloy as a pinhole collimator material in preclinical small-animal imaging: A Monte Carlo evaluation

International Nuclear Information System (INIS)

Peterson, Mikael; Strand, Sven-Erik; Ljungberg, Michael

2015-01-01

Purpose: Pinhole collimation is the most common method of high-resolution preclinical single photon emission computed tomography imaging. The collimators are usually constructed from dense materials with high atomic numbers, such as gold and platinum, which are expensive and not always flexible in the fabrication step. In this work, the authors have investigated the properties of a fusible alloy called Rose’s metal and its potential in pinhole preclinical imaging. When compared to current standard pinhole materials such as gold and platinum, Rose’s metal has a lower density and a relatively low effective atomic number. However, it is inexpensive, has a low melting point, and does not contract when solidifying. Once cast, the piece can be machined with high precision. The aim of this study was to evaluate the imaging properties for Rose’s metal and compare them with those of standard materials. Methods: After validating their Monte Carlo code by comparing its results with published data and the results from analytical calculations, they investigated different pinhole geometries by varying the collimator material, acceptance angle, aperture diameter, and photon incident angle. The penetration-to-scatter and penetration-to-total component ratios, sensitivity, and the spatial resolution were determined for gold, tungsten, and Rose’s metal for two radionuclides, 99 Tc m and 125 I. Results: The Rose’s metal pinhole-imaging simulations show higher penetration/total and scatter/total ratios. For example, the penetration/total is 50% for gold and 75% for Rose’s metal when simulating 99 Tc m with a 0.3 mm aperture diameter and a 60° acceptance angle. However, the degradation in spatial resolution remained below 10% relative to the spatial resolution for gold for acceptance angles below 40° and aperture diameters larger than 0.5 mm. Conclusions: Extra penetration and scatter associated with Rose’s metal contribute to degradation in the spatial resolution, but

Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

Science.gov (United States)

Healing, Guy; Sulemann, Tabassum; Cotton, Peter; Harris, Jayne; Hargreaves, Adam; Finney, Rowena; Kirk, Sarah; Schramm, Carolin; Garner, Clare; Pivette, Perrine; Burdett, Lisa

2016-01-01

Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation. Copyright © 2015 John Wiley & Sons, Ltd.

Deep Machine Learning Application to the Detection of Preclinical Neurodegenerative Diseases of Aging

Directory of Open Access Journals (Sweden)

Mathew J. Summers

2017-12-01

Full Text Available Artificial intelligence (AI deep learning protocols offer solutions to complex data processing and analysis. Increasingly these solutions are being applied in the healthcare field, most commonly in processing complex medical imaging data used for diagnosis. Current models apply AI to screening populations of patients for markers of disease and report detection accuracy rates exceeding those of human data screening. In this paper, we explore an alternate model for AI deployment, that of monitoring and analysing an individual’s level of function over time. In adopting this approach, we propose that AI may provide highly accurate and reliable detection of preclinical disease states associated with aging-related neurodegenerative diseases. One of the key challenges facing clinical detection of preclinical phases of diseases such as dementia is the high degree of inter-individual variability in aging-related changes to cognitive function. AI based monitoring of an individual over time offers the potential for the early detection of change in function for the individual, rather than relying on comparing the individual’s performance to population norms. We explore an approach to developing AI platforms for individual monitoring and preclinical disease detection and examine the potential benefits to the stakeholders in this technological development.

Nuclear criticality safety aspects of gaseous uranium hexafluoride (UF{sub 6}) in the diffusion cascade

Energy Technology Data Exchange (ETDEWEB)

Huffer, J.E. [Parallax, Inc., Atlanta, GA (United States)

1997-04-01

This paper determines the nuclear safety of gaseous UF{sub 6} in the current Gaseous Diffusion Cascade and auxiliary systems. The actual plant safety system settings for pressure trip points are used to determine the maximum amount of HF moderation in the process gas, as well as the corresponding atomic number densities. These inputs are used in KENO V.a criticality safety models which are sized to the actual plant equipment. The ENO V.a calculation results confirm nuclear safety of gaseous UF{sub 6} in plant operations..

U.S. safety legislation a bonanza for suppliers

Energy Technology Data Exchange (ETDEWEB)

Tollinsky, N.

2007-09-01

New safety requirements for coal mines in the United States requires the installation of wireless two-way tracking systems. The Office of Miners' Health Safety and Training has demanded that the owners of West Virginia's 170 coal mines submit plans by July 31, 2007 that describe how and when they intend to procure communication and electonic tracking systems. An estimated 430 additional coal mines across the U.S. will be required to file their plans concerning communications and tracking equipment by June 15, 2009, according to the U.S. federal government's Mine Improvement and New Emergency Response (MINER) Act. Radio communication and leaky feeder systems are routine in Canada's hard rock mines. Several Ontario-based supply companies are well placed to take advantage of this opportunity. The plans of three Ontario suppliers regarding proposed communications systems, quotations, costs, and tracking are outlined. 3 figs.

Preclinical and Clinical Development of a YFV 17 D-Based Chimeric Vaccine against West Nile Virus

Directory of Open Access Journals (Sweden)

Gustavo H. Dayan

2013-12-01

Full Text Available Substantial success has been achieved in the development and implementation of West Nile (WN vaccines for horses; however, no human WN vaccines are approved. This review focuses on the construction, pre-clinical and clinical characterization of ChimeriVax-WN02 for humans, a live chimeric vaccine composed of a yellow fever (YF 17D virus in which the prM-E envelope protein genes are replaced with the corresponding genes of the WN NY99 virus. Pre-clinical studies demonstrated that ChimeriVax-WN02 was significantly less neurovirulent than YF 17D in mice and rhesus and cynomolgus monkeys. The vaccine elicited neutralizing antibody titers after inoculation in hamsters and monkeys and protected immunized animals from lethal challenge including intracerebral inoculation of high dose of WN NY99 virus. Safety, viremia and immunogenicity of ChimeriVax-WN02 were assessed in one phase I study and in two phase II clinical trials. No safety signals were detected in the three clinical trials with no remarkable differences in incidence of adverse events (AEs between vaccine and placebo recipients. Viremia was transient and the mean viremia levels were low. The vaccine elicited strong and durable neutralizing antibody and cytotoxic T cell responses. WN epidemiology impedes a classical licensure pathway; therefore, innovative licensure strategies should be explored.

Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk.

Science.gov (United States)

Gintant, Gary A

2008-08-01

The successful development of novel drugs requires the ability to detect (and avoid) compounds that may provoke Torsades-de-Pointes (TdeP) arrhythmia while endorsing those compounds with minimal torsadogenic risk. As TdeP is a rare arrhythmia not readily observed during clinical or post-marketing studies, numerous preclinical models are employed to assess delayed or altered ventricular repolarization (surrogate markers linked to enhanced proarrhythmic risk). This review evaluates the advantages and limitations of selected preclinical models (ranging from the simplest cellular hERG current assay to the more complex in vitro perfused ventricular wedge and Langendorff heart preparations and in vivo chronic atrio-ventricular (AV)-node block model). Specific attention is paid to the utility of concentration-response relationships and "risk signatures" derived from these studies, with the intention of moving beyond predicting clinical QT prolongation and towards prediction of TdeP risk. While the more complex proarrhythmia models may be suited to addressing questionable or conflicting proarrhythmic signals obtained with simpler preclinical assays, further benchmarking of proarrhythmia models is required for their use in the robust evaluation of safety margins. In the future, these models may be able to reduce unwarranted attrition of evolving compounds while becoming pivotal in the balanced integrated risk assessment of advancing compounds.

Efficacy and Safety of Pomegranate Medicinal Products for Cancer

OpenAIRE

Vlachojannis, Christian; Zimmermann, Benno F.; Chrubasik-Hausmann, Sigrun

2015-01-01

Preclinical in vitro and in vivo studies demonstrate potent effects of pomegranate preparations in cancer cell lines and animal models with chemically induced cancers. We have carried out one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety. The PubMed search provided 162 references for pomegranate and cancer and 122 references for pomegranate and safety/toxicity. We identified 4 clinical studies investigating 3 pomegranate ...

Probability safety assessment of the Kozloduy-5 and Kozloduy-6 reactors

Energy Technology Data Exchange (ETDEWEB)

Boyadzhiev, A; Manchev, B [Risk Engineering Ltd., Sofia (Bulgaria)

1996-12-31

A probability safety assessment (PSA) of Level 1 (assessment of plant failures leading to the determination of core damage frequency) has been carried out for the NPP Kozloduy Units 5 and 6 (reactors WWER-1000). The scope of the study includes all significant accident initiators including seismic (earthquake) and fire initiators. Event trees for all initiators and fault trees for front line systems, support systems and major safety systems have been built. A distribution of the different initiators has been established as follows: internal initiators - 85%, seismic initiators - 5%, fire initiators- 10%. The loss of offsite power was identified as main contributor from the internal initiators with frequency 1,1.10{sup -4}/y. It is concluded that the safety functions of WWER-1000 are adequately covered by the safety systems. 4 refs., 2 tabs.

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

Energy Technology Data Exchange (ETDEWEB)

Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com [Genentech, Inc., South San Francisco, CA (United States); Flagella, Kelly; Beyer, Joseph [Genentech, Inc., South San Francisco, CA (United States); Tibbitts, Jay [UCB, Brussels (Belgium); Kaur, Surinder; Saad, Ola; Yi, Joo-Hee; Girish, Sandhya; Dybdal, Noel; Reynolds, Theresa [Genentech, Inc., South San Francisco, CA (United States)

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and pharmacologic

Reload safety evaluation report for Ulchin nuclear power plant unit 2, cycle 6

International Nuclear Information System (INIS)

Chung, Jin Gon; Park, Jin Ha; Kim, Oh Hwan; Oh, Dong Seok; Kim, Du Ill; Choi, Han Rim; Ku, Dong Uk; Bae, Hoo Gun

1994-07-01

This report presents a reload safety evaluation for Ulchin-2, cycle 6 and demonstrates that the core being composed of various fuel types as described in the report will not adversely affect the safety of the public and the plant. All of the accidents comprising the licensing bases which could potentially be affected by the fuel reload have been reviewed for the cycle 6 core and results are described in the report. (Author) 1 ref., 3 figs., 7 tabs

EC6 safety enhancement - including impact of Fukushima lessons learned

Energy Technology Data Exchange (ETDEWEB)

Yu, S.; Zemdegs, R.; Boyle, S.; Soulard, M., E-mail: stephen.yu@candu.com [Candu Energy Inc., Mississauga, Ontario (Canada)

2012-09-15

The Enhanced CANDU 6 (EC6) is the new Generation III CANDU reactor design that meets the most up to date regulatory requirements and customer expectations. EC6 builds on the proven high performance design inch as the Qinshan CANDU 6 units and has made improvements to safety and operational performance, and has incorporated extensive operational feedback including Fukushima. The Fukushima Dai-ichi March 11, 2011 event has demonstrated the importance of defence-in-depth considerations for beyond-design basis events, including severe accidents. The EC6 design is based on the defence-in-depth principles and provides further design features that address the lessons learned from Fukushima. (author)

Cardiac safety strategies. 25-26 October 2005, the Radisson SAS Hotel, Nice, France.

Science.gov (United States)

Hanton, Gilles; Tilbury, Lorraine

2006-03-01

This meeting was organised by IIR Life Sciences. It was chaired by Brian Guth, (head of General Pharmacology at Boehringer Ingelheim Pharma) and brought together scientists and clinicians from the pharmaceutical industry, university and regulatory agencies. The meeting presented emerging trends in cardiac safety, including its regulatory context pertaining to ICH S7A, S7B and E14. ICH S7A and S7B highlight the importance of the hERG test and telemetric studies in non-rodents. ICH E14 describes the clinical 'thorough QT study' that is required by the FDA for any new drug. Marked physiological variability in QT interval over time can be observed, partly as a result of fluctuation in autonomic tone. Beat-to-beat QT variability and T-wave morphology should be considered as a part of an integrated estimate of proarrhythmic risk. A case study illustrated the predictivity of preclinical data for proarrhythmic risk in humans, showing the importance of evaluating QT effects in patients to establish a safety margin.

Safety systems I/C reliability analysis of the Kozloduy NPP units 5 and 6; Analiz nadezhnosti KIP i sistem bezopasnosti pyatogo i shestogo bloka AEhS `Kozloduy`

Energy Technology Data Exchange (ETDEWEB)

Marinova, B [Risk Engineering Ltd., Sofia (Bulgaria)

1996-12-31

The purpose of the analysis is to assess the safety systems I/C equipment reliability of the Kozloduy-5 and the Kozloduy-6 reactors. The assessment of quantitative and qualitative effect of control systems unavailability on the safety systems unavailability is performed. The analysis is limited to the following systems: sprinkler management, low pressure emergency spray, emergency injection of boric acid, hydro accumulators, pressure compensator and compressed air. The code for probabilistic safety assessment PSAPACK has been used in analysis. Fault trees for all analysed safety systems have been constructed. Results indicates a high reliability of the safety systems management.

A preclinical simulated dataset of S-values and investigation of the impact of rescaled organ masses using the MOBY phantom

International Nuclear Information System (INIS)

Kostou, Theodora; Papadimitroulas, Panagiotis; Kagadis, George C; Loudos, George

2016-01-01

Nuclear medicine and radiation therapy, although well established, are still rapidly evolving, by exploiting animal models, aiming to define precise dosimetry in molecular imaging protocols. The purpose of the present study was to create a dataset based on the MOBY phantom for the calculation of organ-to-organ S-values of commonly used radionuclides. S-values of most crucial organs were calculated using specific biodistributions with a whole-body heterogeneous source. In order to determine the impact of the varying organs’ size on the S-values, and based on the fact that the anatomic properties of the organs are correlated with S-values, dosimetric calculations were performed by simulating the MOBY-version 2 model with different whole-body masses. The GATE Monte Carlo simulation toolkit was used for all simulations. Two mouse models of different body masses were developed to calculate the S-values of eight commonly used radioisotopes in nuclear imaging studies, namely 18 F, 68 Ga, 131 I, 111 In, 177 Lu, and 99m Tc, 90 Y and 188 Re. The impact of modified mass of the source organs in S-values was investigated with 18 F, and 90 Y in five different scalings of the source organs. Based on realistic preclinical exams, three mouse models, 22, 28 and 34 g, were used as input in the GATE simulator based on realistic preclinical exams to calculate the S-values of the six radioisotopes used. Whole body activity distributions were used as the source organ. The simulation procedure was validated in terms of extracting individual organ-to-organ S-values, and consequently in calculating the new S-values using a heterogeneous activity distribution as a source. The calculation was validated with 18 F source in a 30 g mouse model. For the generation of the new S-values with heterogeneous activity sources, four organs were used for the calculation of a single S-value. The absorbed doses per organ were compared with previously published reports. The validation procedure of 18 F

The Inspector General's report on Nuclear Safety and Radiation Protection 2017

International Nuclear Information System (INIS)

2018-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's view of 2017; 2 - Nuclear safety results; 3 - Nuclear safety priority affirmed; 4 - Risk prevention: important to remain vigilant; 5 - Adapting people skills; 6 - Operating experience: contrasting approaches; 7 - Operations fundamentals to be reaffirmed; 8 - Importance of working closely with contract partners; 9 - Engineering support for the French fleet and new-build projects; 10 - Spares: an area for greater engagement by owners on-site; 11 - Appendices

Safety and efficacy of opicinumab in acute optic neuritis (RENEW)

DEFF Research Database (Denmark)

Cadavid, Diego; Balcer, Laura J; Galetta, Steven L

2017-01-01

BACKGROUND: The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. METHODS: This randomised, doub...

Trend analysis of incidents involving setpoint drift in safety or safety/relief valves at U.S. LWRs

International Nuclear Information System (INIS)

Watanabe, Norio

2008-01-01

Since the beginning of the 1980's, in the United States, there have been many licensee event reports (LERs) involving setpoint drift in safety or safety/relief valves. The United States Nuclear Regulatory Commission (NRC) has issued a lot of generic communications on this issue and the industry has made efforts to resolve the issue. However, the NRC staff recently highlighted that over 70 LERs involved instances where safety or safety/relief valves failed to meet the allowed setpoint tolerance from 2001 through August 2006. In the present study, we analyzed the U.S. experience with setpoint drift in safety/relief valves (SRVs) at BWRs, pressurizer safety valves (PSVs), and main steam safety valves (MSSVs) at PWRs by reviewing approximately 90 LERs from 2000 to 2006 and examined the trend focusing on causes and setpoint deviation ranges. This study indicates that for SRVs and MSSVs, disc-seat bonding is a dominant cause of the setpoint drifting high and has a tendency to result in a relatively large deviation of the setpoint. This means that disc-seat bonding might be a safety concern from the view point of overpressure protection. For PSVs, the deviation of setpoints is generally small, although its causes are not specified in many instances. (author)

NCI Pediatric Preclinical Testing Consortium

Science.gov (United States)

NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

Enhanced CANDU 6 design assist probabilistic safety assessment results and insights

International Nuclear Information System (INIS)

Torabi, T.; Bettig, R.; Iliescu, P.; Robinson, J.; Santamaura, P.; Skorupska, B.; Tyagi, A.K.; Vencel, I.

2013-01-01

The Enhanced CANDU 6(EC6) is a 700 MWe reactor, which has evolved from the well-established CANDU line of reactors, which are heavy-water moderated, and heavy-water cooled horizontal pressure tube reactors, using natural uranium fuel. The EC6 design retains the generic CANDU design features, while incorporating innovations and state-of-the-art technologies to ensure competitiveness with other design with respect to operation, performance and economics. A design assist probabilistic safety assessment (PSA) was conducted during the design change phase of the project. The purpose of the assessment was to assess internal events during at-power operation and identify the design improvements and additional features needed to comply with the latest regulatory requirements in Canada and compete with other reactor designs, internationally. The PSA results show that the EC6 plant response to the postulated initiating events is well balanced, and the design meets its safety objectives. This paper summarizes the results and insights gained during the development of the PSA models for at-power internal events. (author)

Aviation’s Normal Operations Safety Audit: a safety management and educational tool for health care? Results of a small-scale trial

Directory of Open Access Journals (Sweden)

Bennett SA

2017-08-01

Full Text Available Simon A Bennett Civil Safety and Security Unit, School of Business, University of Leicester, Leicester, UK Background: A National Health Service (NHS contingent liability for medical error claims of over £26 billion. Objectives: To evaluate the safety management and educational benefits of adapting aviation’s Normal Operations Safety Audit (NOSA to health care. Methods: In vivo research, a NOSA was performed by medical students at an English NHS Trust. After receiving training from the author, the students spent 6 days gathering data under his supervision. Results: The data revealed a threat-rich environment, where errors – some consequential – were made (359 threats and 86 errors were recorded over 2 weeks. The students claimed that the exercise improved their observational, investigative, communication, teamworking and other nontechnical skills. Conclusion: NOSA is potentially an effective safety management and educational tool for health care. It is suggested that 1 the UK General Medical Council mandates that all medical students perform a NOSA in fulfillment of their degree; 2 the participating NHS Trusts be encouraged to act on students’ findings; and 3 the UK Department of Health adopts NOSA as a cornerstone risk assessment and management tool. Keywords: aviation, safety audit, health care, management benefits, educational benefits

A comparison of some Mexican/U.S. safety regulations

Energy Technology Data Exchange (ETDEWEB)

Bunner, W.R. [Training Associates, Columbus, OH (United States)

1994-12-31

In the US, safety and hygiene began to be enforced broadly with the formation of the US Department of Labor`s, Occupational Safety and Health Administration (OSHA) in 1970. In Mexico, the 1917 Constitution required companies to protect their workers against safety and hygiene hazards in the workplace. Additional requirements were added with the Federal Labor Law of 1931. General safety and hygiene regulations were added in 1934. Modern-day federal labor law in Mexico requires the creation of mixed safety and hygiene commissions in all industries. However, only about 114,000 workplaces have registered mixed commissions. In a similar vein, the most favored OSHA reform bill in the US proposes to require safety and health committees in all work places. At this time such committees are common in larger companies but not in smaller ones.

Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

Science.gov (United States)

Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

2015-01-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

MNR's role in public safety around dams

Energy Technology Data Exchange (ETDEWEB)

Keyes, Jennifer [Ministry of Natural Resources, Peterborough, ON (Canada)

2011-07-01

The Ministry of Natural Resources (MNR) is the largest dam owner in Ontario with around 400 dams located all across the province. MNR works to exercise stewardship of Ontario's water resources in a context of public safety, employee safety and environmental awarenes. This presentation shows the different measures MNR implemented to reduce risks. Warning signs, safety booms, barrel buoys and pedestrian fencing have been installed around dams to alert the public to possible dangers. In addition, MNR employees receive training in how to inspect dams for safety concerns, how to identify problems which could result in hazards to the public and how to work safely.

Modeling the Western Diet for Preclinical Investigations.

Science.gov (United States)

Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

2018-05-01

Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

Development of computational small animal models and their applications in preclinical imaging and therapy research.

Science.gov (United States)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

Energy Technology Data Exchange (ETDEWEB)

Xie, Tianwu [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Geneva Neuroscience Center, Geneva University, Geneva CH-1205 (Switzerland); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen 9700 RB (Netherlands)

2016-01-15

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

International Nuclear Information System (INIS)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Science.gov (United States)

Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

2017-08-01

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

SAFETY ANALYSIS METHODOLOGY FOR AGED CANDU® 6 NUCLEAR REACTORS

Directory of Open Access Journals (Sweden)

WOLFGANG HARTMANN

2013-10-01

Full Text Available This paper deals with the Safety Analysis for CANDU® 6 nuclear reactors as affected by main Heat Transport System (HTS aging. Operational and aging related changes of the HTS throughout its lifetime may lead to restrictions in certain safety system settings and hence some restriction in performance under certain conditions. A step in confirming safe reactor operation is the tracking of relevant data and their corresponding interpretation by the use of appropriate thermalhydraulic analytic models. Safety analyses ranging from the assessment of safety limits associated with the prevention of intermittent fuel sheath dryout for a slow Loss of Regulation (LOR analysis and fission gas release after a fuel failure are summarized. Specifically for fission gas release, the thermalhydraulic analysis for a fresh core and an 11 Effective Full Power Years (EFPY aged core was summarized, leading to the most severe stagnation break sizes for the inlet feeder break and the channel failure time. Associated coolant conditions provide the input data for fuel analyses. Based on the thermalhydraulic data, the fission product inventory under normal operating conditions may be calculated for both fresh and aged cores, and the fission gas release may be evaluated during the transient. This analysis plays a major role in determining possible radiation doses to the public after postulated accidents have occurred.

Health and Safety Plan for Waste Area Grouping 6 at Oak Ridge National Laboratory, Oak Ridge, Tennessee

International Nuclear Information System (INIS)

Van Hoesen, S.D.; Clark, C. Jr.; Burman, S.N.; Manis, L.W.; Barre, W.L.

1993-12-01

The Martin Marietta Energy Systems, Inc. (Energy Systems), policy is to provide a safe and healthful workplace for all employees and subcontractors. The accomplishment of this policy requires that operations at Waste Area Grouping (WAG) 6 at the Department of Energy (DOE) Oak Ridge National Laboratory are guided by an overall plan and consistent proactive approach to safety and health (S ampersand H) issues. The plan is written to utilize past experience and best management practices to minimize hazards to human health or the environment from events such as fires, explosions, falls, mechanical hazards, or any unplanned release of hazardous or radioactive materials to air, soil, or surface water This plan explains additional site-specific health and safety requirements such as Site Specific Hazards Evaluation Addendums (SSHEAs) to the Site Safety and Health Plan which should be used in concert with this plan and existing established procedures

An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

International Nuclear Information System (INIS)

Noor, Fozia; Niklas, Jens; Mueller-Vieira, Ursula; Heinzle, Elmar

2009-01-01

Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC 50 values 100 μM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

Prevention approaches in a preclinical canine model of Alzheimer’s disease: Benefits and challenges

Directory of Open Access Journals (Sweden)

Paulina R. Davis

2014-03-01

Full Text Available Aged dogs spontaneously develop many features of human aging and Alzheimer’s disease (AD including cognitive decline and neuropathology. In this review, we discuss age-dependent learning tasks, memory tasks, and functional measures that can be used in aged dogs for sensitive treatment outcome measures. Neuropathology that is linked to cognitive decline is described along with examples of treatment studies that show reduced neuropathology in aging dogs (dietary manipulations, behavioral enrichment, immunotherapy, and statins. Studies in canine show that multi-targeted approaches may be more beneficial than single pathway manipulations (e.g. antioxidants combined with behavioral enrichment. Aging canine studies show good predictive validity for human clinical trials outcomes (e.g. immunotherapy and several interventions tested in dogs strongly support a prevention approach (e.g. immunotherapy and statins. Further, dogs are ideally suited for prevention studies as they the age because onset of cognitive decline and neuropathology strongly support longitudinal interventions that can be completed within a 3-5 year period. Disadvantages to using the canine model are that they lengthy, use labor-intensive comprehensive cognitive testing, and involve costly housing (almost as high as that of nonhuman primates. However overall, using the dog as a preclinical model for testing preventive approaches for AD may complement work in rodents and nonhuman primates.

Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

International Nuclear Information System (INIS)

Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; Hart, Marieke van der; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

2012-01-01

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

Energy Technology Data Exchange (ETDEWEB)

Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Wisialowski, Todd A. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Cremers, Thomas; Hart, Marieke van der [Brains On-Line B.V., University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen (Netherlands); Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States)

2012-11-01

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

Evaluating the short-term effects of a communication skills program for preclinical medical students.

Science.gov (United States)

Lee, Young-Mee; Lee, Young Hee

2014-09-01

Regardless of the growing importance of communication skills as a core clinical competence, few studies have determined the effects of communication skills courses in undergraduate medical curricula in Asian medical schools. The purpose of this study was to examine the effectiveness of a communication skills program for preclinical medical students. A communication skills course was provided to 111 second-year medical students in a medical college in Korea. Students' self-assessed competency of communication skills was evaluated by a questionnaire survey. To examine the improvement in observed communication skills, the students' encounters with standardized patients (SPs) were assessed at the first session and at the final course assessment. A structured checklist, consisting of 25 communication skills items, was used for the assessment. Students' self-assessed competency of communication skills increased significantly after completion of the course (pcommunication skills scores also improved significantly at the end of the course; the mean scores of the first SPs encounters was 49.6 (standard deviation [SD], 11.1), and those of cases A and B at the final assessment were 61.5 (SD, 8.4) and 69.6 (SD, 7.8), respectively (F61=269.54, pcommunication skills course was beneficial in developing and improving communication skills competency in preclinical medical students. Further studies should be followed to examine whether the acquisition of communication skills during preclinical studies can be sustained into clerkship and actual practice.

The state of radiologic teaching practice in preclinical medical education: survey of American medical, osteopathic, and podiatric schools.

Science.gov (United States)

Rubin, Zachary; Blackham, Kristine

2015-04-01

This study describes the state of preclinical radiology curricula in North American allopathic, osteopathic, and podiatric medical schools. An online survey of teaching methods, radiology topics, and future plans was developed. The Associations of American Medical Colleges, Colleges of Osteopathic Medicine, and Colleges of Podiatric Medicine listing for all US, Canadian, and Puerto Rican schools was used for contact information for directors of anatomy and/or radiology courses. Letters were sent via e-mail to 198 schools, with a link to the anonymous survey. Of 198 schools, 98 completed the survey (48%). Radiology curricula were integrated with other topics (91%), and taught by anatomists (42%) and radiologists (43%). The majority of time was spent on the topic of anatomy correlation (35%). Time spent teaching general radiology topics in the curriculum, such as physics (3%), modality differences (6%), radiation safety (2%), and contrast use (2%) was limited. Most schools had plans to implement an innovative teaching method in the near future (62%). The major challenges included limits on: time in the curriculum (73%); resources (32%); and radiology faculty participation (30%). A total of 82% reported that their curriculum did not model the suggestions made by the Alliance of Medical Student Educators in Radiology. This survey describes the current state of preclinical radiology teaching: curricula were nonstandard, integrated into other courses, and predominantly used for anatomy correlation. Other important contextual principles of the practice of radiology were seldom taught. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Development, validation, and application of ELISA for detection of anti-HD105 antibodies in pre-clinical safety evaluation using monkeys.

Science.gov (United States)

Choi, Woo Hyuck; Jo, Hye Ryun; Jeon, Eun-Jeong; Youm, So-Young; Jeon, Jang Su; Son, Yong-Gyu; You, Weon-Kyoo; Koh, Woo Suk; Lee, Sang Hoon; Kim, Sang Kyum

2016-11-30

Unwanted immunogenicity of protein therapeutics can result in severe side effects and should be assessed in animals before applying the treatment to humans. Monkeys are the most relevant choice for pre-clinical toxicity testing of antibody-based therapeutics. To assess the immunogenicity of HD105, a novel antibody therapeutic that targets both vascular endothelial growth factor and Delta-like-ligand 4, a bridging enzyme-linked immunosorbent assay was developed as an anti-drug antibody (ADA) assay and validated for use in pre-clinical studies using non-human primates. This method was found to have suitable assay sensitivity, intra- and inter-assay precision, confirmation, drug tolerance, recovery, and sample stability for measuring ADA in monkey serum samples. The results showed that ADA elevation occurred following repeated doses of HD105, and that ADA production was negatively associated with serum HD105 concentration. These results suggest that intravenous administration of HD105 induces production of ADA in monkeys and that the detection of ADA may be negatively influenced by free HD105 in serum. Copyright © 2016 Elsevier B.V. All rights reserved.

Utility of immunodeficient mouse models for characterizing the preclinical pharmacokinetics of immunogenic antibody therapeutics.

Science.gov (United States)

Myzithras, Maria; Bigwarfe, Tammy; Li, Hua; Waltz, Erica; Ahlberg, Jennifer; Giragossian, Craig; Roberts, Simon

Prior to clinical studies, the pharmacokinetics (PK) of antibody-based therapeutics are characterized in preclinical species; however, those species can elicit immunogenic responses that can lead to an inaccurate estimation of PK parameters. Immunodeficient (SCID) transgenic hFcRn and C57BL/6 mice were used to characterize the PK of three antibodies that were previously shown to be immunogenic in mice and cynomolgus monkeys. Four mouse strains, Tg32 hFcRn SCID, Tg32 hFcRn, SCID and C57BL/6, were administered adalimumab (Humira®), mAbX and mAbX-YTE at 1 mg/kg, and in SCID strains there was no incidence of immunogenicity. In non-SCID strains, drug-clearing ADAs appeared after 4-7 days, which affected the ability to accurately calculate PK parameters. Single species allometric scaling of PK data for Humira® in SCID and hFcRn SCID mice resulted in improved human PK predictions compared to C57BL/6 mice. Thus, the SCID mouse model was demonstrated to be a useful tool for assessing the preclinical PK of immunogenic therapeutics.

Studies of the relationship between employee`s safety consciousness, morale, and supervisor`s leadership in nuclear power plant

Energy Technology Data Exchange (ETDEWEB)

Misumi, Jyuji; Hiraki, Tadao; Sakurai, Yukihiro [Institute of Nuclear Safety System Inc., Kyoto (Japan); Yoshida, Michio; Misumi, Emiko; Tokudome, Eiji

1996-09-01

This study examined the relationship between employee`s safety consciousness, morale, and supervisor`s leadership using multiple regression analysis. Respondents were 2152 male employees who were working at nuclear power plants (operation division, maintenance division, and joint companies). Main results were as follows. (1) Individual morale variables, such as `work motivation` and `mental hygine`, were correlated with leadership M behavior rather than with P behavior. On the other hand, group morale variables, such as `teamwork` and `meeting quality`, were correlated with both P and M behavior. These results shows P and M leadership affect the employee`s morale. (2) With regard to safety consciousness variables, `communication` and `work place norm` to ensure safety were strongly correlated to leadership both P and M behavior. However, neither `sense of tension to ensure safety` nor `experiencing cold shiver` were related to leadership P or M behavior. It was suggested that practices for accidents prevention in workplace are related to supervisor`s P and M leadership behavior. (3) `Sense of tension` to ensure safety and `experiencing cold shiver` were negatively correlated with `mental hygine`, but positively correlated with `work motivation`. These results suggest that increase of the work motivation might improve employee`s awareness and ability for detecting human errors. (author)

The official website of the U.S. department of energy's nuclear criticality safety program

Energy Technology Data Exchange (ETDEWEB)

Koponen, B.; Heinrichs, D.; Lee, C. [Lawrence Livermore National Laboratory, CA (United States); Scott, L. [SAIC, Solana Beach, CA (United States)

2014-07-01

The U.S. Department of Energy (DOE) Nuclear Criticality Safety Program (NCSP) mission is to provide sustainable expert leadership, direction, and the technical infrastructure necessary to develop, maintain, and disseminate the essential technical tools, training, and data to support safe, efficient fissionable material operations within the DOE. The NCSP Website site makes a variety of information available to the criticality safety practitioner, including reference materials, training modules and links to related sites. It assists criticality safety personnel to keep abreast of NCSP activities or current developments in criticality safety via a 'What's New' section within the Website. Convenient access to the many useful features of the Website is available via drop-down menus. The Website is also available to non-DOE and international professionals tasked with ensuring safe operations involving fissionable nuclear materials. (author)

Development of NPP Safety Requirements into Kenya's Grid Codes

Energy Technology Data Exchange (ETDEWEB)

Ndirangu, Nguni James; Koo, Chang Choong [KEPCO International Nuclear Graduate School, Ulsan (Korea, Republic of)

2015-10-15

As presently drafted, Kenya's grid codes do not contain any NPP requirements. Through case studies of selected grid codes, this paper will study frequency, voltage and fault ride through requirements for NPP connection and operation, and offer recommendation of how these requirements can be incorporated in the Kenya's grid codes. Voltage and frequency excursions in Kenya's grid are notably frequently outside the generic requirement and the values observed by the German and UK grid codes. Kenya's grid codes require continuous operation for ±10% of nominal voltage and 45.0 to 52Hz on the grid which poses safety issues for an NPP. Considering stringent NPP connection to grid and operational safety requirements, and the importance of the TSO to NPP safety, more elaborate requirements need to be documented in the Kenya's grid codes. UK and Germany have a history of meeting high standards of nuclear safety and it is therefore recommended that format like the one in Table 1 to 3 should be adopted. Kenya's Grid code considering NPP should have: • Strict rules for voltage variation, that is, -5% to +10% of the nominal voltage • Strict rules for frequency variation, that is, 48Hz to 52Hz of the nominal frequencyand.

Development of NPP Safety Requirements into Kenya's Grid Codes

International Nuclear Information System (INIS)

Ndirangu, Nguni James; Koo, Chang Choong

2015-01-01

As presently drafted, Kenya's grid codes do not contain any NPP requirements. Through case studies of selected grid codes, this paper will study frequency, voltage and fault ride through requirements for NPP connection and operation, and offer recommendation of how these requirements can be incorporated in the Kenya's grid codes. Voltage and frequency excursions in Kenya's grid are notably frequently outside the generic requirement and the values observed by the German and UK grid codes. Kenya's grid codes require continuous operation for ±10% of nominal voltage and 45.0 to 52Hz on the grid which poses safety issues for an NPP. Considering stringent NPP connection to grid and operational safety requirements, and the importance of the TSO to NPP safety, more elaborate requirements need to be documented in the Kenya's grid codes. UK and Germany have a history of meeting high standards of nuclear safety and it is therefore recommended that format like the one in Table 1 to 3 should be adopted. Kenya's Grid code considering NPP should have: • Strict rules for voltage variation, that is, -5% to +10% of the nominal voltage • Strict rules for frequency variation, that is, 48Hz to 52Hz of the nominal frequencyand

The Inspector General's report on Nuclear Safety and Radiation Protection 2014

International Nuclear Information System (INIS)

2015-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's view of 2014; 2- Contrasting trends in nuclear safety in different sets of plants; 3 - Making safety culture central to management; 4 - Towards an integrated approach to risk management; 5 - Relying on professional unified operations; 6 - The quest for robust maintenance; 7 - Nuclear engineering: a major asset for the operator; 8 - Nuclear managers - confidence builders; 9 - on course for reactor operation beyond 40 years in France; 10 - Service life challenges in the UK; 11 - Preparing the future: from the EPR to other new models; 12 - Noteworthy operational events; 13- Appendices: Results for the nuclear fleets (EDF SA, EDF Energy; Maps of the nuclear power plants(EDF SA, EDF Energy); Key dates for the nuclear units (EDF SA, EDF Energy); Abbreviations

The Inspector General's report on Nuclear Safety and Radiation Protection 2015

International Nuclear Information System (INIS)

2016-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's view of 2015; 2 - Operational safety: mixed results; 3 - Nuclear safety clearly prioritised; 4 - Risk prevention: progress in France; 5 - Reinforced emergency preparedness post-Fukushima; 6 - Fire prevention: still a weak link; 7 - Continuous investment in training and careers; 8 - Using maintenance to leverage improved operational quality; 9 - Chemistry in France: a transition in need of strong support; 10 - Decommissioning projects are progressing; 11 - EPRs in China, France and the UK; 12 - Preparing for the future; 13 - A window on the world; 14 - Appendices: Results for the nuclear fleets (EDF SA, EDF Energy; Maps of the nuclear power plants(EDF SA, EDF Energy); Key dates for the nuclear units (EDF SA, EDF Energy); Abbreviations

The 4p-5d, 6d and 4p-6s, 7s transitions of Mo IX

International Nuclear Information System (INIS)

Khatoon, S.; Chaghtai, M.S.Z.; Rahimullah, K.

1979-01-01

The transitions 4p-5d, 6d and 4p-6s, 7s have been studied for the first time in Mo IX. The authors have identified 42 4p-5d, 36 4p-6d, 22 4p-6s and 22 4p-7s transitions, establishing 16 4p 3 5d, 14 4p 3 6d and all the ten 4p 3 6s, 7s levels of the spectrum concerned. The ionization energy is estimated to be (1 323 700 +- 700)cm -1 or (164.11 +- 0.09)eV. The spectrum was recorded in sliding and open spark discharges with a 5 m grazing incidence spectrograph of Lund University (Sweden) from about 40 A to 440 A. (Auth.)

The Economics of Reproducibility in Preclinical Research.

Directory of Open Access Journals (Sweden)

Leonard P Freedman

2015-06-01

Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

Science.gov (United States)

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Science.gov (United States)

Avey, Marc T; Moher, David; Sullivan, Katrina J; Fergusson, Dean; Griffin, Gilly; Grimshaw, Jeremy M; Hutton, Brian; Lalu, Manoj M; Macleod, Malcolm; Marshall, John; Mei, Shirley H J; Rudnicki, Michael; Stewart, Duncan J; Turgeon, Alexis F; McIntyre, Lauralyn

2016-01-01

Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs) as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments) reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47%) of all sub-items (median 51 items; range 37-64). Across all studies, the Methods Section reported less than half (45%) and the Results Section reported less than a third (29%). There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

High level waste storage tank farms/242-A evaporator Standards/Requirements Identification Document (S/RID), Volume 6

Energy Technology Data Exchange (ETDEWEB)

1994-04-01

The High-Level Waste Storage Tank Farms/242-A Evaporator Standards/Requirements Identification Document (S/RID) is contained in multiple volumes. This document (Volume 6) outlines the standards and requirements for the sections on: Environmental Restoration and Waste Management, Research and Development and Experimental Activities, and Nuclear Safety.

High level waste storage tank farms/242-A evaporator Standards/Requirements Identification Document (S/RID), Volume 6

International Nuclear Information System (INIS)

1994-04-01

The High-Level Waste Storage Tank Farms/242-A Evaporator Standards/Requirements Identification Document (S/RID) is contained in multiple volumes. This document (Volume 6) outlines the standards and requirements for the sections on: Environmental Restoration and Waste Management, Research and Development and Experimental Activities, and Nuclear Safety

Development of safety analysis methodology for moderator system failure of CANDU-6 reactor by thermal-hydraulics/physics coupling

International Nuclear Information System (INIS)

Kim, Jong Hyun; Jin, Dong Sik; Chang, Soon Heung

2013-01-01

Highlights: • Developed new safety analysis methodology of moderator system failures for CANDU-6. • The new methodology used the TH-physics coupling concept. • Thermalhydraulic code is CATHENA, physics code is RFSP-IST. • Moderator system failure ends to the subcriticality through self-shutdown. -- Abstract: The new safety analysis methodology for the CANDU-6 nuclear power plant (NPP) moderator system failure has been developed by using the coupling technology with the thermalhydraulic code, CATHENA and reactor core physics code, RFSP-IST. This sophisticated methodology can replace the legacy methodology using the MODSTBOIL and SMOKIN-G2 in the field of the thermalhydraulics and reactor physics, respectively. The CATHENA thermalhydraulic model of the moderator system can simulate the thermalhydraulic behaviors of all the moderator systems such as the calandria tank, head tank, moderator circulating circuit and cover gas circulating circuit and can also predict the thermalhydraulic property of the moderator such as moderator density, temperature and water level in the calandria tank as the moderator system failures go on. And these calculated moderator thermalhydraulic properties are provided to the 3-dimensional neutron kinetics solution module – CERBRRS of RFSP-IST as inputs, which can predict the change of the reactor power and provide the calculated reactor power to the CATHENA. These coupling calculations are performed at every 2 s time steps, which are equivalent to the slow control of CANDU-6 reactor regulating systems (RRS). The safety analysis results using this coupling methodology reveal that the reactor operation enters into the self-shutdown mode without any engineering safety system and/or human interventions for the postulated moderator system failures of the loss of heat sink and moderator inventory, respectively

Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

Science.gov (United States)

Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

2017-11-01

Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Stress, Burnout and Coping Strategies in Preclinical Medical Students

Science.gov (United States)

Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-01-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students’ stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted. PMID:27042604

Stress, Burnout and Coping Strategies in Preclinical Medical Students.

Science.gov (United States)

Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-02-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

Results of 6th Review Meeting and Perspective of the 7th Review Meeting of the Convention on Nuclear Safety

International Nuclear Information System (INIS)

Lee, Sukho; Kim, Manwoong; You, Jeongwon; Lee, Youngeal

2017-01-01

This paper highlighted the objective and role of the Convention on Nuclear Safety organized by the IAEA. The Convention provides Member States to demonstrate and share how to maintain and improve the level of nuclear safety. The results of the 6 th review meeting were implemented for safety improvements and to prepare for 7 th national report. Seven and a half months before the 7 th Review Meeting, the National Report has submitted on steps and measures taken to implement Convention obligations. The Contracting Parties reviewed each other’s reports, and exchanged written questions, written answers and comments. The discussions in the Country Group sessions were generally good with a lively and frank exchange of information. The Country Groups noted the significant measures taken by Contracting Parties to improve nuclear safety and identified a number of good practices to be shared with all Contracting Parties.

Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic Diseases and Pregnancy Outcome.

Science.gov (United States)

Spinillo, Arsenio; Beneventi, Fausta; Locatelli, Elena; Ramoni, Vèronique; Caporali, Roberto; Alpini, Claudia; Albonico, Giulia; Cavagnoli, Chiara; Montecucco, Carlomaurizio

2016-10-01

To evaluate the impact of preclinical systemic autoimmune rheumatic disorders on pregnancy outcome. In this longitudinal cohort study, patients were enrolled during the first trimester of pregnancy if they reported having had connective tissue disorder symptoms, were found to be positive for circulating autoantibodies, and on clinical evaluation were judged to have a preclinical or incomplete rheumatic disorder. The incidence of fetal growth restriction (FGR), preeclampsia, and adverse pregnancy outcomes in patients with preclinical rheumatic disorders was compared with that in selected controls, after adjustment for confounders by penalized logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Of 5,232 women screened, 150 (2.9%) were initially diagnosed as having a suspected rheumatic disorder. After a mean ± SD postpartum follow-up of 16.7 ± 5.5 months, 64 of these women (42.7%) had no clinically apparent rheumatic disease and 86 (57.3%) had persistent symptoms and positive autoantibody results, including 10 (6.7%) who developed a definitive rheumatic disease. The incidences of preeclampsia/FGR and of small for gestational age (SGA) infants were 5.1% (23 of 450) and 9.3% (42 of 450), respectively, among controls, 12.5% (8 of 640) (OR 2.7 [95% CI 1.1-6.4]) and 18.8% (12 of 64) (OR 2.2 [95% CI 1.1-4.5]), respectively, among women with no clinically apparent disease, and 16.3% (14 of 86) (OR 3.8 [95% CI 1.9-7.7]) and 18.6% (16 of 86) (OR 2.3 [95% CI 1.2-4.3]), respectively, among those with persisting symptoms at follow-up. Mean ± SD umbilical artery Doppler pulsatility indices were higher among women with no clinically apparent disease (0.95 ± 0.2) and those with persisting symptoms (0.96 ± 0.21) than in controls (0.89 ± 0.12) (P = 0.01 and P rheumatic disorders were associated with an increased risk of FGR/preeclampsia and SGA. The impact of these findings and their utility in screening

Preclinical evaluation of a Haemophilus influenzae type b conjugate vaccine process intended for technology transfer.

Science.gov (United States)

Hamidi, Ahd; Verdijk, Pauline; Kreeftenberg, Hans

2014-01-01

Introduction of Haemophilus influenzae type b (Hib) vaccine in low- and middle-income countries has been limited by cost and availability of Hib conjugate vaccines for a long time. It was previously recognized by the Institute for Translational Vaccinology (Intravacc, originating from the former Vaccinology Unit of the National Institute of Public Health [RIVM] and the Netherlands Vaccine Institute [NVI]) that local production of a Hib conjugate vaccine would increase the affordability and sustainability of the vaccine and thereby help to speed up Hib introduction in these countries. A new affordable and a non-infringing production process for a Hib conjugate vaccine was developed, including relevant quality control tests, and the technology was transferred to a number of vaccine manufacturers in India, Indonesia, and China. As part of the Hib technology transfer project managed by Intravacc, a preclinical toxicity study was conducted in the Netherlands to test the safety and immunogenicity of this new Hib conjugate vaccine. The data generated by this study were used by the technology transfer partners to accelerate the clinical development of the new Hib conjugate vaccine. A repeated dose toxicity and local tolerance study in rats was performed to assess the reactogenicity and immunogenicity of a new Hib conjugate vaccine compared to a licensed vaccine. The results showed that the vaccine was well tolerated and immunogenic in rats, no major differences in both safety and immunogenicity in rats were found between the vaccine produced according to the production process developed by Intravacc and the licensed one. Rats may be useful to verify the immunogenicity of Hib conjugate vaccines and for preclinical evaluation. In general, nonclinical evaluation of the new Hib conjugate vaccine, including this proof of concept (safety and immunogenicity study in rats), made it possible for technology transfer partners, having implemented the original process with no changes

[99mTc]Demotensin 5 and 6 in the NTS1-R-targeted imaging of tumours: synthesis and preclinical results

International Nuclear Information System (INIS)

Maina, Theodosia; Nikolopoulou, Anastasia; Stathopoulou, Eleni; Nock, Berthold A.; Galanis, Athanassios S.; Cordopatis, Paul

2007-01-01

The aim of this study was to evaluate the applicability of [ 99m Tc]Demotensin 5 and 6 ([ 99m Tc- N 0 4 ,(β)Ala 7 ,Dab 9 ,X 12 AA ]NT(7-13); X AA =Ile/5,Tle/6,NT=neurotensin) in the targeted diagnostic imaging of neurotensin subtype 1 receptor (NTS1-R)-expressing tumours. Labelling of Demotensin 5 and 6 with 99m Tc was conducted by brief incubation with 99m TcO 4 - , SnCl 2 and citrate anions in alkaline medium at ambient temperature. Affinities of conjugates for the NTS1-R were determined by competition binding experiments in WiDr cell membranes using [ 125 I-Tyr 3 ]NT as the radioligand. Saturation binding assays were conducted for [ 99m Tc/ 99g Tc]Demotensin 6 in WiDr cell membranes. Internalisation of [ 99m Tc]Demotensin 5 and 6 was studied at 37 C in WiDr cells. Biodistribution of [ 99m Tc]Demotensin 5 and 6 was performed in female Swiss nu/nu mice bearing human WiDr xenografts. Unlabelled conjugates showed a high affinity for the human NTS1-R (Demotensin 5 IC 50 =0.03±0.01 nM; Demotensin 6 IC 50 =0.08±0.02 nM), while high affinity was also exhibited by (radio)metallated [ 99m Tc/ 99g Tc]Demotensin 6 (K d =0.13±0.01 nM). [ 99m Tc]Demotensin 5 and 6 internalised rapidly and specifically in WiDr cells. After injection in WiDr tumour-bearing mice, radiopeptides, and especially the doubly stabilised [ 99m Tc]Demotensin 6, showed NTS1-R-mediated uptake in the intestines and in the implanted tumour (4.30±0.45%ID/g at 1 h post injection) and rapid renal excretion from non-target tissues into the urine. [ 99m Tc]Demotensin 6 shows a favourable preclinical profile and further testing in patients is warranted to monitor its eventual applicability as a radiotracer in the diagnostic imaging of NTS1-R-positive tumours. (orig.)

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Science.gov (United States)

Tucker, Laura B.; Fu, Amanda H.

2016-01-01

Abstract To date, clinical trials have failed to find an effective therapy for victims of traumatic brain injury (TBI) who live with motor, cognitive, and psychiatric complaints. Pre-clinical investigators are now encouraged to include male and female subjects in all translational research, which is of particular interest in the field of neurotrauma given that circulating female hormones (progesterone and estrogen) have been demonstrated to exert neuroprotective effects. To determine whether behavior of male and female C57BL6/J mice is differentially impaired by TBI, male and cycling female mice were injured by controlled cortical impact and tested for several weeks with functional assessments commonly employed in pre-clinical research. We found that cognitive and motor impairments post-TBI, as measured by the Morris water maze (MWM) and rotarod, respectively, were largely equivalent in male and female animals. However, spatial working memory, assessed by the y-maze, was poorer in female mice. Female mice were generally more active, as evidenced by greater distance traveled in the first exposure to the open field, greater distance in the y-maze, and faster swimming speeds in the MWM. Statistical analysis showed that variability in all behavioral data was no greater in cycling female mice than it was in male mice. These data all suggest that with careful selection of tests, procedures, and measurements, both sexes can be included in translational TBI research without concern for effect of hormones on functional impairments or behavioral variability. PMID:25951234

Road Safety Data, Collection, Transfer and Analysis DaCoTa. Workpackage 6, Driver Behaviour Monitoring through Naturalistic Driving: Deliverable 6.4: Naturalistic Driving for monitoring safety performance indicators and exposure: considerations for implementation.

NARCIS (Netherlands)

Schagen, I.N.L.G. van & Reed, S.

2015-01-01

DaCoTA was a Collaborative Project under the European Seventh Framework Programme that aimed to develop tools and methodologies to support road safety policy and further extend and enhance the European Road Safety Observatory (ERSO). One of the Work Packages in DaCoTA, WP6, focused on the usefulness

Safety assessment of the Area 6 Decontamination Pad and Laundry

International Nuclear Information System (INIS)

Chilton, M.W.; Orcutt, J.A.

1984-10-01

The Safety Assessment of the Area 6 Decontamination Pad and Laundry, prepared in accordance with DOE Order 5481.1A, identifies and evaluates potential radiation and chemical hazards to personnel, and impacts on the environment. Site and facility characteristics, as well as routine and nonroutine operations are discussed. Hypothetical incidents and accidents are described and evaluated. 3 figures, 1 table

Characterization of novel preclinical dose distributions for micro irradiator

International Nuclear Information System (INIS)

Kodra, J; Miles, D; Yoon, S W; Kirsch, D G; Oldham, M

2017-01-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm 3 ) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters. (paper)

Characterization of novel preclinical dose distributions for micro irradiator

Science.gov (United States)

Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

2017-05-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

West Valley UF6 Facility. Environmental report and safety evaluation, supplement 1

International Nuclear Information System (INIS)

1975-01-01

Revised pages are provided for the Environmental Report and the Safety Evaluation Report which reflect design changes and more detailed information on the items requested in the USAEC letter to NFS dated September 6, 1974

Theory of mind and empathy in preclinical and clinical Huntington's disease.

Science.gov (United States)

Adjeroud, Najia; Besnard, Jérémy; El Massioui, Nicole; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique; Allain, Philippe

2016-01-01

We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

Science.gov (United States)

Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

2016-01-01

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

Directory of Open Access Journals (Sweden)

Yuan Feng

Full Text Available Tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5 induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Directory of Open Access Journals (Sweden)

Marc T Avey

Full Text Available Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47% of all sub-items (median 51 items; range 37-64. Across all studies, the Methods Section reported less than half (45% and the Results Section reported less than a third (29%. There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

The U.S.A. and the energy safety in East Asia

International Nuclear Information System (INIS)

Harmat, K.

2006-01-01

In the contribution under consideration the author reports on the impact of the United States of America (U.S.A.) in East Asia. The American policy in East Asia is based on two fundamental principles: providing, that no regional authority may provoke the position of the U.S.A., as well as protection of the access to regional markets for the American economy. The U.S.A. fulfill their protective function of their Asiatic partners by means of their maritime superiority with the pacific fleet. Strong-points and safety contracts with Japan and the Republic of Korea form the support of the presence of the U.S. American military. The According to energy security, the interests of the U.S.A. in East Asia are: (a) Secure supply of the national economies in East Asia; (b) Security of the maritime supply systems; (c) Stability and liberalization of the international oil markets; (d) Responsible handling of nuclear energy; (e) Environmental protection. Furthermore, the author describes the conflict potentials between the U.S.A. and the energy safety in East Asia as well as the long-term significance of the energy safety in East Asia

First exposure in man: toxicological considerations

DEFF Research Database (Denmark)

Spindler, Per; Sjöberg, P; Knudsen, Lisbeth E.

2000-01-01

The safety of a volunteer/patient who participate in the very first human trial relies on data from animal experimentation and on the design of the trial. Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed...... for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test...

Rat animal model for preclinical testing of microparticle urethral bulking agents.

Science.gov (United States)

Mann-Gow, Travis K; Blaivas, Jerry G; King, Benjamin J; El-Ghannam, Ahmed; Knabe, Christine; Lam, Michael K; Kida, Masatoshi; Sikavi, Cameron S; Plante, Mark K; Krhut, Jan; Zvara, Peter

2015-04-01

To develop an economic, practical and readily available animal model for preclinical testing of urethral bulking therapies, as well as to establish feasible experimental methods that allow for complete analysis of hard microparticle bulking agents. Alumina ceramic beads suspended in hyaluronic acid were injected into the proximal urethra of 15 female rats under an operating microscope. We assessed overall lower urinary tract function, bulking material intraurethral integrity and local host tissue response over time. Microphotographs were taken during injection and again 6 months postoperatively, before urethral harvest. Urinary flow rate and voiding frequency were assessed before and after injection. At 6 months, the urethra was removed and embedded in resin. Hard tissue sections were cut using a sawing microtome, and processed for histological analysis using scanning electron microscopy, light microscopy and immunohistochemistry. Microphotographs of the urethra showed complete volume retention of the bulking agent at 6 months. There was no significant difference between average urinary frequency and mean urinary flow rate at 1 and 3 months postinjection as compared with baseline. Scanning electron microscopy proved suitable for evaluation of microparticle size and integrity, as well as local tissue remodeling. Light microscopy and immunohistochemistry allowed for evaluation of an inflammatory host tissue reaction to the bulking agent. The microsurgical injection technique, in vivo physiology and novel hard tissue processing for histology, described in the present study, will allow for future comprehensive preclinical testing of urethral bulking therapy agents containing microparticles made of a hard material. © 2015 The Japanese Urological Association.

Ocular safety of Viagra, (sildenafil citrate).

Science.gov (United States)

Laties, A M; Fraunfelder, F T

1999-01-01

To date, sildenafil citrate (Viagra) gives every evidence of being a safe drug for the eye despite a series of expressed concerns. A review of how its ocular safety profile has been identified offers insights into the strengths and weaknesses of present systems and resources for judging the ocular safety of Viagra or, for that matter, of any new drug. Such insights include: The great value of careful, informed assessment of preclinical information gleaned from laboratory experiments. By and large, such assessments point the way toward appropriate clinical evaluation. For Viagra, early in its development it was noted that besides exerting a major inhibitory effect on the intended target, the vascular-associated enzyme phosphodiesterase 5 (PDE5), the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6, located in the retina. For this reason, preclinical evaluation of the drug included electroretinography plus postmortem histology. In addition, an extended eye examination was incorporated into clinical protocols. The often chaotic but invaluable information stream that becomes available once marketing approval has been gained and large populations begin to use a drug. False alarms, misattribution, and erroneous information are the order of the day. Nevertheless, as information accumulates, patterns of response clarify and the true nature of special susceptibility for subpopulations, if any, becomes apparent. A role for the astute clinician remains: Subtle changes or unusual risks for subpopulations can be missed entirely for long periods of time. A manifest need for improvement in evaluation of postmarketing side-effects. This need has led to the establishment of a new discipline: pharmacoepidemiology. In ophthalmology, the National Registry of Drug Induced Ocular Side-Effects maintains a constant and invaluable surveillance. Examples are supplied to illustrate each of these major points: Our presentation will include data gleaned from

Aluminum hypophosphite microencapsulated to improve its safety and application to flame retardant polyamide 6

International Nuclear Information System (INIS)

Ge, Hua; Tang, Gang; Hu, Wei-Zhao; Wang, Bi-Bo; Pan, Ying; Song, Lei; Hu, Yuan

2015-01-01

Highlights: • MCAHP was prepared and applied in polyamide 6. • MCA as the capsule material can improve the fire safety of AHP. • Flame retardant polyamide 6 composites with MCAHP show good flame retardancy. - Abstract: Aluminum hypophosphite (AHP) is an effective phosphorus-containing flame retardant. But AHP also has fire risk that it will decompose and release phosphine which is spontaneously flammable in air and even can form explosive mixtures with air in extreme cases. In this paper, AHP has been microencapsulated by melamine cyanurate (MCA) to prepare microencapsulated aluminum hypophosphite (MCAHP) with the aim of enhancing the fire safety in the procedure of production, storage and use. Meanwhile, MCA was a nitrogen-containing flame retardant that can work with AHP via the nitrogen-phosphorus synergistic effect to show improved flame-retardant property than other capsule materials. After microencapsulation, MCA presented as a protection layer inhibit the degradation of AHP and postpone the generation of phosphine. Furthermore, the phosphine concentration could be effectively diluted by inert decomposition products of MCA. These nonflammable decomposition products of MCA could separate phosphine from air delay the oxidizing reaction with oxygen and decrease the heat release rate, which imply that the fire safety of AHP has been improved. Furthermore, MCAHP was added into polyamide 6 to prepare flame retardant polyamide 6 composites (FR-PA6) which show good flame retardancy

Aluminum hypophosphite microencapsulated to improve its safety and application to flame retardant polyamide 6

Energy Technology Data Exchange (ETDEWEB)

Ge, Hua [State Key Laboratory of Fire Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026 (China); Tang, Gang [School of Architecture and Civil Engineering, Anhui University of Technology, 59 Hudong Road, Ma’anshan, Anhui 243002 (China); Hu, Wei-Zhao; Wang, Bi-Bo; Pan, Ying [State Key Laboratory of Fire Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026 (China); Song, Lei, E-mail: leisong@ustc.edu.cn [State Key Laboratory of Fire Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026 (China); Hu, Yuan, E-mail: yuanhu@ustc.edu.cn [State Key Laboratory of Fire Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026 (China); Suzhou Key Laboratory of Urban Public Safety, Suzhou Institute for Advanced Study, University of Science and Technology of China, 166 Ren’ai Road, Suzhou, Jiangsu 215123 (China)

2015-08-30

Highlights: • MCAHP was prepared and applied in polyamide 6. • MCA as the capsule material can improve the fire safety of AHP. • Flame retardant polyamide 6 composites with MCAHP show good flame retardancy. - Abstract: Aluminum hypophosphite (AHP) is an effective phosphorus-containing flame retardant. But AHP also has fire risk that it will decompose and release phosphine which is spontaneously flammable in air and even can form explosive mixtures with air in extreme cases. In this paper, AHP has been microencapsulated by melamine cyanurate (MCA) to prepare microencapsulated aluminum hypophosphite (MCAHP) with the aim of enhancing the fire safety in the procedure of production, storage and use. Meanwhile, MCA was a nitrogen-containing flame retardant that can work with AHP via the nitrogen-phosphorus synergistic effect to show improved flame-retardant property than other capsule materials. After microencapsulation, MCA presented as a protection layer inhibit the degradation of AHP and postpone the generation of phosphine. Furthermore, the phosphine concentration could be effectively diluted by inert decomposition products of MCA. These nonflammable decomposition products of MCA could separate phosphine from air delay the oxidizing reaction with oxygen and decrease the heat release rate, which imply that the fire safety of AHP has been improved. Furthermore, MCAHP was added into polyamide 6 to prepare flame retardant polyamide 6 composites (FR-PA6) which show good flame retardancy.

Pilot research on a pupil’s psychological safety in the multicultural educational environment

Directory of Open Access Journals (Sweden)

Kulikova, Tatyana I.

2016-09-01

Full Text Available In the modern world, the environment of any educational institution represents a spectrum of ethnic groups and subcultures: a multicultural educational environment. Pupils who are aware of their national identity often demonstrate intolerance toward students of other nationalities, which threatens pupils’ psychological safety. In this article, we present the results of pilot research examining the level of a pupil’s psychological safety in the multicultural educational environment and identifying the criteria that influence a pupil’s psychological safety. The research sample comprised 127 pupils aged 13–14 years from different schools living in various places that differed by the type of settlement, industrial development and level of science and culture. We isolated the following criteria for a pupil’s psychological safety in the multicultural educational environment: satisfaction with the educational environment, protection from psychological abuse and self-confidence. According to pupils, the essential characteristics of safety in the educational environment, regardless of school category and type, are being able to ask for help, protection of personal dignity, interactions with other students, and self-respect. Empirical data reveal the current status of the psychological safety of the entire sample group (n = 127 and compare indices of psychological safety in the educational institutions under study. Analysis of the results of our research indicates that protecting a pupil’s personality in the multicultural educational environment has the greatest influence on his/her psychological safety. In addition, a comfortable psychological atmosphere, mutual aid and support of pupils and low levels of classmates’ and coevals’ aggression positively influence the protection experience.

Proceedings of the 6. Argentine congress on radiation protection and nuclear safety; Actas del 6. congreso argentino de proteccion radiologica y seguridad nuclear

Energy Technology Data Exchange (ETDEWEB)

NONE

1999-12-31

The 6th Argentine Congress on Radiation Protection and Nuclear Safety was organized by the Radioprotection Argentine Society, in Buenos Aires, between the 22 and 24 of september of 1998. In this event, were presented almost 66 papers in the following sessions, about these subjects: 1.- Safety in nuclear installations. 2.- Control of nuclear material and physical protection of nuclear installations. 3.- Programs of quality assurance. 4.- Training, technical information and public information. 5.- Physical dosimetry. 6.- Physical dosimetry and occupational radiation protection. 7.- Exposure of the natural radiation. 8.- Environmental radiological safety. 9.- Biological effects of the ionizing radiations and biological dosimetry. 10.- Radiological protection of the medical practice and the radiological emergencies. 11.- Radioactive wastes management. 12.- Transport of radioactive materials

Microbiological food safety in Malaysia from the academician’s perspective

Directory of Open Access Journals (Sweden)

New, C.Y.,

2017-07-01

Full Text Available Food safety in Malaysia is not considered an issue yet. From the previous year (2005- 2015 records, the incidence rate of food poisoning had been fluctuating and despite that, cases continue to occur especially among school students. As a developing nation, it is high-time that Malaysia begins to emphasize on food safety to reduce the burden of foodborne illness in the socio-economic development of the country, and at the same time, gain benefits in terms of economic returns and trade through food safety enforcement. Most importantly, public health is achieved through food safety implementation and accentuation. The current standing point of the Malaysia’s food safety is discussed in this review. In addition, the review will also discuss the role of academicians as intervention contributions in tackling food safety issues. The review is hoped to provide valuable and concentrated information and knowledge to readers in the light to drive Malaysia into ensuring safer food for the public.

Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children ≥6 Months and Older Adults

Directory of Open Access Journals (Sweden)

Emanuele Montomoli

2018-03-01

Full Text Available Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs. This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs, to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra® formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged ≥6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6–35 months and its immunogenicity in older subjects (aged 66–80 years.

Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

Directory of Open Access Journals (Sweden)

Cheng eWang

2012-10-01

Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

Experience gained in enhancing operational safety at ComEd`s nuclear power plants

Energy Technology Data Exchange (ETDEWEB)

Elias, D [Commonwealth Edison Co. (United States)

1997-09-01

The following aspects of experience gained in enhancing operational safety at Comed`s nuclear power plants are discussed: nuclear safety policy; centralization/decentralization; typical nuclear operating organization; safety review boards; human performance enhancement; elements of effective nuclear oversight.

Pursuing for the case of safety

Energy Technology Data Exchange (ETDEWEB)

Hansen, H.; Salaber, A. (Geco-Prakla, Paris (France)); Myers, S. (Sedco Forex, Montrouge (France)); Redd, E. (Sedco Forex, Aberdeen (United Kingdom)); Shannon, R. (Anadrill HSE, London (United Kingdom))

1993-01-01

Ever since the Piper Alpha disaster, safety has become one of the industry's hottest issues. Attention to safety leads to improved communication within organizations as well as between operators and contractors, and ultimately to more efficient operations. In this article descriptions are given of safety management systems, the safety-case philosophy and legislative changes hat are helping promote these new safety tools. 6 figs., 4 ills., 3 refs.

Spectral analysis of 5s25p2(6p+6d+7s) configurations of Ba VI

International Nuclear Information System (INIS)

Sharma, M.K.; Tauheed, A.; Rahimullah, K.

2014-01-01

The sixth spectrum of barium (Ba VI) has been investigated with the aid of experimental recordings made on a 3-m normal incidence vacuum spectrograph of Antigonish laboratory (Canada) in the wavelength region 300–2080 Å using triggered spark as an excitation source. The spectral analysis has been extended considerably to include new configuration the 5s 2 5p 2 6p in odd parity matrix and the 5s 2 5p 2 6d and 5s 2 5p 2 7s configurations in even parity matrix. Previously reported levels of the ground configuration (5s 2 5p 3 ) and three lowest excited configurations the 5s5p 4 , 5s 2 5p 2 5d and 5s 2 5p 2 6s have been confirmed and the two unknown levels of the 5s 2 5p 2 5d configuration with J=9/2, have now been established through the identification of transitions from the 5s 2 5p 2 6p levels. All twenty one levels of the 5s 2 5p 2 6p configuration and twenty nine levels out of thirty six of the 5s 2 5p 2 6d and 5s 2 5p 2 7s configurations have now been established. Hartree–Fock calculations involving configuration interactions support the analyses. The accuracy of our wavelength measurement is ±0.005 Å for sharp lines. - Highlights: • The spectrum of Ba was recorded on a 3-m spectrograph with triggered spark source. • Atomic transitions for Ba VI were identified to established new energy levels. • CI calculations with relativistic corrections were made for theoretical predictions. • Weighted oscillator strength (gf) and transition probabilities (gA) were calculated

Extracurricular activities associated with stress and burnout in preclinical medical students

Directory of Open Access Journals (Sweden)

Jawad Fares

2016-09-01

Full Text Available This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12 while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS. The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62% and burnout (75%. Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study.

Extracurricular activities associated with stress and burnout in preclinical medical students.

Science.gov (United States)

Fares, Jawad; Saadeddin, Zein; Al Tabosh, Hayat; Aridi, Hussam; El Mouhayyar, Christopher; Koleilat, Mohamad Karim; Chaaya, Monique; El Asmar, Khalil

2016-09-01

This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Ethical Considerations of Preclinical Testing

Directory of Open Access Journals (Sweden)

Allen Goldenthal

2015-12-01

Full Text Available The numbers of animal tests being conducted are on a sharp incline.  Much of this increase is directly due to our ability to generate transgenic models and knock-outs, thereby increasing the validity of the animal model but not necessarily correlating directly with any translational medical benefits to the human counterpart.  In spite of our best efforts, there still exist species differences that prevent the application directly from animal to human, and in some examples having a completely different and adverse effect from that seen in the animal model. There are several ways in which we can improve the opportunity for a positive test outcome and at the same time reduce the animal usage which is associated with our current animal testing practices. The benefit of the 3R’s is that they encourage us not only to avoid wastage of life but that they require us to provide considerable foresight and extrapolated thought before directly engaging in the preclinical testing phase.

SU-E-T-606: Performance of MR-Based 3D FXG Dosimetry for Preclinical Irradiation

Energy Technology Data Exchange (ETDEWEB)

Welch, M [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Jaffray, D [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON (Canada); Department of Radiation Oncology, University of Toronto, Toronto, ON (Canada); TECHNA Institute for the Advancement of Technology for Health, Toronto, ON (Canada)

2015-06-15

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MR and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation

Preclinical experimental stress studies: protocols, assessment and comparison.

Science.gov (United States)

Bali, Anjana; Jaggi, Amteshwar Singh

2015-01-05

Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

Safety-efficacy balance of S-ketamine and S-norketamine in acute and chronic pain

OpenAIRE

Noppers, Ingeborg Marieke

2011-01-01

The balance between safety and efficacy is important in pharmacotherapy. When the indication of a registered drug shifts to another disease or a different patient population, studies on safety and efficacy need to be performed. Ketamine is a relatively ‘old’ drug and used for almost 50 years as an anesthetic. Recently there has been a renewed interest for the treatment of therapy-resistant chronic pain with subanesthetic doses of ketamine. This thesis describes the effects of S-ketamine in pa...

Preclinical evaluation of radiolabelled nimotuzumab, a promising monoclonal antibody targeting the epidermal growth factor receptor

Czech Academy of Sciences Publication Activity Database

Bárta, P.; Lázníčková, A.; Lázníček, M.; Beckford, Denis R.; Beran, Miloš

2013-01-01

Roč. 56, č. 5 (2013), s. 280-288 ISSN 0362-4803 Grant - others:GA ČR(CZ) GAP304/10/1738 Institutional support: RVO:61389005 Keywords : radiopharmaceutical * 177Lu * 131I * nimotuzumab * EGFR * preclinical biodistribution Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 1.187, year: 2013

SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

Shang, M; Sands, M; Bolch, W [University of Florida, Gainesville, FL (United States)

2015-06-15

Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adult beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.

It’s all about safety signs!

CERN Multimedia

2013-01-01

Their first occurrence may date back to the Egyptian hieroglyphs, but today they can be found everywhere: on our clothes labels as care labels, in train stations and airports to guide us, during the Olympics to identify various sports, on our dashboards, etc.   Safety wise, they are used to indicate a danger, a prohibition, an obligation, a safety exit, firefighting equipment, etc. The HSE Unit has decided to update the 150 safety signs used on the CERN site and, to correspond with this, recently published a Safety Guideline GS-1-0-1, available on the Safety Unit website. The Guideline contains more than 150 safety signs as well as diverse information regarding the meaning of the signs, their location and how to use them. The Guideline will shortly be completed with a new Safety Rule that will replace the former Security Code A3, “Safety colours and safety signs”. Please be informed that you also have the option to create new safety signs, provided that you first g...

Review of SKB's interim report of SR-Can: SKI's and SSI's evaluation of SKB's up-dated methodology for safety assessment

Energy Technology Data Exchange (ETDEWEB)

Dverstorp, Bjoern; Moberg, Leif; Wiebert, Anders; Xu Shulan [Swedish Radiation Protection Authority, Stockholm (Sweden); Stroemberg, Bo; Kautsky, Fritz; Lilja, Christina; Simic, Eva; Sundstroem, Benny; Toverud, Oeivind [Swedish Nuclear Power Inspectorate, Stockholm (Sweden)

2005-07-01

This report presents the findings of a review of the Swedish Nuclear Fuel and Waste Management Co.'s (SKB) interim report of the safety assessment SR-Can (SKB TR 04-11), conducted by the Swedish Radiation Protection Authority (SSI) and the Swedish Nuclear Power Inspectorate (SKI). SKB's interim report describes and exemplifies the safety assessment methodology that SKB plans to use in the oncoming licence applications for an encapsulation plant and a final repository for spent nuclear fuel. The authorities' review takes into account the findings of an international peer review of SKB's interim report. The authorities conclude that SKB has improved its safety assessment methodology in several aspects compared to earlier safety reports. Among other things the authorities commend SKB for giving a comprehensive account of relevant regulations and guidance, and for the systematic approach to identification and documentation of features, events and processes that need to be considered in the safety assessment. However, the authorities also conclude that important parts of SKB's method need to be further developed before they are mature enough to be used as a basis for a license application. The authorities' overall assessment is summarised in chapter 8 of this report.

Samsung Galaxy S6 for dummies

CERN Document Server

Hughes, Bill

2015-01-01

Explore the capabilities of your Samsung Galaxy S 6 with this definitive guide! Learning to use a new phone can be both difficult and frustrating. With confusing documentation and baffling support, the references provided by phone manufacturers can be intimidating. Enter Samsung Galaxy S 6 For Dummies! This extensive yet practical guide walks you through the most useful features of your new Samsung Galaxy S 6-and it shows you all the best tricks to getting the most out of your device. With an accessible and fun, yet informative writing style, this is a text that you'll refer to again and agai

IAEA’s Approach to Leadership, Management and Culture for Safety

International Nuclear Information System (INIS)

Rzentkowski, G.

2016-01-01

In this session the director of the Division of Nuclear Installation Safety (NSNI) will describe the division’s approach to leadership, management and culture for safety and outline the strategy adopted for this work. The IAEA has developed a safety culture foundation framework which is used to support all installations’ and organisations’ work for continuous improvement to achieve excellence in nuclear safety performance. The framework has been developing since 1986 through the work of the IAEA and the nuclear community, and is based on nuclear organisations’ experiences (both in practices applied and events experienced) and the development of scientific knowledge on human and organisation factors that support nuclear safety performance. The main aim for the IAEA is to assist the Member States to translate the knowledge into practical and successful practise, and to further enhance the safety on nuclear installations. The Strategy of the division is to share the common foundation of the framework across the different nuclear sectors and ensure that application of improvement activities are firmly based on knowledge and appropriate context based solutions.

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

Science.gov (United States)

Provencher, Steeve; Archer, Stephen L; Ramirez, F Daniel; Hibbert, Benjamin; Paulin, Roxane; Boucherat, Olivier; Lacasse, Yves; Bonnet, Sébastien

2018-03-30

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from

S100A6 - New facts and features

Energy Technology Data Exchange (ETDEWEB)

Lesniak, Wieslawa; Slomnicki, Lukasz P. [Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, 02-093 Warsaw (Poland); Filipek, Anna, E-mail: a.filipek@nencki.gov.pl [Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, 02-093 Warsaw (Poland)

2009-12-25

S100A6 (calcyclin) is a 10.5 kDa Ca{sup 2+}-binding protein that belongs to the S100 protein family. S100A6 contains two EF-hand motifs responsible for binding of Ca{sup 2+}. It also binds Zn{sup 2+} through not yet identified structures. Binding of Ca{sup 2+} induces a conformational change in the S100A6 molecule which in consequence increases its overall hydrophobicity and allows for interaction with target proteins. S100A6 was found in different mammalian and avian (chicken) tissues. A high level of S100A6 is observed in epithelial cells, fibroblasts and in different kinds of cancer cells. The function of S100A6 is not clear at present, but it has been suggested that it may be involved in cell proliferation, cytoskeletal dynamics and tumorigenesis. Additionally, S100A6 might have some extracellular activities. This review presents new facts and features concerning the S100A6 protein.

Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics.

Science.gov (United States)

Jain, Shweta; Khaiser, Imran M; Thakur, Sophia; Jain, Shikha

2014-05-01

Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases.

Aerosol measles vaccination in macaques: Preclinical studies of immune responses and safety

NARCIS (Netherlands)

R.L. de Swart (Rik); T. Kuiken (Thijs); J. Fernandez-de Castro (Jorge); M.J. Papania (Mark); J.V. Bennett (John); J.L. Valdespino (José); P.D. Minor; C.L. Witham (Clyde); S. Yüksel (Selma); H.W. Vos (Helma); G. van Amerongen (Geert); A.D.M.E. Osterhaus (Albert)

2006-01-01

textabstractThe comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston-Zagreb measles virus (MV) vaccine and compared different

Nuclear regulatory policy concept on safety, security, safeguards and emergency preparedness (3S+EP)

International Nuclear Information System (INIS)

Ilyas, Zurias

2009-01-01

Regulatory Policy is formulated in regulations that stipulate the assurance of workers and public safety and environmental protection. Legislation and regulations on nuclear energy should consider nuclear safety, security and safeguards, as well as nuclear emergency preparedness (3S+EP) and liability for nuclear damage. Specific requirements stipulated in international conventions and agreements should also be taken into account. Regulatory Policy is formulated in regulations that stipulate the assurance of workers and public safety and environmental protection. Legislation and regulations on nuclear energy should consider nuclear safety, security and safeguards, as well as nuclear emergency preparedness (3S+EP) and liability for nuclear damage. Specific requirements stipulated in international conventions and agreements should also be taken into account. By undertaking proper regulatory oversight on Safety, Security and Emergency Preparedness (3S+EP) as an integrated and comprehensive system, safe and secure use of nuclear energy can be assured. Licence requirements and conditions should fulfil regulatory requirements pertaining to 3S+EP for nuclear installation as an integrated system. An effective emergency capacity that can be immediately mobilized is important. The capacity in protecting the personnel before, during and after the disaster should also be planned. Thus, proper emergency preparedness should be supported by adequate resources. The interface between safety, security, safeguards and emergency preparedness has to be set forth in nuclear regulations, such as regulatory requirements; 3S+EP; components, systems and structures of nuclear installations and human resources. Licensing regulations should stipulate, among others, DIQ, installations security system, safety analysis report, emergency preparedness requirements and necessary human resources that meet the 3S+EP requirements.

Anatomy meets dentistry! Linking anatomy and clinical practice in the preclinical dental curriculum

Directory of Open Access Journals (Sweden)

Nicole Rafai

2016-11-01

Full Text Available Abstract Background Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on “Palpation of the Head and Neck Muscles” and to measure the learning outcomes. Methods For the curricular development of the expanded course module, Kern’s 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module on learning outcomes. Four learning methods were compared: (1 lecture, (2 lecture + e-module, (3 lecture + skills training, (4 lecture + skills training + e-module. An objective structured clinical examination (OSCE was used to measure and compare learning outcomes. Results The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007. Students who participated in the skills training did better (φ 107.4 ± 14.4 points than students who only attended the lecture (φ 88.8 ± 26.2 points. Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points, thus making it the ideal method for achieving the learning objectives defined in this study. Conclusions The “Palpation of

Preclinical incorporation dosimetry of (+)-[18F) flubatine in piglets

International Nuclear Information System (INIS)

Sattler, B.; Patt, M.; Sabri, O.; Kranz, M.; Donat, C.K.; Deuther-Conrad, W.; Fischer, S.; Brust, P.; Sattler, T.; Smits, R.; Hoepping, A.; Steinbach, J.

2015-01-01

Full text of publication follows. Aim: (+)-[ 18 F] flubatine is the mirror image isomer of (-)-[ 18 F] flubatine, which is successfully used for neuroimaging of alpha4beta2 nAChRs with PET. To assess the radiation risk by this new radiotracer, biodistribution, organ doses (OD) and the effective dose (ED) were investigated in a preclinical trials using piglets. Method: whole body dosimetry of (+)-[ 18 F] flubatine was performed in 3 female piglets (age: 43 ± 1.2 days, weight: 14 ± 1.0 kg). The animals were narcotized using 20 mg/kg Ketamine, 2 mg/kg Azaperone; 1.5% Isoflurane in 70% N 2 O/30% O 2 and sequentially PET-imaged up to 5 hours post i.v. injection of 183.5 ± 9.0 MBq on a SIEMENS Biograph16 PET/CT-system on 7 bed positions (BP) per frame, 1.5 to 6 min/BP, CT-attenuation correction (AC) and iterative reconstruction. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (%ID/g, and %ID/organ). Time- and mass-scales were adapted to the human order of magnitude. The ODs were calculated using the adult male model with OLINDA. The ED was calculated using tissue weighting factors as published in the ICRP103. Results: The highest OD was received by the urinary bladder (71.7 ± 26.3 μSv/MBq), the kidneys (45.1 ± 6.5 μSv/MBq) and the brain (32.3 ± 3.24 μSv/MBq). The highest contribution to the ED was by the urinary bladder (2.9 ± 1.1 μSv/MBq), the lungs (1.7 ± 0.02 μSv/MBq) and the red marrow (1.4 ± 0.1μSv/MBq). According to this data, the ED to humans is 14.3 ± 0.3 μSv/MBq. Conclusion: considering 40% underestimation of the ED to humans by preclinical dosimetry [1] the expected ED to humans after 300 MBq i.v. is 7.2 mSv, which is about the ED by (-)-[ 18 F]flubatine (6.8 mSv/300 MBq) and well within the range of what other 18 F-labeled compounds cause to humans. This risk assessment encourages to transfer (+)-[F 18 ] flubatine from preclinical to clinical study phases and to further develop

The Р60-S6K1 isoform of ribosomal protein S6 kinase 1 is a product of alternative mRNA translation

Directory of Open Access Journals (Sweden)

I. V. Zaiets

2018-07-01

Full Text Available Ribosomal protein S6 kinase 1 (S6K1 is a well-known downstream effector of mTORC1 (mechanistic target of rapamycin complex 1 participating primarily in the regulation of cell growth and metabolism. Deregulation of mTOR/S6K1 signaling can promote numerous human pathologies, including cancer, neurodegeneration, cardiovascular disease, and metabolic disorders. As existing data suggest, the S6K1 gene encodes several protein isoforms, including p85-S6K1, p70-S6K1, and p60-S6K1. The two of these isoforms, p85-S6K1 and p70-S6K1, were extensively studied to date. The origin and functional significance of the p60-S6K1 isoform remains a mystery, however, it was suggested that the isoform could be a product of alternative S6K1 mRNA translation. Herein we report the generation of HEK-293 cells exclusively expressing p60-S6K1 as a result of CRISPR/Cas9-mediated inactivation of p85/p70-S6K1 translation. Moreover, the generated modified cells displayed the elevated level of p60-S6K1 expression compared to that in wild-type HEK-293 cells. Our data confirm an assumption that p60-S6K1 is alternatively translated, most probably, from the common for both p70- and p85-S6K1 mRNA transcript and reveal a link between p60-S6K1 expression and such cellular processes as cell proliferation and motility. In addition, our findings indicate that the p60-S6K1 isoform of S6K1 may undergo a mode of regulation distinct from p70- and p85-S6K1 due to the absence of mTOR-regulated p60-S6K1 phosphorylation at T389 that is important for S6K1 activation.

Health and Safety Plan for Waste Area Grouping 6 at Oak Ridge National Laboratory, Oak Ridge, Tennessee. Environmental Restoration Program

Energy Technology Data Exchange (ETDEWEB)

Van Hoesen, S.D.; Clark, C. Jr.; Burman, S.N. [Oak Ridge National Lab., TN (United States); Manis, L.W.; Barre, W.L. [Analysas Corp., Oak Ridge, TN (United States)

1993-12-01

The Martin Marietta Energy Systems, Inc. (Energy Systems), policy is to provide a safe and healthful workplace for all employees and subcontractors. The accomplishment of this policy requires that operations at Waste Area Grouping (WAG) 6 at the Department of Energy (DOE) Oak Ridge National Laboratory are guided by an overall plan and consistent proactive approach to safety and health (S&H) issues. The plan is written to utilize past experience and best management practices to minimize hazards to human health or the environment from events such as fires, explosions, falls, mechanical hazards, or any unplanned release of hazardous or radioactive materials to air, soil, or surface water This plan explains additional site-specific health and safety requirements such as Site Specific Hazards Evaluation Addendums (SSHEAs) to the Site Safety and Health Plan which should be used in concert with this plan and existing established procedures.

The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

International Nuclear Information System (INIS)

Amacher, David E.

2010-01-01

Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in

Observation of the strongest 5s2 5p6 5d-(5s2 5p5 5d6s+5s25p6 7p) transitions in Au XI to Bi XV ions

International Nuclear Information System (INIS)

Churilov, S.S.; Joshi, Y.N.

2001-01-01

The spectra of gold till bismuth were studied in the 90-135 A region. Nine most intense lines belonging to the 5s 2 5p 6 5d-5s 2 5p 5 5d6s array were identified in Au XI to Bi XV ions. The 5s 2 5p 6 7p 2 P 3/2,1/2 levels in Au XI and the 5s 2 5p 6 7p 2 P 3/2 level in Hg XII were also identified. The observed wavelengths and intensities agree quite well with the Hartree-Fock calculations. (orig.)

Kinetic modeling in pre-clinical positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Kuntner, Claudia [AIT Austrian Institute of Technology GmbH, Seibersdorf (Austria). Biomedical Systems, Health and Environment Dept.

2014-07-01

Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges of deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data.

Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

Science.gov (United States)

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

2016-01-01

The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

Role of SimMan in teaching clinical skills to preclinical medical students

Directory of Open Access Journals (Sweden)

Swamy Meenakshi

2013-02-01

Full Text Available Abstract Background Simulation training has potential in developing clinical skills in pre-clinical medical students, but there is little evidence on its effectiveness. Methods Twenty four first year graduate entry preclinical medical students participated in this crossover study. They were divided into two groups, one performed chest examination on each other and the other used SimMan. The groups then crossed over. A pretest, midtest and post-test was conducted in which the students answered the same questionnaire with ten questions on knowledge, and confidence levels rated using a 5 point Likert scale. They were assessed formatively using the OSCE marking scheme. At the end of the session, 23 students completed a feedback questionnaire. Data was analyzed using one-way ANOVA and independent t-test. Results When the two groups were compared, there was no significant difference in the pretest and the post-test scores on knowledge questions whereas the midtest scores increased significantly (P Mean confidence ratings increased from the pretest to midtest and then further in the post-test for both groups. Their confidence ratings increased significantly in differentiating between normal and abnormal signs [Group starting with SimMan, between pretest and midtest (P= 0.01 and group starting with peer examination, between midtest and post-test (P=0.02]. When the students’ ability to perform examination on each other for both groups was compared, there was a significant increase in the scores of the group starting with SimMan (P=0.007. Conclusions This pilot study demonstrated a significant improvement in the students’ knowledge and competence to perform chest examination after simulation with an increase in the student’s perceived levels of confidence. Feedback from the students was extremely positive. SimMan acts as a useful adjunct to teach clinical skills to preclinical medical students by providing a simulated safe environment and thus aids

Rigor or mortis: best practices for preclinical research in neuroscience.

Science.gov (United States)

Steward, Oswald; Balice-Gordon, Rita

2014-11-05

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

Science.gov (United States)

Sprouse, Alyssa A.

2016-01-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

[DIFFERENCE IN THE PREVALENCE OF BURNOUT SYNDROME IN PRECLINICAL AND CLINICAL TEACHING DOCTORS OF MOSTAR SCHOOL OF MEDICINE].

Science.gov (United States)

Vukojevič, Mladenka; Antunovič, Andelka; Petrov, Božo

2015-01-01

The aim of this study was to determine the difference in the prevalence of burnout syndrome in preclinical and clinical teaching doctors of Mostar School of Medicine in the academic year 2011/2012. Special attention was also focused on finding out the possible difference between the syndrome incidence that was correlated to gender and years of service. The main hypothesis was that the probability of burnout syndrome incidence was higher in the group of female clinical teaching doctors having more years of service. The study involved 62 people with high academic education employed at Mostar School of Medicine who were surveyed during a randomly selected consecutive 3-month period (February to May) of the academic year 2011/2012. The data were prospectively collected through a standardized questionnaire survey. The studied parameters were gender, years of work experience and the engagement in preclinical or clinical departments of the Medical School. The survey showed that 43 out of 62 (69.4%) respondents did not suffer the burnout syndrome, while moderate syndrome was recodred in 19 (30.6%) of them. No person had serious symptoms of the syndrome. The difference between the respondents who suffered the syndrome and those who did not was not statistically significant (P=0.002). Considering the gender of respondents, statistically significant differences were not confirmed (P=0.444). Considering the years of service, the highest incidence of the syndrome was found in people with more work experience (in the group of 21-25 years), but the difference between the groups was not statistically significant (P=0.271). Observing the work in preclinical and clinical departments, because of the limited number of patients we could not confirm the hypothesis. The syndrome had affected 13 (21%) clinical teaching doctors and 6 (9,7%) preclinical doctors, while the differenece between them was not statistically significant (P=0.054). Considering the results of this research, it has

Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.

Science.gov (United States)

Robert, Philippe; Frenzel, Thomas; Factor, Cécile; Jost, Gregor; Rasschaert, Marlène; Schuetz, Gunnar; Fretellier, Nathalie; Boyken, Janina; Idée, Jean-Marc; Pietsch, Hubertus

2018-04-13

Gadolinium (Gd)-based contrast agents (GBCAs) are pharmaceuticals that have been approved for 30 years and used daily in millions of patients worldwide. Their clinical benefits are indisputable. Recently, unexpected long-term presence of Gd in the brain has been reported by numerous retrospective clinical studies and confirmed in preclinical models particularly after linear GBCA (L-GBCA) compared with macrocyclic GBCA (M-GBCA). Even if no clinical consequences of Gd presence in brain tissue has been demonstrated so far, in-depth investigations on potential toxicological consequences and the fate of Gd in the body remain crucial to potentially adapt the clinical use of GBCAs, as done during the nephrogenic systemic fibrosis crisis. Preclinical models are instrumental in the understanding of the mechanism of action as well as the potential safety consequences. However, such models may be associated with risks of biases, often related to the protocol design. Selection of adequate terminology is also crucial. This review of the literature intends to summarize and critically discuss the main methodological aspects for accurate design and translational character of preclinical studies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Overview of the U. S. flight safety process for space nuclear power

International Nuclear Information System (INIS)

Bennett, G.L.

1981-01-01

The two current types of nuclear power sources used in U. S. spacecraft are described along with the flight safety philosophies governing their use. In the case of radioisotope thermoelectric generators, the design philosophy consists of containment, immobilization, and recovery of the nuclear materials. For reactors, the emphasis is on maintaining a subcritical configuration in all credible accident environments. To document the safety activities, a safety analysis report is prepared for each mission. These reports, which are based on the probabilistic risk assessment methodology pioneered by the space nuclear safety community, are subjected to an interagency safety review before a recommendation is made to approve the launch of a nuclear-powered spacecraft

International Aspects of Nuclear Safety

International Nuclear Information System (INIS)

Lash, T.R.

2000-01-01

Even though not all the world's nations have developed a nuclear power industry, nuclear safety is unquestionably an international issue. Perhaps the most compelling proof is the 1986 accident at Chornobyl nuclear power plant in what is now Ukraine. The U.S. Department of Energy conducts a comprehensive, cooperative effort to reduce risks at Soviet-designed nuclear power plants. In the host countries : Armenia, Ukraine, Russia, Bulgaria, the Czech Republic, Hungary, Lithuania, Slovakia, and Kazakhstan joint projects are correcting major safety deficiencies and establishing nuclear safety infrastructures that will be self-sustaining.The U.S. effort has six primary goals: 1. Operational Safety - Implement the basic elements of operational safety consistent with internationally accepted practices. 2. Training - Improve operator training to internationally accepted standards. 3. Safety Maintenance - Help establish technically effective maintenance programs that can ensure the reliability of safety-related equipment. 4. Safety Systems - Implement safety system improvements consistent with remaining plant lifetimes. 5. Safety Evaluations - Transfer the capability to conduct in-depth plant safety evaluations using internationally accepted methods. 6. Legal and Regulatory Capabilities - Facilitate host-country implementation of necessary laws and regulatory policies consistent with their international treaty obligations governing the safe use of nuclear power

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies.

Science.gov (United States)

Versteegden, Luuk R M; de Jonge, Paul K J D; IntHout, Joanna; van Kuppevelt, Toin H; Oosterwijk, Egbert; Feitz, Wout F J; de Vries, Rob B M; Daamen, Willeke F

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study

Marker for the pre-clinical development of bone substitute materials

Directory of Open Access Journals (Sweden)

de Wild Michael

2017-09-01

Full Text Available Thin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting. The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

RA-6 reactor's probabilistic safety evaluation. Identification and selection of starting events

International Nuclear Information System (INIS)

Kay, J.; Chiossi, C.; Felizia, E.; Vallerga, H.; Kalejman, G.; Navarro, R.; Caruso, G.J.

1987-01-01

A summary of the 'Identification and selection of starting events' stage of the previous probabilistic safety evaluation of RA-6 reactor is presented. This evaluation was performed to verify if the safety criteria required for the licensing of RA-6 are met and to promote the diffusion of its meaning and usefulness with educational purposes. At this stage the starting events of RA-6 are determined and the probability that such events occur is calculated. The identification and selection of starting events is performed in two steps: determination of proposed starting events and determination of postulated starting events. The proposed starting events are determined by means of the master logic diagram (MLD) method, while the postulated starting events are obtained by grouping the proposed starting events. The simplifying hypothesis required for the application of MLD to the reactor are also formulated. The probability that the proposed and postulated starting events occur is afterwards calculated, adopting different fault models, in accordance with the nature of events that are considered. Conservative hypothesis on the characteristics of these events and the uncertainty of parameter values of those models are also formulated. The numerical values of the above mentioned probabilities are obtained by giving the parameters suitable values that are extracted from specialized publications. (Author)

The Inspector General's report on Nuclear Safety and Radiation Protection 2008

International Nuclear Information System (INIS)

2009-01-01

This report, written for the Chairman of EDF, gives the Inspector General's assessment of nuclear safety and radiation protection within the EDF Group. The report is also intended for all those in the company who contribute in any way to nuclear safety and radiation protection through their day-to-day actions and decisions. It also aims to identify any early warning signs and recommend areas for improvement. It therefore focuses on difficulties and weaknesses rather than strengths and progress. It is based on information gathered and observations made during the year, both in France and the UK, whether from workers in the field, or during visits to plants and meetings with the main stakeholders: managers, staff representatives, members of the medical profession, chairmen of local information commissions in France and of Site stakeholder groups (British equivalent of the French Local Information Commissions) in the UK, and contractors. It also makes use of visits and comparisons with other international players on the nuclear scene, and of dialogue with WANO (World Association of Nuclear Operators) and the nuclear safety authorities. Content: 1 - the Inspector General's analysis and conclusions at the end of 2008; 2 - Nuclear safety management; 3 - Radiation protection; 4 - A changing relationship with the nuclear safety authority; 5 - Support for the nuclear plants in service; 6 - Succeeding with the EPR; 7 - Operating the installations for longer; 8 - Further opening up to the outside world; 9 - Renewal of skills; 10 - Labour relations; 11 - The driving forces of cultural change; 12 - Promote change and regulate its pace; 13 - The contribution of the medical staff; 14 - Relations with contractors; 15 - The fire hazard; 16 - Nuclear fuel; 17 - Decommissioning; 18 - Emergency response management; 19 - Events at EDF; 19.1 - The Tricastin nuclear power plant fuel assemblies; 19.2 - Steam generator behaviour; 19.3 - Reactor building evacuation; 20 - Visits

Canada's regulatory framework: The Canadian Nuclear Safety Commission's regulatory framework

International Nuclear Information System (INIS)

Howard, D.

2011-01-01

This paper will discuss the Canadian Nuclear Safety Commission and Canada's Regulatory Framework with respect to Low- and Intermediate-Level Radioactive Waste. The management of low and intermediate level radioactive waste must be ensured in a consistent, environmentally responsible and economical manner throughout its lifecycle -- from its production to the final disposal option. Radioactive waste has been produced in Canada since the early 1930s when the first radium/uranium mine began operating at Port Radium in the Northwest Territories. Pitchblende ore was transported from the Port Radium mine to Port Hope, Ontario where it was refined to produce radium for medical purposes. At present, radioactive waste is generated in Canada from the various stages and uses associated with the nuclear fuel cycle from uranium mining/milling to nuclear reactor operations to radioisotope manufacture and use. The Canadian Nuclear Safety Commission (CNSC regulates the use of nuclear energy and materials to protect the health, safety and security of Canadians and the environment; and to implement Canada's international commitments on the peaceful use of nuclear energy. The CNSC was established in 2000 under the Nuclear Safety and Control Act and reports to Parliament through the Minister of Natural Resources. The CNSC was created to replace the former Atomic Energy Control Board (AECB), which was founded in 1946. Under the Nuclear Safety and Control Act, CNSC's mandate involves four major areas: regulation of the development, production and use of nuclear energy in Canada to protect health, safety and the environment; regulation of the production, possession, use and transport of nuclear substances, and the production, possession and use of prescribed equipment and prescribed information; implementation of measures respecting international control of the development, production, transport and use of nuclear energy and substances, including measures respecting the

Digital controls for plant control systems at the Ulchin 5 and 6 NPP: Lessons for the U.S. NPP retrofits?

International Nuclear Information System (INIS)

McCreary, T.; Stevens, J.

2006-01-01

South Korea, through its nuclear operating arm, Korea Hydro and Nuclear Power, Ltd. (KHNP), has been one of the leading countries in the routine construction and operation of nuclear power plants. While standardizing on certain design approaches in the plant, KHNP continues to stress the need for the most reliable and cutting edge I and C technologies available for safety and non safety related NSSS and BOP functions. Its specifications are among the most challenging in the world with regard to the system performance and reliability requirements that must be met for the systems to be supplied. The Ulchin Units 5 and 6 (1000 MW each) nuclear power plants have been recently commissioned (2004 and 2005 respectively) with advanced programmable digital control systems in the NSSS and BOP (which includes both safety and non-safety applications). The systems supplied met what the authors believe are the most rigorous performance and functional specification criteria in use today. The authors will highlight a number of the specification requirements, the rationale for same and the plant experiences in the resultant supplied systems. As the existing U.S. nuclear fleet is faced with the prospect of upgrading legacy controls with digital controls, there are valuable lessons to be learned in the Ulchin 5 and 6 experiences that can be applied to retrofits and even new U.S. plant designs. Ulchin 5 and 6 is one of the success stories in the application of advanced digital technology to nuclear power plants. The specification focus that guided the selection and project execution for the digital controls supplied for Ulchin was on several key areas: a) a high reliable fault tolerant system, b)functional segmentation to minimize the failure effects on operation, c) validation and verification of the owner's engineer's application design (for regulatory compliance) as well as validation and verification of the system architecture and operation (to assure system performance met

[Impact of microdose clinical trials in the preclinical stage].

Science.gov (United States)

Kim, Soonih

2014-01-01

A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

Application of feedback system in optimizing safety performance of "6"0Co radiation apparatus

International Nuclear Information System (INIS)

Luo Shishi; Wang Zegang; Ge Cailin; Ma Fei; Gong Zheng

2001-01-01

To ensure "6"0Co apparatus runs safely applying the basic principle of cybernetics to optimizing safety performance was studied. Through several decades of practice the cybernetic system is shown to be safe and effective, and it will be an example for small and middle "6"0Co radiation apparatus to rebuild the cybernetic system. (authors)

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

International Nuclear Information System (INIS)

Medin, Paul M.; Boike, Thomas P.

2011-01-01

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Cognitive Deficits in Schizophrenia and Other Neuropsychiatric Disorders: Convergence of Preclinical and Clinical Evidence

Czech Academy of Sciences Publication Activity Database

Stuchlík, Aleš; Sumiyoshi, T.

2014-01-01

Roč. 8, - (2014), s. 444 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GA14-03627S; GA ČR(CZ) GBP304/12/G069; GA MZd(CZ) NT13386; GA MŠk(CZ) LH14053 Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : cognition * neuropsychiatric disorders * animal models * clinical studies * preclinical studies Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

Science.gov (United States)

Mrena, S; Savola, K; Kulmala, P; Reijonen, H; Ilonen, J; Akerblom, H K; Knip, M

2003-06-01

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P siblings of affected children.

Genetic modification of hematopoietic cells using retroviral and lentiviral vectors: safety considerations for vector design and delivery into target cells.

Science.gov (United States)

Dropulic, Boro

2005-07-01

The recent development of leukemia in three patients following retroviral vector gene transfer in hematopoietic stem cells, resulting in the death of one patient, has raised safety concerns for the use of integrating gene transfer vectors for human gene therapy. This review discusses these serious adverse events from the perspective of whether restrictions on vector design and vector-modified target cells are warranted at this time. A case is made against presently establishing specific restrictions for vector design and transduced cells; rather, their safety should be ascertained by empiric evaluation in appropriate preclinical models on a case-by-case basis. Such preclinical data, coupled with proper informed patient consent and a risk-benefit ratio analysis, provide the best available prospective evaluation of gene transfer vectors prior to their translation into the clinic.

Construction of a preclinical multimodality phantom using tissue-mimicking materials for quality assurance in tumor size measurement.

Science.gov (United States)

Lee, Yongsook C; Fullerton, Gary D; Goins, Beth A

2013-07-29

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for radiologic assessment of solid tumors in response to anti-tumor drug therapy in the 1980s and 1990s, respectively. WHO criteria measure solid tumors in two-dimensions, whereas RECIST measurements use only one-dimension which is considered to be more reproducible (1, 2, 3,4,5). These criteria have been widely used as the only imaging biomarker approved by the United States Food and Drug Administration (FDA) (6). In order to measure tumor response to anti-tumor drugs on images with accuracy, therefore, a robust quality assurance (QA) procedures and corresponding QA phantom are needed. To address this need, the authors constructed a preclinical multimodality (for ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI)) phantom using tissue-mimicking (TM) materials based on the limited number of target lesions required by RECIST by revising a Gammex US commercial phantom (7). The Appendix in Lee et al. demonstrates the procedures of phantom fabrication (7). In this article, all protocols are introduced in a step-by-step fashion beginning with procedures for preparing the silicone molds for casting tumor-simulating test objects in the phantom, followed by preparation of TM materials for multimodality imaging, and finally construction of the preclinical multimodality QA phantom. The primary purpose of this paper is to provide the protocols to allow anyone interested in independently constructing a phantom for their own projects. QA procedures for tumor size measurement, and RECIST, WHO and volume measurement results of test objects made at multiple institutions using this QA phantom are shown in detail in Lee et al. (8).

Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

Science.gov (United States)

Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

2015-06-01

Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

Pre-clinical medical student experience in a pediatric pulmonary clinic

Directory of Open Access Journals (Sweden)

Thomas G. Saba

2015-11-01

Full Text Available Objective: Our objective was to evaluate the educational value of introducing pre-clinical medical students to pediatric patients and their families in a subspecialty clinic setting. Methods: First- and second-year medical students at the University of Michigan seeking clinical experience outside of the classroom attended an outpatient pediatric pulmonary clinic. Evaluation of the experience consisted of pre- and post-clinic student surveys and post-clinic parent surveys with statements employing a four-point Likert scale as well as open-ended questions. Results: Twenty-eight first-year students, 6 second-year students, and 33 parents participated in the study. Post-clinic statement scores significantly increased for statements addressing empathic attitudes, confidence communicating with children and families, comfort in the clinical environment, and social awareness. Scores did not change for statements addressing motivation, a sense of team membership, or confidence with career goals. Students achieved their goals of gaining experience interacting with patients, learning about pulmonary diseases, and observing clinic workflow. Parents felt that they contributed to student education and were not inconvenienced. Conclusions: Students identified several educational benefits of exposure to a single pediatric pulmonary clinic. Patients and families were not inconvenienced by the participation of a student. Additional studies are warranted to further investigate the value of this model of pre-clinical medical student exposure to subspecialty pediatrics.

(Ph4P)S6—A Compound Containing the Cyclic Radical Anion S6.−

NARCIS (Netherlands)

Neumuller, F.; Schmock, R.; Kirmse, A.; Voigt, A.; Diefenbach, A.; Bickelhaupt, F.M.; Dehnicke, K.

2000-01-01

Two long S−S bonds link the two S3 fragments in the cyclic radical anion S6.−. This forms as orange‐red crystals with PPh4+ as the counterion in the reaction of sulfane with (tetraphenylphosphonium) hydrogen diazide. The anion has a chair conformation with C2h symmetry (see picture).

Alberta Environment's weir safety program : options for rehabilitation to improve public safety : a case study of the Calgary weir

Energy Technology Data Exchange (ETDEWEB)

Blakely, D. [Alberta Environment, Edmonton, AB (Canada)

2009-07-01

Alberta Environment Water Management Operations (WMO) owns and operates 46 dams and 800 kilometres of canals in Alberta. The WMO consists of 120 staff and several contract operators to take care of this infrastructure. Most of the infrastructure supplies water for irrigation use, which adds 5 billion dollars to the provincial economy annually. Other water uses include stock watering, domestic use, municipal use, recreational use and habitat. Alberta Environment's weir safety program was also discussed along with options for rehabilitation to improve public safety. A case study of Calgary's Weir Dam on the Bow River was highlighted. A brief history of the dam was offered and safety programs around provincially-owned weirs were discussed. Photographs were included to illustrate some of the additional safety measures at the Calgary weir, such as suspended safety buoys upstream of the boom directing paddlers to the portage trail, and signage on the river that can be activated when the boom is out. Typical river users on the Calgary Bow River and safety history at the Calgary Weir were discussed along with other topics such as the Calgary Bow River weir project criteria; project design progress; pre-feasibility options; scale modelling; final design analysis; construction funding; and proposed changes to the safety program for the new weir configuration. figs.

Microbubbles combined with ultrasound therapy in ischemic stroke: A systematic review of in-vivo preclinical studies.

Directory of Open Access Journals (Sweden)

Laurent Auboire

Full Text Available Microbubbles (MBs combined with ultrasound sonothrombolysis (STL appears to be an alternative therapeutic strategy for acute ischemic stroke (IS, but clinical results remain controversial.The aim of this systematic review is to identify the parameters tested; to assess evidence on the safety and efficacy on preclinical data on STL; and to assess the validity and publication bias.Pubmed® and Web of ScienceTM databases were systematically searched from January 1995 to April 2017 in French and English. We included studies evaluating STL on animal stroke model. This systematic review was conducted in accordance with the PRISMA guidelines. Data were extracted following a pre-defined schedule by two of the authors. The CAMARADES criteria were used for quality assessment. A narrative synthesis was conducted.Sixteen studies met the inclusion criteria. The result showed that ultrasound parameters and types of MBs were heterogeneous among studies. Numerous positive outcomes on efficacy were found, but only four studies demonstrated superiority of STL versus recombinant tissue-type plasminogen activator on clinical criteria. Data available on safety are limited.Quality assessment of the studies reviewed revealed a number of biases.Further in vivo studies are needed to demonstrate a better efficacy and safety of STL compared to currently approved therapeutic options.http://syrf.org.uk/protocols/.

Surgeon Involvement in Pre-Clinical Medical Education: Attitudes of Directors of Education

Directory of Open Access Journals (Sweden)

Simon Turner

2012-04-01

Full Text Available Background: Application rates to surgical residencies have shown a downward trend recently. Introducing students to surgeons early in medical school can increase interest in surgery as a career and enhance the instruction of important surgical topics. Directors of undergraduate medical education have unique insight and influence regarding the participation of surgeons in pre-clinical education. Methods: To understand the attitudes of these educators towards surgeons as teachers in pre-clinical programs, a survey was administered to the directors of undergraduate medical education at each of the English-language medical schools in Canada. Results: Educators estimate the participation of surgeons in all categories of pre-clinical education to be low, despite being valuable, and think that it should be increased. The most significant barrier to participation identified was a lack of surgeons’ time. Conclusions: Despite the value of surgeons participating in pre-clinical education, their rate of participation is low. Steps should be taken to facilitate the involvement of surgeons in this phase of education, which may lead to improved education for students and increased student interest in surgery residencies.

IAEA Sees Safety Commitment at Spain’s Almaraz Nuclear Power Plant, Areas for Enhancement

International Nuclear Information System (INIS)

2018-01-01

An International Atomic Energy Agency (IAEA) team of experts said the operator of Spain’s Almaraz Nuclear Power Plant demonstrated a commitment to the long-term safety of the plant and noted several good practices to share with the nuclear industry globally. The team also identified areas for further enhancement. The Operational Safety Review Team (OSART) today concluded an 18-day mission to Almaraz, whose two 1,050-MWe pressurized-water reactors started commercial operation in 1983 and 1984, respectively. Centrales Nucleares Almaraz-Trillo (CNAT) operates the plant, located about 200 km southwest of Madrid. OSART missions aim to improve operational safety by objectively assessing safety performance using the IAEA’s safety standards and proposing recommendations for improvement where appropriate. Nuclear power generates more than 21 per cent of electricity in Spain, whose seven operating power reactors all began operation in the 1980s.The mission made a number of recommendations to improve operational safety, including: • The plant should implement further actions related to management, staff and contractors to enforce standards and expectations related to industrial safety. • The plant should take measures to reinforce and implement standards to enhance the performance of reactivity manipulations in a deliberate and carefully-controlled manner. • The plant should improve the support, training and documented guidance for Severe Accident Management Guideline users in order to mitigate complex severe accident scenarios. The team provided a draft report of the mission to the plant’s management. The plant management and the Nuclear Safety Council (CSN), which is responsible for nuclear safety oversight in Spain, will have the opportunity to make factual comments on the draft. These will be reviewed by the IAEA and the final report will be submitted to the Government of Spain within three months. The plant management said it would address the areas

Impact of biomarker development on drug safety assessment

International Nuclear Information System (INIS)

Marrer, Estelle; Dieterle, Frank

2010-01-01

Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

Efficacy and safety of praziquantel in preschool-aged children in an area co-endemic for Schistosoma mansoni and S. haematobium.

Directory of Open Access Journals (Sweden)

Jean T Coulibaly

Full Text Available In sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied.We assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (<6 years in the Azaguié district, south Côte d'Ivoire, where Schistosoma mansoni and S. haematobium coexist. Using a cross-sectional design, children provided two stool and two urine samples before and 3 weeks after treatment. Crushed praziquantel tablets, mixed with water, were administered at a dose of 40 mg/kg. Adverse events were assessed and graded 4 and 24 hours posttreatment by interviewing mothers/guardians.Overall, 160 preschool-aged children had at least one stool and one urine sample examined with duplicate Kato-Katz thick smears and a point-of-care circulating cathodic antigen (POC-CCA cassette for S. mansoni, and urine filtration for S. haematobium diagnosis before and 3 weeks after praziquantel administration. According to the Kato-Katz and urine filtration results, we found high efficacy against S. mansoni (cure rate (CR, 88.6%; egg reduction rate (ERR, 96.7% and S. haematobium (CR, 88.9%; ERR, 98.0%. POC-CCA revealed considerably lower efficacy against S. mansoni (CR, 53.8%. Treatment was generally well tolerated, but moderately severe adverse events (i.e., body and face inflammation, were observed in four Schistosoma egg-negative children.Crushed praziquantel administered to preschool-aged children at a dose of 40 mg/kg is efficacious against S. mansoni and S. haematobium in a co-endemic setting of Côte d'Ivoire. Further research is required with highly sensitive

Engineered safeguards and passive safety features (safety analysis detailed report no. 6)

Energy Technology Data Exchange (ETDEWEB)

1988-01-15

The Safety-Analysis Summary lists the reactor's safety aspects for passive and active prevention of severe accidents and mitigation of accident consequences, i.e., intrinsic and passive protections of the plant; intrinsic and passive protections of the core; inherent decay-heat removal systems; rapid-shutdown systems; four physical containment barriers. This report goes into further details regarding some of this aspects.

Prospects for nuclear safety research

Energy Technology Data Exchange (ETDEWEB)

Beckjord, E.S.

1995-04-01

This document is the text of a paper presented by Eric S. Beckjord (Director, Nuclear Regulatory Research/NRC) at the 22nd Water Reactor Safety Meeting in Bethesda, MD in October 1994. The following topics are briefly reviewed: (1) Reactor vessel research, (2) Probabilistic risk assessment, (3) Direct containment heating, (4) Advanced LWR research, (5) Nuclear energy prospects in the US, and (6) Future nuclear safety research. Subtopics within the last category include economics, waste disposal, and health and safety.

Neurovirulence safety testing of mumps vaccines--historical perspective and current status.

Science.gov (United States)

Rubin, S A; Afzal, M A

2011-04-05

Many live, attenuated viral vaccines are derived from wild type viruses with known neurovirulent properties. To assure the absence of residual neurotoxicity, pre-clinical neurovirulence safety testing of candidate vaccines is performed. For mumps virus, a highly neurotropic virus, neurovirulence safety testing is performed in monkeys. However, laboratory studies suggest an inability of this test to correctly discern among virus strains of varying neurovirulence potential in man, and, further, some vaccines found to be neuroattenuated in monkeys were later found to be neurovirulent in humans when administered in large numbers. Over the past decade, concerted efforts have been made to replace monkey-based neurovirulence safety testing with more informative, alternative methods. This review summarizes the current status of mumps vaccine neurovirulence safety testing and insights into models currently approved and those under development. Published by Elsevier Ltd.

Playground Safety

Science.gov (United States)

... Prevention Fall Prevention Playground Safety Poisoning Prevention Road Traffic Safety Sports Safety Get Email Updates To receive ... at the Consumer Product Safety Commission’s Playground Safety website . References U.S. Consumer Product Safety Commission. Injuries and ...

[Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994-95

International Nuclear Information System (INIS)

DeNardo, S.J.

1995-01-01

The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and 90 Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of 90 Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, 67 Cu imaging studies for lymphoma cancer, and 111 In MoAb imaging studies for breast cancer to predict 90 Y MoAb therapy

Development of 4S and related technologies. (3) Statistical evaluation of safety performance of 4S on ULOF event

International Nuclear Information System (INIS)

Ishii, Kyoko; Matsumiya, Hisato; Horie, Hideki; Miyagi, Kazumi

2009-01-01

The purpose of this work is to evaluate quantitatively and statistically the safety performance of Super-Safe, Small, and Simple reactor (4S) by analyzing with ARGO code, a plant dynamics code for a sodium-cooled fast reactor. In this evaluation, an Anticipated Transient Without Scram (ATWS) is assumed, and an Unprotected Loss of Flow (ULOF) event is selected as a typical ATWS case. After a metric concerned with safety design is defined as performance factor a Phenomena Identification Ranking Table (PIRT) is produced in order to select the plausible phenomena that affect the metric. Then a sensitivity analysis is performed for the parameters related to the selected plausible phenomena. Finally the metric is evaluated with statistical methods whether it satisfies the given safety acceptance criteria. The result is as follows: The Cumulative Damage Fraction (CDF) for the cladding is defined as a metric, and the statistical estimation of the one-sided upper tolerance limit of 95 percent probability at a 95 percent confidence level in CDF is within the safety acceptance criterion; CDF < 0.1. The result shows that the 4S safety performance is acceptable in the ULOF event. (author)

Detection of preclinical Parkinson's disease with PET

International Nuclear Information System (INIS)

Brooks, D.J.

1991-01-01

Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology

Exploring the Υ(6S) → χ{sub bJ}φ and Υ(6S) → χ{sub bJ}ω hidden-bottom hadronic transitions

Energy Technology Data Exchange (ETDEWEB)

Huang, Qi; Wang, Bo; Liu, Xiang [Lanzhou University, School of Physical Science and Technology, Lanzhou (China); Lanzhou University and Institute of Modern Physics of CAS, Research Center for Hadron and CSR Physics, Lanzhou (China); Chen, Dian-Yong [Southeast University, Department of Physics, Nanjing (China); Matsuki, Takayuki [Tokyo Kasei University, Itabashi, Tokyo (Japan); Nishina Center, RIKEN, Theoretical Research Division, Wako, Saitama (Japan)

2017-03-15

In this work, we investigate the hadronic loop contributions to the Υ(6S) → χ{sub bJ}φ (J = 0, 1, 2) along with Υ(6S) → χ{sub bJ}ω (J=0, 1, 2) transitions. We predict that the branching ratios of Υ(6S) → χ{sub b0}φ, Υ(6S) → χ{sub b1}φ and Υ(6S) → χ{sub b2}φ are (0.68-4.62) x 10{sup -6}, (0.50-3.43) x 10{sup -6} and (2.22-15.18) x 10{sup -6}, respectively, and those of Υ(6S) → χ{sub b0}ω, Υ(6S) → χ{sub b1}ω and Υ(6S) → χ{sub b2}ω are (0.15-2.81) x 10{sup -3}, (0.63-11.68) x 10{sup -3}, and (1.08-20.02) x 10{sup -3}, respectively. Especially, some typical ratios, which reflect the relative magnitudes of the predicted branching ratios, are given, i.e., for Υ(6S) → χ{sub bJ}φ transitions, R{sup φ}{sub 10} = B[Υ(6S) → χ{sub b1}φ]/B[Υ(6S) → χ{sub b0}φ] ∼ 0.74, R{sup φ}{sub 20} = B[Υ(6S) → χ{sub b2}φ]/B[Υ(6S) → χ{sub b0}φ] ∼ 3.28, and R{sup φ}{sub 21} = B[Υ(6S) → χ{sub b2}φ]/B[Υ(6S) → χ{sub b1}φ] ∼ 4.43, and for Υ(6S) → χ{sub bJ}ω transitions, R{sup ω}{sub 10} = B[Υ(6S) → χ{sub b1}ω]/B[Υ(6S) → χ{sub b0}ω] ∼ 4.11, R{sup ω}{sub 20} = B[Υ(6S) → χ{sub b2}ω]/B[Υ(6S) → χ{sub b0}ω] ∼ 7.06, and R{sup ω}{sub 21} = B[Υ(6S) → χ{sub b2}ω]/B[Υ(6S) → χ{sub b1}ω] ∼ 1.72. With the running of BelleII in the near future, experimental measurement of these two kinds of transitions will be a potential research issue. (orig.)

Preclinical quantitative MicroPET imaging in evaluation of neuroprotective drug candidates

International Nuclear Information System (INIS)

Son, Ji Yeon; Kim, Yu Kyeong; Kim, Ji Sun; Lee, Byung Chul; Kim, Kyeong Min; Choi, Tae Hyun; Cheon, Gi Jeong; Lee, Won Woo; Kim, Sang Eun

2007-01-01

Using in vivo molecular imaging with microPET/SPECT has been expected to facilitate drug discovery and development. In this study, we applied quantitative microPET to the preclinical evaluation of the effects of two neuroprotective drug candidates to the nigrostriatal dopaminergic neuronal damage. Fifteen SD rats were divided into three groups. The rats of each group were orally administrated one of neuroprotective candidate; NeuProtec (100mg/kg bid) and SureCero (10mg/kg, qd) or normal saline (0.1ml, qd) for 3 weeks. 6-OHDA was sterotactically placed to the right striatum on eighth day after starting while continuing the medication for additional 14 days. [ 124 I]FP-ClT PET scans were obtained using microPET R4 scanner. The behavioral test by amphetamine-induced rotation and the histological examination after thyrosine hydroxylase (TH) immunohistochemical staining were performed. Different uptake in the lesioned striatum among the groups were demonstrated on [ 124 I]FP-CIT PET images. The rats with NeuProtec showed higher binding in the lesion than controls. No differences were observed in SureCere groups. The FP-CIT uptake in the lesioned striatum was well correlated with the % reduction of TH(+) cells (rho =0.73, p=0.025), and also correlated with rotation test (rho =0.79, p=0.001) [ 124 I]FP-CIT animal PET depicted the neuroprotective effects of NeuProtec to the 6-OHDA neurotoxicity in the rat striatum. No demonstrable effect of SureCero might indicate that inadequate dosage was used in this study. MicroPET imaging with small animal could be a great tool in preclinical evaluation of drug efficacy

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

Science.gov (United States)

Wu, Fan; Bansal, Loveleena; Bradshaw‐Pierce, Erica; Chan, Jason R.; Liederer, Bianca M.; Mettetal, Jerome T.; Schroeder, Patricia; Schuck, Edgar; Tsai, Alice; Xu, Christine; Chimalakonda, Anjaneya; Le, Kha; Penney, Mark; Topp, Brian; Yamada, Akihiro

2018-01-01

A cross‐industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering. PMID:29349875

Safety analysis - current and future regulatory challenges

Energy Technology Data Exchange (ETDEWEB)

Jamieson, T., E-mail: Terry.Jamieson@cnsc-ccsn.gc.ca [Canadian Nuclear Safety Commission, Ottawa, ON (Canada)

2015-07-01

'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

Safety analysis - current and future regulatory challenges

International Nuclear Information System (INIS)

Jamieson, T.

2015-01-01

'Full text:' The current and future regulatory challenges associated with deterministic safety analysis are reviewed, including: 1. The CNSC's and safety control areas. 2. Traditional safety analysis approach. 3. Experience gained and impact. 4. Current analysis and regulatory approaches. 5. Current status. 6. Complexity and challenges In particular, the technical, regulatory and strategic aspects of these challenges are discussed. (author)

Reproducibility of preclinical animal research improves with heterogeneity of study samples

Science.gov (United States)

Vogt, Lucile; Sena, Emily S.; Würbel, Hanno

2018-01-01

Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research. PMID:29470495

Regulatory Experience on Safety Smart Transmitter's CCF of SKN 3 and 4

Energy Technology Data Exchange (ETDEWEB)

Kim, Y. M.; Jeong, C. H. [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

2014-10-15

Smart transmitters are digital I and C equipment which can replace analog transmitters. Non safety grade smart transmitters have been used for I and C systems of NPP(Nuclear Power Plant).. But, recently, smart transmitters have been used for safety grade I and C systems as well as non-safety grade I and C system for SKN 3 and 4. Smart transmitters execute measuring sensor values, generating output signals and adjusting range using software. Also, smart transmitters are basically capable of remote calibration through digital communication. The operating capability is more reliable and effective with remote calibration of smart transmitters, but there is potential vulnerability that causes the result no one wanted such as cyber attacks or software CCF. This paper addresses our regulatory experiences how to evaluate safety smart transmitter's CCF of SKN 3 and 4. Nuclear I and C equipment have increased the use on digital technology in safety system. According that, interest in a postulated software CCF is increasing. The software may be firmware or operating system of digital equipment. During SKN 3 and 4 operating license process, safety grade smart transmitter's adequacy was reviewed such as software V and V processes and equipment qualification. Also, it was analyzed that effect of the software CCFs of smart transmitters under DBA condition. Main concern was whether the postulated smart transmitter's software CCF may lead to an adverse safety consequence. We have future research plan to execute proof tests about our concerns and develop regulatory guide for smart transmitters.

Long-term preclinical magnetic resonance imaging alterations in sporadic Creutzfeldt-Jakob disease.

Science.gov (United States)

Zanusso, Gianluigi; Camporese, Giulia; Ferrari, Sergio; Santelli, Luca; Bongianni, Matilde; Fiorini, Michele; Monaco, Salvatore; Manara, Renzo; Cagnin, Annachiara

2016-10-01

An asymptomatic 74-year-old woman, on follow-up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion-weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629-632. © 2016 American Neurological Association.

Preclinical and phase 1 clinical safety of Setarud (IMOD™, a novel immunomodulator

Directory of Open Access Journals (Sweden)

P Khairandish

2009-10-01

Full Text Available "n "n  Background: A new herbal drug, Setarud (IMODTM that has been shown to have beneficial immune effects was tested to determine its acute and chronic toxicity in animals and to establish its intravenous form maximum tolerated dose (MTD in an open-labeled phase I clinical trial. Methods: BALB/c and C57BL/6 mice and Wistar rats were monitored for general state and biochemical markers for chronic test. At the end of chronic test, animals examined macroscopically and histologically. HIV-infected asymptomatic male patients with CD4 counts more than 200, were enrolled in the trial. Baseline dose was calculated from the 10% lethal dose (LD10 established in laboratory animal studies. Dose escalation was performed in four cohorts of 3 patients receiving IMODTM intravenously at a cohort-specific dose of 2, 4, 6.7, and 10 ml daily for 4 weeks. Patients were clinically examined at days of 1, 2, 3 and then weekly; and the safety was assessed on the basis of reports of adverse events, laboratory-test data and toxicity signs. Results: LD50 values in acute toxicity test were 42-66 and 50-56 ml/kg in i.m. and i.p. injections, respectively. Total scores of embryotoxicity during pregnancy were significantly lower in the Setarud group (p < 0.05. Pre-implantational deaths in the Setarud group were significantly higher, but post-implantational deaths level was lower than those in the control group. Inhibition of ossification in the skeletons of the fetuses and incidence of still birth were significantly higher while body weight of new-born rats of treatment group in the first month of their lifes were lower than those of the control group.In all four cohorts, there were no major side effects or dose-limiting toxicity, except for a mild sweating and weight loss in two patients from the first group that was reversed without discontinuation of the treatment. No clinically relevant trends in laboratory test results or ECG changes were noted. No adverse effect due to

Identification of new epilepsy treatments: issues in preclinical methodology.

Science.gov (United States)

Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J; Moshé, Solomon L; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L; Pitkänen, Asla; Stables, James; White, H Steve; O'Brien, Terence J; Simonato, Michele

2012-03-01

Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Safety evaluation for packaging 222-S laboratory cargo tank for onetime type B material shipment

International Nuclear Information System (INIS)

Nguyen, P.M.

1994-01-01

The purpose of this Safety Evaluation for Packaging (SEP) is to evaluate and document the safety of the onetime shipment of bulk radioactive liquids in the 222-S Laboratory cargo tank (222-S cargo tank). The 222-S cargo tank is a US Department of Transportation (DOT) MC-312 specification (DOT 1989) cargo tank, vehicle registration number HO-64-04275, approved for low specific activity (LSA) shipments in accordance with the DOT Title 49, Code of Federal Regulations (CFR). In accordance with the US Department of Energy, Richland Operations Office (RL) Order 5480.1A, Chapter III (RL 1988), an equivalent degree of safety shall be provided for onsite shipments as would be afforded by the DOT shipping regulations for a radioactive material package. This document demonstrates that this packaging system meets the onsite transportation safety criteria for a onetime shipment of Type B contents

Users manual for Aerospace Nuclear Safety Program six-degree-of-freedom reentry simulation (TMAGRA6C)

International Nuclear Information System (INIS)

Sharbaugh, R.C.

1990-02-01

This report documents the updated six-degree-of-freedom reentry simulation TMAGRA6C used in the Aerospace Nuclear Safety Program, ANSP. The simulation provides for the inclusion of the effects of ablation on the aerodynamic stability and drag of reentry bodies, specifically the General Purpose Heat Source, GPHS. The existing six-degree-of-freedom reentry body simulations (TMAGRA6A and TMAGRA6B) used in the JHU/APL Nuclear Safety Program do not include aerodynamic effects resulting from geometric changes to the configuration due to ablation from reentry flights. A wind tunnel test was conducted in 1989 to obtain the effects of ablation on the hypersonic aerodynamics of the GPHS module. The analyzed data were used to form data sets which are included herein in tabular form. These are used as incremental aerodynamic inputs in the new TMAGRA6C six-degree-of-freedom reentry simulation. 20 refs., 13 figs., 2 tabs

Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

Science.gov (United States)

Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

2015-01-01

High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

A cost-effective simulation curriculum for preclinical endodontics.

Science.gov (United States)

Pileggi, Roberta; Glickman, Gerald N

2004-02-01

A challenge in contemporary dental education is to achieve a smooth transition from preclinical teaching environments to patient-care clinics in a cost-effective manner. The preclinical endodontic courses at The University of Texas, Dental Branch at Houston provide a unique learning environment that enables the student to perform endodontic treatment on extracted teeth in a typodont, and be involved in diagnosis and treatment-planning discussions. The specially designed stone typodont used has built-in radiographic capability, and is mounted at each chair in the clinic. During each preclinical session, students are assigned clinical cubicles and proper aseptic protocol is followed. Students are required to wear gloves, masks and eyewear, and place a rubber dam during treatment. Written self-assessment evaluations based upon prescribed criteria are utilised; feedback is given by faculty composed of both full-time endodontists and graduate students who periodically rotate and are calibrated on a regular basis. In the lecture phase, clinical case scenarios are presented to reinforce concepts of diagnosis and emergency care and to help integrate endodontics with other disciplines; a Socratic-like teaching style is established by the faculty facilitator to create an environment for developing critical-thinking and problem-solving skills. The overall feedback from graduating students has been very positive. Advantages of this format are an easier transition to patient management, a more keen interest in specialsation and a perceived increase in levels of confidence.

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

International Nuclear Information System (INIS)

Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G.; Heinen, U.; Reitmeier, A.

2015-01-01

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

Energy Technology Data Exchange (ETDEWEB)

Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Weber, O. [Philips Medical Systems DMC GmbH, Hamburg (Germany); Heinen, U. [Bruker BioSpin MRI GmbH, Ettlingen (Germany); Reitmeier, A. [Medical Center Hamburg-Eppendorf, Hamburg (Germany). Animal Facility; Knopp, T. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Hamburg University of Technology, Hamburg (Germany)

2015-05-15

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination

DEFF Research Database (Denmark)

Theander, Thor Grundtvig; Lusingu, John Peter Andrea

2014-01-01

BACKGROUND: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. METHODS AND FINDINGS: 6,537 infants aged 6......-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p... after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants...

Preclinical Safety Assessment of Standardized Extract of Centella asiatica (L.) Urban Leaves

OpenAIRE

Deshpande, Pallavi O.; Mohan, Vishwaraman; Thakurdesai, Prasad

2015-01-01

Context: Centella asiatica (CA) leaves extract has been shown therapeutic potential. However, safety information is lacking. Aims: To evaluate acute oral toxicity (AOT), sub-chronic toxicity, and mutagenic potential of standardized extract of CA (L.) Urban leaves (INDCA). Materials and Methods: For the acute toxicity study, INDCA was orally administered to Sprague-Dawley rats at a dose range of 0?2000 mg/kg. For the repeated dose toxicity study, the rats of either sex were orally administered...

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

Directory of Open Access Journals (Sweden)

Kothe, Christian

2014-05-01

Full Text Available [english] Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.

Efficacy and Safety of Ibuprofen in Infants Aged Between 3 and 6 Months.

Science.gov (United States)

Ziesenitz, Victoria C; Zutter, Andreas; Erb, Thomas O; van den Anker, Johannes N

2017-08-01

Ibuprofen is a non-steroidal anti-inflammatory drug frequently administered to children of various ages for relief of fever and pain and is approved as an over-the-counter medication in many countries worldwide. Although there are extensive data on its efficacy and safety in children and adults, there are divergent dosing recommendations for analgesia and treatment of fever in infants, especially in the age group between 3 and 6 months of age. In this article, we have assessed the safety and efficacy of ibuprofen use in infants in an attempt to find the optimal method of pain and fever management in this specific age group. Based on the current evidence, short-term use of ibuprofen is considered safe in infants older than 3 months of age having a body weight above 5-6 kg when special attention is given to the hydration of the patient. Ibuprofen should be prescribed based on body weight using a dose of 5-10 mg/kg. This dose can be administered 3-4 times a day resulting in a maximum total daily dose of 30-40 mg/kg. The rectal route has been shown to be less reliable because of erratic absorption, especially in young infants. Since most efficacy and safety data have been derived from trials in infants with fever, future studies should focus on the efficacy of ibuprofen in young infants with pain.

Quetiapine: recent developments in preclinical research

Directory of Open Access Journals (Sweden)

Marco Orsetti

2010-03-01

Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

Spatial reversal learning in preclinical scrapie-inoculated mice.

Science.gov (United States)

Lysons, A M; Woollard, S J

1996-04-10

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

Tungsten phosphanylarylthiolato complexes [W{PhP(2-SC6H4)2-kappa3S,S',P} 2] and [W{P(2-SC6H4)3-kappa4S,S',S",P}2]: synthesis, structures and redox chemistry.

Science.gov (United States)

Hildebrand, Alexandra; Lönnecke, Peter; Silaghi-Dumitrescu, Luminita; Hey-Hawkins, Evamarie

2008-09-14

PhP(2-SHC6H4)2 (PS2H2) reacts with WCl6 with reduction of tungsten to give the air-sensitive tungsten(IV) complex [W{PhP(2-SC6H4)2-kappa(3)S,S',P}2] (1). 1 is oxidised in air to [WO{PhPO(2-SC6H4)2-kappa(3)S,S',O}{PhP(2-SC6H4)2-kappa(3)S,S',P}] (2). The attempted synthesis of 2 by reaction of 1 with iodosobenzene as oxidising agent was unsuccessful. [W{P(2-SC6H4)3-kappa(4)S,S',S",P}2] (3) was formed in the reaction of P(2-SHC6H4)3 (PS3H3) with WCl6. The W(VI) complex 3 contains two PS3(3-) ligands, each coordinated in a tetradentate fashion resulting in a tungsten coordination number of eight. The reaction of 3 with AgBF4 yields the dinuclear tungsten complex [W2{P(2-SC6H4)3-kappa(4)S,S',S",P}3]BF4 (4). Complexes 1-4 were characterised by spectral methods and X-ray structure determination.

Scientific Opinion on the safety and suitability for use by infants of follow-on formulae with a protein content of at least 1.6 g/100 kcal

DEFF Research Database (Denmark)

Sjödin, Anders Mikael

2017-01-01

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the safety and suitability for use by infants of follow-on formulae (FOF) based on cow’s milk intact protein with a protein content...... of at least 1.6 g/100 kcal (rounded value) that meet otherwise the requirements of relevant EU legislation. If the formula under evaluation is considered to be safe and suitable for use by infants, the NDA Panel is also asked to advise on whether FOF based on goat’s milk intact protein, soy protein isolates...... legislation is safe and suitable for healthy infants living in Europe with an intake of complementary foods of a sufficient quality. This conclusion does not apply to infant formula (IF). The Panel also concludes that the safety and suitability of FOF with a protein content of at least 1.6 g/100 kcal...

A probabilistic safety analysis of UF{sub 6} handling at the Portsmouth Gaseous Diffusion Plant

Energy Technology Data Exchange (ETDEWEB)

Boyd, G.J.; Lewis, S.R.; Summitt, R.L. [Safety and Reliability Optimization Services (SAROS), Inc., Knoxville, TN (United States)

1991-12-31

A probabilistic safety study of UF{sub 6} handling activities at the Portsmouth Gaseous Diffusion Plant has recently been completed. The analysis provides a unique perspective on the safety of UF{sub 6} handling activities. The estimated release frequencies provide an understanding of current risks, and the examination of individual contributors yields a ranking of important plant features and operations. Aside from the probabilistic results, however, there is an even more important benefit derived from a systematic modeling of all operations. The integrated approach employed in the analysis allows the interrelationships among the equipment and the required operations to be explored in depth. This paper summarizes the methods used in the study and provides an overview of some of the technical insights that were obtained. Specific areas of possible improvement in operations are described.

Operation safety of complex industrial systems

International Nuclear Information System (INIS)

Zwingelstein, G.

1999-01-01

Zero fault or zero risk is an unreachable goal in industrial activities like nuclear activities. However, methods and techniques exist to reduce the risks to the lowest possible and acceptable level. The operation safety consists in the recognition, evaluation, prediction, measurement and mastery of technological and human faults. This paper analyses each of these points successively: 1 - evolution of operation safety; 2 - definitions and basic concepts: failure, missions and functions of a system and of its components, basic concepts and operation safety; 3 - forecasting analysis of operation safety: reliability data, data-banks, precautions for the use of experience feedback data; realization of an operation safety study: management of operation safety, quality assurance, critical review and audit of operation safety studies; 6 - conclusions. (J.S.)

International Expert Review of Sr-Can: Safety Assessment Methodology - External review contribution in support of SSI's and SKI's review of SR-Can

Energy Technology Data Exchange (ETDEWEB)

Sagar, Budhi (Center for Nuclear Waste Regulatory Analyses, Southwest Research Inst., San Antonio, TX (US)); Egan, Michael (Quintessa Limited, Henley-on-Thames (GB)); Roehlig, Klaus-Juergen (Gesellschaft fuer Anlagen- und Reaktorsicherheit mbH (DE)); Chapman, Neil (Independent Consultant (XX)); Wilmot, Roger (Galson Sciences Limited, Oakham (GB))

2008-03-15

In 2006, SKB published a safety assessment (SR-Can) as part of its work to support a licence application for the construction of a final repository for spent nuclear fuel. The purposes of the SR-Can project were stated in the main project report to be: 1. To make a first assessment of the safety of potential KBS-3 repositories at Forsmark and Laxemar to dispose of canisters as specified in the application for the encapsulation plant. 2. To provide feedback to design development, to SKB's research and development (R and D) programme, to further site investigations and to future safety assessments. 3. To foster a dialogue with the authorities that oversee SKB's activities, i.e. the Swedish Nuclear Power Inspectorate, SKI, and the Swedish Radiation Protection Authority, SSI, regarding interpretation of applicable regulations, as a preparation for the SR-Site project. To help inform their review of SKB's proposed approach to development of the longterm safety case, the authorities appointed three international expert review teams to carry out a review of SKB's SR-Can safety assessment report. Comments from one of these teams - the Safety Assessment Methodology (SAM) review team - are presented in this document. The SAM review team's scope of work included an examination of SKB's documentation of the assessment ('Long-term safety for KBS-3 Repositories at Forsmark and Laxemar - a first evaluation' and several supporting reports) and hearings with SKB staff and contractors, held in March 2007. As directed by SKI and SSI, the SAM review team focused on methodological aspects and sought to determine whether SKB's proposed safety assessment methodology is likely to be suitable for use in the future SR-Site and to assess its consistency with the Swedish regulatory framework. No specific evaluation of long-term safety or site acceptability was undertaken by any of the review teams. SKI and SSI's Terms of Reference for the SAM

Road Safety Data, Collection, Transfer and Analysis DaCoTa. Workpackage 6, Driver Behaviour Monitoring through Naturalistic Driving: Deliverable 6.3: Report on small scale naturalistic driving pilot.

NARCIS (Netherlands)

Pilgerstorfer, M. Runda, K. Brandstätter, C. Christoph, M. Hakkert, S. Ishaq, R. Toledo, T. & Gatscha, M.

2012-01-01

WP6 of DaCoTA, Driver Behaviour Monitoring through Naturalistic Driving, aims to develop an implementation plan for a large scale activity that uses Naturalistic Driving (ND) Observations to continuously monitor relevant road safety data within the framework of the European Road Safety Observatory.

Role of systems safety in maintaining affordable safety in the 1980's

International Nuclear Information System (INIS)

Hollister, H.; Trauth, C.A. Jr.

1979-01-01

Historically, the Department of Energy and its predecessors have used and supported the development of systems safety programs, practices, and principles, finding them by and large adequate, effective, and managerially efficient. Today, attempts are bing made to resolve increasingly complex environmental, safety, and health problems by turning to increasingly complex and detailed regulation as the primary governmental answer. It is increasingly doubtful that such an approach will provide management of these issues and problems that is either effective or efficient. Challenge is issued to those in systems safety to develop and apply systems safety principles and practices more broadly to total operational systems and not just to hardware and to environmental and health protection and not just to safety, so that the total universe of environmental, safety, and health can be managed effectively and efficiently with encouragement of innovation and creativity, using a relatively brief and concise, but adequate, regulatory base

Laparoscopy training in surgical education: the utility of incorporating a structured preclinical laparoscopy course into the traditional apprenticeship method.

Science.gov (United States)

De Win, Gunter; Van Bruwaene, Siska; Aggarwal, Rajesh; Crea, Nicola; Zhang, Zhewen; De Ridder, Dirk; Miserez, Marc

2013-01-01

To investigate whether preclinical laparoscopy training offers a benefit over standard apprenticeship training and apprenticeship training in combination with simulation training. This randomized controlled trial consisted of 3 groups of first-year surgical registrars receiving a different teaching method in laparoscopic surgery. The KU LEUVEN Faculty of Medicine is the largest medical faculty in Belgium. Thirty final-year medical students starting a general surgical career in the next academic year. Thirty final-year medical students were randomized into 3 groups, which differed in the way they were exposed to laparoscopic simulation training but were comparable in regard to ambidexterity, sex, age, and laparoscopic psychomotoric skills. The control group received only clinical training during surgical residentship, whereas the interval group received clinical training in combination with simulation training. The registrars were allowed to do deliberate practice. The Centre for Surgical Technologies Preclinical Training Programme (CST PTP) group received a preclinical simulation course during the final year as medical students, but was not exposed to any extra simulation training during surgical residentship. At the beginning of surgical residentship and 6 months later, all subjects performed a standardized suturing task and a laparoscopic cholecystectomy in a POP Trainer. All procedures were recorded together with time and motion tracking parameters. All videos were scored by a blinded observer using global rating scales. At baseline the 3 groups were comparable. At 6 months, for suturing, the CST PTP group was better than both the other groups with respect to time, checklist, and amount of movements. The interval group was better than the control group on only the time and checklist score. For the cholecystectomy evaluation, there was a statistical difference between the CST PTP study group and both other groups on all evaluation scales in favor of the CST PTP

Legal framework of Preclinical Molecular Imaging radioactive facilities; Marco legal de las instalaciones radiactivas de Imagen Molecular Preclínica

Energy Technology Data Exchange (ETDEWEB)

Álvarez, C.; Lorenz, P.

2014-07-01

Preclinical Molecular Imaging facilities are 2ª category radioactive facilities, so the regulation that applies to them is the same as the rest of the radioactive facilities, both the regime of authorizations and the establishment of the basic standards of radiation protection of workers and members of the public. There are also specific and mandatory technical regulations coming from Nuclear Safety Council safety instructions and ministerial orders, applicable for installations using unsealed radioactive material and equipment generating ionizing radiation for diagnosis, also taking account the possible existence of sealed radioactive sources of verification. [Spanish] Las instalaciones de Imagen Molecular Preclínica son instalaciones radiactivas de 2ª categoría, por lo que la reglamentación que les aplica es la misma que al resto de las instalaciones radiactivas, tanto en el régimen de autorizaciones, como en el establecimiento de las normas básicas de protección radiológica para los trabajadores y los miembros del público. Existe además normativa técnica específica y de obligado cumplimiento, procedente de instrucciones de seguridad del Consejo de Seguridad Nuclear y de Órdenes Ministeriales , aplicable para instalaciones donde se utilice material radiactivo no encapsulado y equipos generadores de radiaciones ionizantes para diagnóstico, teniendo en cuenta también la posible existencia de fuentes radiactivas encapsuladas de verificación.

An economic evaluation of preclinical testing strategies compared to the compulsory scrapie flock scheme in the control of classical scrapie.

Directory of Open Access Journals (Sweden)

Lisa Boden

Full Text Available Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS. However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years. Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic. The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS.

A magneto-motive ultrasound platform designed for pre-clinical and clinical applications

Directory of Open Access Journals (Sweden)

Diego Ronaldo Thomaz Sampaio

Full Text Available Abstract Introduction Magneto-motive ultrasound (MMUS combines magnetism and ultrasound (US to detect magnetic nanoparticles in soft tissues. One type of MMUS called shear-wave dispersion magneto-motive ultrasound (SDMMUS analyzes magnetically induced shear waves (SW to quantify the elasticity and viscosity of the medium. The lack of an established presets or protocols for pre-clinical and clinical studies currently limits the use of MMUS techniques in the clinical setting. Methods This paper proposes a platform to acquire, process, and analyze MMUS and SDMMUS data integrated with a clinical ultrasound equipment. For this purpose, we developed an easy-to-use graphical user interface, written in C++/Qt4, to create an MMUS pulse sequence and collect the ultrasonic data. We designed a graphic interface written in MATLAB to process, display, and analyze the MMUS images. To exemplify how useful the platform is, we conducted two experiments, namely (i MMUS imaging to detect magnetic particles in the stomach of a rat, and (ii SDMMUS to estimate the viscoelasticity of a tissue-mimicking phantom containing a spherical target of ferrite. Results The developed software proved to be an easy-to-use platform to automate the acquisition of MMUS/SDMMUS data and image processing. In an in vivo experiment, the MMUS technique detected an area of 6.32 ± 1.32 mm2 where magnetic particles were heterogeneously distributed in the stomach of the rat. The SDMMUS method gave elasticity and viscosity values of 5.05 ± 0.18 kPa and 2.01 ± 0.09 Pa.s, respectively, for a tissue-mimicking phantom. Conclusion Implementation of an MMUS platform with addressed presets and protocols provides a step toward the clinical implementation of MMUS imaging equipment. This platform may help to localize magnetic particles and quantify the elasticity and viscosity of soft tissues, paving a way for its use in pre-clinical and clinical studies.

Index to Nuclear Safety: a technical progress review by chronology, permuted title, and author. Vol. 11(1)--Vol. 18(6)

Energy Technology Data Exchange (ETDEWEB)

Cottrell, W.B.; Klein, A.

1978-04-11

This index to Nuclear Safety covers articles published in Nuclear Safety, Vol. 11, No. 1 (January-February 1970), through Vol. 18, No. 6 (November-December 1977). It is divided into three sections: a chronological list of articles (including abstracts) followed by a permuted-title (KWIC) index and an author index. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center (NSIC), covers all safety aspects of nuclear power reactors and associated facilities. Over 450 technical articles published in Nuclear Safety in the last eight years are listed in this index.

Index to Nuclear Safety: a technical progress review by chronology, permuted title, and author. Vol. 11(1)--Vol. 18(6)

International Nuclear Information System (INIS)

Cottrell, W.B.; Klein, A.

1978-01-01

This index to Nuclear Safety covers articles published in Nuclear Safety, Vol. 11, No. 1 (January-February 1970), through Vol. 18, No. 6 (November-December 1977). It is divided into three sections: a chronological list of articles (including abstracts) followed by a permuted-title (KWIC) index and an author index. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center (NSIC), covers all safety aspects of nuclear power reactors and associated facilities. Over 450 technical articles published in Nuclear Safety in the last eight years are listed in this index

Cued memory decline in biomarker-defined preclinical Alzheimer disease.

Science.gov (United States)

Papp, Kathryn V; Rentz, Dorene M; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Quiroz, Yakeel; Johnson, Keith A; Sperling, Reisa A

2017-04-11

To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging. Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ +/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education. A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ + participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ - peers. Furthermore, Aβ + participants who scored ≤46/48 had smaller hippocampal volumes ( t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ 2 = 14.30, p recall. Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ + clinically normal individuals at greatest risk of short-term clinical progression. © 2017 American Academy of Neurology.

Preclinical good laboratory practice-compliant safety study to evaluate biodistribution and tumorigenicity of a cartilage advanced therapy medicinal product (ATMP).

Science.gov (United States)

Zscharnack, Matthias; Krause, Christoph; Aust, Gabriela; Thümmler, Christian; Peinemann, Frank; Keller, Thomas; Smink, Jeske J; Holland, Heidrun; Somerson, Jeremy S; Knauer, Jens; Schulz, Ronny M; Lehmann, Jörg

2015-05-20

The clinical development of advanced therapy medicinal products (ATMPs), a new class of drugs, requires initial safety studies that deviate from standard non-clinical safety protocols. The study provides a strategy to address the safety aspects of biodistribution and tumorigenicity of ATMPs under good laboratory practice (GLP) conditions avoiding cell product manipulation. Moreover, the strategy was applied on a human ATMP for cartilage repair. The testing strategy addresses biodistribution and tumorigenicity using a multi-step analysis without any cell manipulation to exclude changes of test item characteristics. As a safeguard measurement for meeting regulatory expectations, the project design and goals were discussed continuously with the regulatory authority using a staggered scientific advice concept. Subsequently, the strategy was applied to co.don chondrosphere® (huChon spheroid), a tissue-engineered matrix-free ATMP of human normal chondrocytes. In both the biodistribution and tumorigenicity studies, huChon spheroids were implanted subcutaneously into 40 immunodeficient mice. Biodistribution was studied 1 month after implantation. A skin disc containing the huChon spheroid, two surrounding skin rings and selected organs were analyzed by validated, gender-specific, highly-sensitive triplex qPCR and by immunohistochemistry (IHC). No human DNA was detected in distant skin rings and analyzed organs. IHC revealed no direct or indirect indications of cell migration. Tumorigenicity was assessed 6 months after huChon spheroid implantation by palpation, macroscopic inspection, histology and IHC. No mice from the huChon spheroid group developed a tumor at the implantation site. In two mice, benign tumors were detected that were negative for HLA-ABC, suggesting that they were of spontaneous murine origin. In summary, the presented strategy using a multi-step analysis was confirmed to be suitable for safety studies of ATMPs.

Value of Entheseal Ultrasonography and Serum Cartilage Oligomeric Matrix Protein in the Preclinical Diagnosis of Psoriatic Arthritis

Directory of Open Access Journals (Sweden)

Moataz Mohammed Samy Elbeblawy

2010-03-01

Full Text Available Objective: To evaluate the utility of entheseal ultrasonography and serum COMP in the preclinical diagnosis of psoriatic arthritis. Methods: 60 psoriatic patients were divided into: 30 patients with psoriasis (group I and 30 patients with psoriatic arthritis as control (group II. They underwent independent clinical and ultrasonographic examination of both lower limbs at the calcaneal insertions of Achilles tendons. Psoriatic arthritis disease activity and severity was assessed by modified DAS28 and Steinbrockers scores. Serum levels of COMP were measured for all patients by ELISA. Results: On clinical examination, no entheseal abnormalities were detected in group I while they were present in 23.3% of group II with statistically significant difference between them (P 0.05. Serum COMP were significantly elevated in group I and II with no statistically significant difference between them (mean ± SD 5.9 ± 3 and 6.8 ± 12 respectively, P > 0.05. Entheseal ultrasound was more specific (67% while serum COMP was more sensitive (87% in the preclinical diagnosis of psoriatic arthritis. Serum COMP levels were significantly correlated with CRP in both groups and with DAS28 and Steinbrockers scores in group II (P < 0.01. Conclusion: Entheseal ultrasonography and serum COMP levels may be used complementary to each other for preclinical diagnosis of psoriatic arthritis. Serum COMP seems to be promising prognostic marker for psoriatic arthritis patients.

Metabolic control by S6 kinases depends on dietary lipids.

Directory of Open Access Journals (Sweden)

Tamara R Castañeda

Full Text Available Targeted deletion of S6 kinase (S6K 1 in mice leads to higher energy expenditure and improved glucose metabolism. However, the molecular mechanisms controlling these effects remain to be fully elucidated. Here, we analyze the potential role of dietary lipids in regulating the mTORC1/S6K system. Analysis of S6K phosphorylation in vivo and in vitro showed that dietary lipids activate S6K, and this effect is not dependent upon amino acids. Comparison of male mice lacking S6K1 and 2 (S6K-dko with wt controls showed that S6K-dko mice are protected against obesity and glucose intolerance induced by a high-fat diet. S6K-dko mice fed a high-fat diet had increased energy expenditure, improved glucose tolerance, lower fat mass gain, and changes in markers of lipid metabolism. Importantly, however, these metabolic phenotypes were dependent upon dietary lipids, with no such effects observed in S6K-dko mice fed a fat-free diet. These changes appear to be mediated via modulation of cellular metabolism in skeletal muscle, as shown by the expression of genes involved in energy metabolism. Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism.

Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice.

Science.gov (United States)

Carriglio, Nicola; Klapwijk, Jan; Hernandez, Raisa Jofra; Vezzoli, Michela; Chanut, Franck; Lowe, Rhiannon; Draghici, Elena; Nord, Melanie; Albertini, Paola; Cristofori, Patrizia; Richards, Jane; Staton, Hazel; Appleby, Jonathan; Aiuti, Alessandro; Sauer, Aisha V

2017-03-01

GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte

Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer

DEFF Research Database (Denmark)

Liu, Ying; Emilion, Gracy; Mungall, Andrew J

2002-01-01

We have previously shown a high frequency of allele loss at D6S193 (62%) on chromosomal arm 6q27 in ovarian tumours and mapped the minimal region of allele loss between D6S297 and D6S264 (3 cM). We isolated and mapped a single non-chimaeric YAC (17IA12, 260-280 kb) containing D6S193 and D6S297...

Preclinical diagnosis of Alzheimer's disease: Prevention or prediction?

Directory of Open Access Journals (Sweden)

Ricardo Nitrini

Full Text Available Abstract The diagnosis of Alzheimer's disease (AD for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer's Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD's dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD.

Evaluation of the safety of a genetically modified DAS-444Ø6-6 soybean meal and hulls in a 90-day dietary toxicity study in rats.

Science.gov (United States)

Papineni, Sabitha; Murray, Jennifer A; Ricardo, Ekmay; Dunville, Christina M; Sura, Radha Krishna; Thomas, Johnson

2017-11-01

A 90-day sub chronic toxicity study was conducted in rats to evaluate the safety of genetically modified DAS-444Ø6-6 soybeans expressing herbicide tolerant proteins when compared with its conventional comparators (non-transgenic near isoline control soybean and three commercially available non-transgenic line control soybeans). Rats were given diets formulated with either 10% or 20% w/w of soybean meal and 1% or 2% hulls of DAS-444Ø6-6 soybean with an equivalent amount of hulls from an isoline non-transgenic control soybean for at least 90 days. In addition, three separate 20% w/w non-transgenic commercially available soybean varieties were also given to groups of rats to serve as reference controls. Animals were evaluated by cage-side and hand-held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, prothrombin time, urinalysis, clinical chemistry, selected organ weights, and gross and histopathologic examinations. Under the conditions of this study, the genetically modified DAS-444Ø6-6 diets did not cause any treatment-related effects in rats following 90 days of dietary administration as compared with rats fed diets with soybean of isoline control or commercial reference controls and are considered equivalent to the diets prepared from conventional comparators. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Validation of MCNP6.1 for Criticality Safety of Pu-Metal, -Solution, and -Oxide Systems

Energy Technology Data Exchange (ETDEWEB)

Kiedrowski, Brian C. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Conlin, Jeremy Lloyd [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Favorite, Jeffrey A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Kahler, III, Albert C. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Kersting, Alyssa R. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Parsons, Donald K. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Walker, Jessie L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2014-05-13

Guidance is offered to the Los Alamos National Laboratory Nuclear Criticality Safety division towards developing an Upper Subcritical Limit (USL) for MCNP6.1 calculations with ENDF/B-VII.1 nuclear data for three classes of problems: Pu-metal, -solution, and -oxide systems. A benchmark suite containing 1,086 benchmarks is prepared, and a sensitivity/uncertainty (S/U) method with a generalized linear least squares (GLLS) data adjustment is used to reject outliers, bringing the total to 959 usable benchmarks. For each class of problem, S/U methods are used to select relevant experimental benchmarks, and the calculational margin is computed using extreme value theory. A portion of the margin of sub criticality is defined considering both a detection limit for errors in codes and data and uncertainty/variability in the nuclear data library. The latter employs S/U methods with a GLLS data adjustment to find representative nuclear data covariances constrained by integral experiments, which are then used to compute uncertainties in k_eff from nuclear data. The USLs for the classes of problems are as follows: Pu metal, 0.980; Pu solutions, 0.973; dry Pu oxides, 0.978; dilute Pu oxide-water mixes, 0.970; and intermediate-spectrum Pu oxide-water mixes, 0.953.

Revisiting the use of sPLA2-sensitive liposomes in cancer therapy

DEFF Research Database (Denmark)

Pourhassan, Houman; Clergeaud Veiga, Gael; Hansen, Anders Elias

2017-01-01

The first developed secretory phospholipase A2 (sPLA2) sensitive liposomal cisplatin formulation (LiPlaCis®) is currently undergoing clinical evaluation. In the present study we revisit and evaluate critical preclinical parameters important for the therapeutic potential and safety of platinum drugs......, here oxaliplatin (L-OHP), formulated in sPLA2 sensitive liposomes. We show the mole percentage of negatively charged phospholipid needed to obtain enzyme-sensitivity for saturated systems is ≥ 25% for 16-carbon chain lipid membranes, and > 40% for 18-chain lipid membranes, which was surprising as 25......% is used clinically in LiPlaCis®. Efficient sPLA2-dependent growth inhibition of colorectal cancer cells was demonstrated in vitro, where cell membrane degradation and cytolysis depends on the sensitivity of the formulation towards the enzyme and is governed by the amount of lysolipids generated...

77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

Science.gov (United States)

2012-11-29

...] Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy... Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products,'' dated November... Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product areas covered by this...

Efficacy and safety of galantamine in the treatment of Alzheimer’s Disease and Alzheimer’s Disease with cerebrovascular (Mixed Dementia (GAL-DEM-402

Directory of Open Access Journals (Sweden)

S. F. Lumempouw

2007-06-01

Full Text Available This study was aimed to evaluate the efficacy and safety of Acetylcholinesterase Inhibitor Galantamine (Reminyl® for patients with Alzheimer’s Disease (AD and Alzheimer’s Disease with cerebrovascular Disease (AD+CVD or mixed Dementia. A 6-month open label observational study of Galantamine has been conducted on 28 patients with AD and AD+CVD patients. Primary endpoints were cognitive performance as assessed using the Mini Mental Scale Examination (MMSE, the Restricted Reminding Test, the Neuropsychology Assessment, the Clinical Dementia Rating (CDR to assess global function and the Neuropsychiatric Inventory (NPI to assess behavioral symptoms. Patients were also monitored for safety evaluation. Six month Galantamine group had a significant better outcome of cognitive performance, global function and behavioral symptoms compared with the baseline data as were assessed using the MMSE (p<0.05, the Restricted Reminding (p<0.05, the Neuropsychology Assessment (p<0.05, the CDR (p<0.05 and the NPI (p<0.05. Minimal adverse events (32% were anorexia and nausea. It is concluded that Galantamine has a significant benefit to improve cognitive, global function, behavioral symptoms and only caused minimal adverse events. (Med J Indones 2007; 16:94-100Keywords: Galantamine, alzheimer, cerebrovascular disease, dementia, AD, AD+CVD

Is performance in pre-clinical assessment a good predictor of the final Doctor of Medicine grade?

Science.gov (United States)

Al-Wardy, Nadia M; Rizvi, Syed G; Bayoumi, Riad A

2009-12-01

To investigate if any correlation exists between students' grades on their final doctor of Medicine (MD) assessment and their overall preclinical grade point average (GPA) and its component parts. Student data available from the Deanship of Admissions and Registration were analyzed. Pearson correlation coefficient was obtained to assess the degree of linear relationship between performance in the preclinical and the MD assessment of 529 students who graduated from the College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman from June 1998 to June 2005. Simple and multiple regression analyses were performed to evaluate individual and combined impact of the preclinical courses' grades on MD grades. Preclinical GPA correlated highly with MD GPA (r=0.641). The science component taught early in the preclinical phase correlated more strongly (r=0.457) than student electives (r=0.246). This correlation was better in the good English group. Students' performance, however, was best in electives, but worst in English. Most students who had low MD GPA (2.5, and limiting the credit hour requirement of electives by the College seems to be justified.

EC6 design features and pre-project licensing review

Energy Technology Data Exchange (ETDEWEB)

Yu, S.; Lee, A.G.; Dinh, N.B.; Soulard, M. [CANDU Energy Inc., Mississauga, Ontario, (Canada)

2013-07-01

The Enhanced CANDU 6 (EC6) is the new Generation III CANDU reactor design that meets the most up to date Canadian regulatory requirements and customer expectations. Candu Energy Inc. is finalizing development of the EC6 which incorporates the CANDU 6's well-proven features, and adds enhancements that strengthened reactor safety margin and improved operability. The EC6 builds on the proven high performance design and the defence-in-depth features of CANDU 6 units, and has incorporated extensive operational feedback including lessons learned from Fukushima. This paper will provide status of the engineering program including progress on the pre-licensing review of the EC6 design by the Canadian Regulator, CNSC, and will also highlight the design and safety enhancements incorporated in the EC6 product. Safety enhancements to meet safety goals and to improve robustness of systems to respond to design basis accidents and beyond design basis accidents include: new severe accident recovery and heat removal system; improved emergency heat removal system; faster shutoff rods with improved safety margins; mechanical guaranteed shutdown rods; daily load cycling capability; robust containment with containment filter venting system; and improved backed-up electrical supply and cooling services. (author)

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

Directory of Open Access Journals (Sweden)

Helen B. Stone

2016-02-01

Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Safety provisions for UF{sub 6} handling in the design of a new UF{sub 6} conversion plant

Energy Technology Data Exchange (ETDEWEB)

Bannister, S.P. [British Nuclear Fuels plc, Preston (United Kingdom)

1991-12-31

British Nuclear Fuels plc (BNFL) Fuel Division is currently undertaking the final design and construction of a new UF{sub 6} conversion plant at its production site at Springfields near Preston in the north of England. The Company has gained much experience in the handling of UF{sub 6} during operation of plants on site since 1961. The major hazard occurs during the liquefication cycle and the basis of the maximum credible incident scenario adopted for safety assessment and design purposes is discussed. This paper considers the design features which have been incorporated in the new plant to counter the hazards presented by the presence of UF{sub 6} in gaseous and liquid form and explains current thinking on operational procedures in areas of potential risk such as cylinder filling. The plant emergency response philosophy and systems are described and specific design provisions which have been included to satisfy the UK regulatory bodies are outlined in some detail.

Posiva's application for a decision in principle concerning a disposal facility for spent nuclear fuel. STUK's statement and preliminary safety appraisal

Energy Technology Data Exchange (ETDEWEB)

Ruokola, E. [ed.

2000-03-01

In May 1999, Posiva Ltd submitted to the Government an application, pursuant to the Nuclear Energy Act, for a Decision in Principle on a disposal facility for spent nuclear fuel from the Finnish nuclear power plants. The Ministry of Trade and Industry requested the Radiation and Nuclear Safety Authority (STUK) to draw up a preliminary safety appraisal concerning the proposed disposal facility. In the beginning of this report, STUK's statement to the Ministry and Industry concerning the proposed disposal facility is given. In that statement, STUK concludes that the Decision in Principle is currently justified from the standpoint of safety. The statement is followed by a safety appraisal, where STUK deems, how the proposed disposal concept, site and facility comply with the safety requirements included in the Government's Decision (478/1999). STUK's preliminary safety appraisal was supported by contributions from a number of outside experts. A collective opinion by an international group of ten distinguished experts is appended to this report. (orig.)

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, SUVN-502, in Healthy Young Adults and Elderly Subjects.

Science.gov (United States)

Nirogi, Ramakrishna; Mudigonda, Koteshwara; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Goyal, Vinod Kumar; Pandey, Santosh Kumar; Palacharla, Raghava Choudary

2018-05-01

SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses. Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods. SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC 0-∞ , and AUC 0-last ) and peak exposures (C max ) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502. SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.

75 FR 52046 - Development of U.S. Nuclear Regulatory Commission Safety Culture Policy Statement: Public Meeting

Science.gov (United States)

2010-08-24

... is working towards increasing the attention that is given to safety culture as part of its efforts to... NUCLEAR REGULATORY COMMISSION Development of U.S. Nuclear Regulatory Commission Safety Culture..., Nevada hearing facility to solicit comments on the revision of its draft safety culture policy statement...

A lattice-based Monte Carlo evaluation of Canada Deuterium Uranium-6 safety parameters

International Nuclear Information System (INIS)

Kim, Yong Hee; Hartanto, Donny; Kim, Woo Song

2016-01-01

Important safety parameters such as the fuel temperature coefficient (FTC) and the power coefficient of reactivity (PCR) of the CANada Deuterium Uranium (CANDU-6) reactor have been evaluated using the Monte Carlo method. For accurate analysis of the parameters, the Doppler broadening rejection correction scheme was implemented in the MCNPX code to account for the thermal motion of the heavy uranium-238 nucleus in the neutron-U scattering reactions. In this work, a standard fuel lattice has been modeled and the fuel is depleted using MCNPX. The FTC value is evaluated for several burnup points including the mid-burnup representing a near-equilibrium core. The Doppler effect has been evaluated using several cross-section libraries such as ENDF/B-VI.8, ENDF/B-VII.0, JEFF-3.1.1, and JENDL-4.0. The PCR value is also evaluated at mid-burnup conditions to characterize the safety features of an equilibrium CANDU-6 reactor. To improve the reliability of the Monte Carlo calculations, we considered a huge number of neutron histories in this work and the standard deviation of the k-infinity values is only 0.5-1 pcm

Development of Novel Protocol for Preclinical Monitoring the Release of Adjuvants Encapsulated Mucosal Delivery Carriers

Directory of Open Access Journals (Sweden)

Mohamed Ibrahim-Saeed

2015-12-01

Full Text Available This work contributes in vaccines down-stream process by introducing a novel platform for in-vitro monitoring of vaccine-adjuvant delivery profile as a crucial preclinical optimizing step in mucosal vaccines. Nano and micro particles of Calcium phosphate (Cap vaccine-adjuvant were encapsulated in Chitosan and Alginate polymeric carriers. Adjuvants release profiles monitored in a permeable bag at 37°C, pH 2, incubated in isotonic buffer for 96 hours. The released Calcium in the outer buffer was monitored and compared in-addition to the carrier’s swelling and biophysical properties. The adjuvants and carriers did not interfere with the proliferation of cultured hepatocytes an indicator of their safe use; Chitosan’s viscosity and swelling were higher than Alginate. Chitosan’s Zeta-potential was significantly high positive, while Cap and Alginate were negative. The prepared CaP and Chitosan particles were in nano-size, while the ready-made CaP adjuvant and Alginate were in micro-size using zeta-seizer and scanning electron-micrograph. The release of nano-size particle was in ascending, extended and controlled manner compared to micro-size adjuvant. Moreover, nano-adjuvant release profile from Chitosan was superior compared to Alginate. The core controlling factors in vaccine-adjuvant sustained release includes; smaller adjuvant particles (nano-size, carrier’s low swelling, high viscosity and importantly carrier-adjuvant entrapment reversibility. Chitosan offers sustained ascending superior capacity in releasing Nano-Cap adjuvant. This novel in-vitro pre-clinical study answer a crucial downstream preparative step for optimizing mucosal vaccines before their direct routine in-vivo trial on animal regardless of adjuvant’s particle size or delivery kinetics.

Content and goals of preclinical prosthodontic programs at german-language dental schools.

Science.gov (United States)

Hey, Jeremias; Stimmelmayr, Michael; Hirsch, Christian; Beuer, Florian

2014-04-01

The Association for Dental Education in Europe (ADEE) makes recommendations regarding the skills graduates of European dental schools need to achieve and advises dental schools regarding necessary changes to be made to the curriculum. In 2010 to 2011, a survey was conducted in German-language dental schools to validate the curricula and goals of preclinical prosthodontic programs with regard to laboratory work. The survey was mailed to the course instructors of the preclinical programs at 37 dental schools. Of these, 35 schools returned the completed survey, resulting in a response rate of 95%. Bent wire, wax-up exercises, metal-ceramic single crowns, fixed dental prostheses, cast metal single crowns, temporary removable dental prostheses, and full dentures were part of the dental laboratory work at most schools; however, most instructors considered laboratory work as less important, and there were few similarities among the programs in this area. According to the instructors responsible for preclinical education, honing of fine motor skills, realistic self-assessment, and the ability to work independently were the main goals of the programs. The results of this survey show that with regard to laboratory work, there were more differences than similarities among preclinical prosthodontic programs at German-language dental schools, contrary to the recommendations of the ADEE. These findings should be taken into account when program reforms are planned. © 2013 by the American College of Prosthodontists.

Safety Assurance Process for FRMS : EJcase Implementation

NARCIS (Netherlands)

Stewart, S.; Koornneef, F.; Akselsson, R.; Barton, P.

2009-01-01

Chapter 6: Safety Assurance Process for FRMS - eJcase Implementation The European Commission HILAS project (Human Integration into the Lifecycle of Aviation Systems - a project supported by the European Commission’s 6th Framework between 2005-2009) was focused on using human factors knowledge and

PHARMACOLOGICAL IN VITRO MODELS IN PRE-CLINICAL DRUG TESTING - EXAMPLE OF hSERT TRANSFECTED HUMAN EMBRYONIC KIDNEY CELLS

Directory of Open Access Journals (Sweden)

Mihajlo Jakovljević

2012-06-01

Full Text Available Preclinical drug testing should be considered an important stage during examinations of its efficiency and safety in any likely indication observed. Purpose of the process is acquisition of substantial amount of particular drug-related data before approaching clinical trials in humans. Historical preclinical testing relied on available testing in microbe cultures and animal models. During recent decades laboratory techniques of human cell lines cultivation have been developed and improved. These provide unique possibility of drug acting mechanism testing in a simplified environment lacking basic homeostatic mechanisms. Some examples of these are measuring drug impact to biochemical transport, signaling or anabolic processes. Humane cell lines of embrional kidney 293 are an example of easy-to-grow and disseminate and quite endurable cell line. This methodological article notices some of the details of HEK293 cells cultivation and breading. We took transfection as an example of in vitro model creation for drug testing. Transfection refers to gene introduction into HEK293 cellular genome in order to achieve membrane expression of coded protein. In our case it would be human serotonin transporter. Article contains description of one particular methodological approach in measuring human serotonin transporter expression. The role and importance of serotonin pump in affective disorders genesis was already widely recognized. Aim of the paper was to emphasize feasibility of cell cultivation and its advantages in comparison with alternative traditional methods.

A questionnaire on the use of digital denture impressions in a preclinical setting.

Science.gov (United States)

Wegner, Kerstin; Michel, Karin; Seelbach, Paul Henryk; Wöstmann, Bernd

Since February 2010, intraoral scanning (Lava COS system, 3M ESPE, Seefeld, Germany) has been integrated into the preclinical curriculum at the Department of Prosthodontics of the Justus Liebig University. All students were given a lecture and were trained using a guided scan exercise. After preparing three teeth (mandibular first premolars and mandibular first molar in the 4th quadrant) for cast crowns, the students were asked to scan the maxillary and mandibular teeth. Their acceptance of the new module, "Scanning," was analyzed with the use of a questionnaire (n = 108). The evaluation showed that 63.9% of the students perceived the digital impression to be informative, and had an overall positive opinion of this new digital technology. Concerning the difficulty of the scanning process, approximately 60.2% considered it to be manageable, while 55.6% reported that the magnified view of their preparations improved their understanding of preparing chamfer finish lines. Altogether, the majority of students appreciated this intraoral scanning device as an enhancement of their education. They indicated that this method contributes to a better understanding of crown preparations. In conclusion, the implementation of intraoral scanning seems promising in preclinical education and will be continued in the curriculum.

Seafood Safety and Quality: The Consumer’s Role

Directory of Open Access Journals (Sweden)

Doris T. Hicks

2016-10-01

Full Text Available All the good news about seafood—the health and nutritional benefits, the wide varieties and flavors—has had a positive effect on consumption: people are eating more seafood (http://www.seagrant.sunysb.edu/seafood/pdfs/SeafoodSavvy.pdf. Yet consumers want to be assured that seafood is as safe as, or safer to eat than, other foods. When you hear “seafood safety”, think of a safety net designed to protect you, the consumer, from food-borne illness. Every facet of the seafood industry, from harvester to consumer, plays a role in holding up the safety net. The role of state and federal agencies, fishermen, aquaculturists, retailers, processors, restaurants, and scientists is to provide, update, and carry out the necessary handling, processing, and inspection procedures to give consumers the safest seafood possible. The consumer’s responsibility is to follow through with proper handling techniques, from purchase to preparation. It doesn’t matter how many regulations and inspection procedures are set up; the final edge of the safety net is held by the consumer. This article will give you the information you need to educate yourself and be assured that the fish and shellfish you consume are safe. The most common food-borne illnesses are caused by a combination of bacteria naturally present in our environment and food handling errors made in commercial settings, food service institutions, or at home.

Addendum to the health and safety plan for Waste Area Grouping 6 at Oak Ridge National Laboratory, Oak Ridge, Tennessee. Environmental Restoration Program

International Nuclear Information System (INIS)

Clark, C. Jr.; Burman, S.N.; Wilson, K.A.

1995-08-01

There are three purposes for this addendum to the health and safety plan for Waste Area Grouping 6. The first purpose is to provide record of a corrective action response concerning an occurrence on WAG 6 in October 1994 (ORO-MMES-ENVRES-1994-0016.) This occurrence involved a precautionary evacuation of subcontractor field crews due to malfunctioning monitor alarms for organic vapors. The corrective action is to revise the WAG 6 Site health and safety plan to improve communications during emergency events. The second purpose is to incorporate any outstanding health and safety issues not addressed in the original health and safety plan for WAG 6 document (ORNL/ER-183). The only variance of note is tritium air monitoring in the Tumulus building. The tritium air monitor is added in this addendum as monitoring equipment for WAG 6 with description of action level and calibration. The third purpose of this addendum is to satisfy a condition of approval for the pending Nuclear Criticality Safety Assessment (NCSA) pertaining to KEMA fuel storage at WAG 6. This approval condition requires the following: ''The location of the KEMA burial shall be recorded and maintained in a controlled document that identifies the quantity and the general physical conditions at the time of the entombment with an admonishment to obtain nuclear criticality safety guidance before altering the burial condition.'' In order to satisfy the approval, this document must be controlled. The predecessor to the pending NCSA is NSR No. 0002WM22001

Multiperiod Telser’s Safety-First Portfolio Selection with Regime Switching

Directory of Open Access Journals (Sweden)

Chuangwei Lin

2018-01-01

Full Text Available This paper investigates a multiperiod Telser’s safety-first portfolio selection model with regime switching where the returns of the assets are assumed to depend on the market states modulated by a discrete-time Markov chain. The investor aims to maximize the expected terminal wealth and does not want the probability of the terminal wealth to fall short of a disaster level to exceed a predetermined number called the risk control level. Referring to Tchebycheff inequality, we modify Telser’s safety-first model to the case that aims to maximize the expected terminal wealth subject to a constraint where the upper bound of the disaster probability is less than the risk control level. By the Lagrange multiplier technique and the embedding method, we study in detail the existence of the optimal strategy and derive the closed-form optimal strategy. Finally, by mathematical and numerical analysis, we analyze the effects of the disaster level, the risk control level, the transition matrix of the Markov chain, the expected excess return, and the variance of the risky return.

Pre-Clinical Medical Students' Exposure to and Attitudes Toward Pharmaceutical Industry Marketing.

Science.gov (United States)

Fein, Eric H; Vermillion, Michelle L; Uijtdehaage, Sebastian H J

2007-12-01

Background - Recent studies have examined the exposures and attitudes of physicians and third- and fourth-year medical students toward pharmaceutical industry marketing, but fewer studies have addressed these topics among pre-clinical medical students. Thus, the purpose of this study was to assess pre-clinical students' level of exposure to the pharmaceutical industry and their attitudes toward marketing. Method - First and second-year medical students at UCLA completed a 40-item survey based on previous studies. Results - Over three quarters of pre-clinical students (78.5% or 226 of 288) responded to the survey. Exposure to pharmaceutical industry marketing started very early in medical school. Most second-year students (77%) had received gifts including drug samples after three semesters. Most felt that this would not affect their future prescribing behavior. Conclusions - These findings and findings from related studies, coupled with the students' desire to learn more about the issue, suggest that an early educational intervention addressing this topic may be warranted in American medical schools.

A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy

Directory of Open Access Journals (Sweden)

Leila Bond

2018-01-01

. Nonetheless, antioxidant-treated SOD1-G93A ALS mice have significantly increased motor performance (p < 0.05 measured via rotarod. With a colossal aggregate preclinical effect size average of 59.6%, antioxidants are promising for increasing function/quality of life in clinical ALS patients, a premise worth exploration via low-risk nutritional supplements. Finally, more direct, quantitative measures of oxidative stress, antioxidant levels and bioavailability are key to developing powerful antioxidant therapeutics that can assert measurable impacts on redox homeostasis in the brain and spinal cord.

Index to Nuclear Safety: a technical progress review by chronology, permuted title, and author, Volume 18 (1) through Volume 22 (6)

International Nuclear Information System (INIS)

Cottrell, W.B.; Passiakos, M.

1982-06-01

This index to Nuclear Safety covers articles published in Nuclear Safety, Volume 18, Number 1 (January-February 1977) through Volume 22, Number 6 (November-December 1981). The index is divided into three section: a chronological list of articles (including abstracts), a permuted-title (KWIC) index, and an author index. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center, covers all safety aspects of nuclear power reactors and associated facilities. Over 300 technical articles published in Nuclear Safety in the last 5 years are listed in this index

Index to Nuclear Safety: a technical progress review by chronology, permuted title, and author, Volume 18 (1) through Volume 22 (6)

Energy Technology Data Exchange (ETDEWEB)

Cottrell, W.B.; Passiakos, M.

1982-06-01

This index to Nuclear Safety covers articles published in Nuclear Safety, Volume 18, Number 1 (January-February 1977) through Volume 22, Number 6 (November-December 1981). The index is divided into three section: a chronological list of articles (including abstracts), a permuted-title (KWIC) index, and an author index. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center, covers all safety aspects of nuclear power reactors and associated facilities. Over 300 technical articles published in Nuclear Safety in the last 5 years are listed in this index.

Identification of new treatments for epilepsy: issues in preclinical methodology

Science.gov (United States)

Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

2013-01-01

Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

Nuclear power performance and safety. V.3. Safety and international co-operation

International Nuclear Information System (INIS)

1988-01-01

The International Conference on Nuclear Power Performance and Safety, organized by the International Atomic Energy Agency, was held at the Austria Centre Vienna (ACV) in Vienna, Austria, from 28 September to 2 October 1987. The objective of the Conference was to promote an exchange of worldwide information on the current trends in the performance and safety of nuclear power and its fuel cycle, and to take a forward look at the expectations and objectives for the 1990s. This objective was accomplished through presentation and discussion of about 200 papers at the Conference. Almost 500 participants and observers from 40 countries and 12 organizations discussed three major questions which were posed as the focus of this Conference: (1) What are the current trends and major issues with regard to performance and safety of nuclear power, the nuclear fuel cycle and radioactive waste management? (2) What steps are being taken or need to be taken to resolve outstanding issues in order to improve the performance of nuclear power with assured safety? (3) What performance objectives and achievements can be anticipated for the 1990s? All presentations of this Conference were divided into six volumes. This is Volume 3 which is devoted to the problems of safety and international cooperation. All presentations of Volume 3 were divided into four sessions as follows: the need for safety in nuclear power programmes (4 papers); international cooperation in nuclear safety (6 papers); technical aspects in plant safety (7 papers); approaches to safety (3 papers). A separate abstract was prepared for each of these 20 papers. Refs, figs and tabs

IAEA Mission Sees Safety Commitment at Finland's New Olkiluoto Reactor Before Planned Start in December

International Nuclear Information System (INIS)

2018-01-01

An International Atomic Energy Agency (IAEA) team of experts observed a commitment to safety by the operator of Unit 3 at Finland’s Olkiluoto Nuclear Power Plant, ahead of the Evolutionary Pressurised Water Reactor’s (EPR) planned connection to the grid in December. The team also identified areas for further enhancements as the operator prepares to put the reactor online. The Pre-Operational Safety Review Team (Pre-OSART) concluded an 18-day mission today to assess operational safety at the 1600 MW reactor, located about 280 km northwest of the capital, Helsinki. Finland has engaged France’s Areva SA together with Germany’s Siemens to construct and commission the unit. The operator is Teollisuuden Voima (TVO). Pre-OSART missions aim to improve operational safety by objectively assessing safety performance using the IAEA’s safety standards and proposing recommendations for improvement where appropriate. The review covered the areas of leadership and management for safety; training and qualification; operations; maintenance; technical support; operating experience; radiation protection; chemistry; emergency preparedness and response; accident management; and commissioning. The team identified a number of good practices that will be shared with the nuclear industry globally, including: • The plant has developed and implemented an efficient system for improving knowledge and skills of staff members. • The plant has developed and validated a unique method for performing suspended solids analysis using a microscope, imaging software and a digital camera. • The plant has introduced a system for systematically assessing nuclear safety culture in the plant supplier organization during construction and commissioning. The mission made several recommendations to improve operational safety, including: • Plant management should set appropriate expectations, communicate them to staff and reinforce them in the field. • The plant should improve the

Progress in the U.S. department of energy sponsored in-depth safety assessments of VVER and RBMK reactors

International Nuclear Information System (INIS)

Binder, J.L.; Petri, M.C.; Pasedag, W.F.

2001-01-01

Since the disastrous accident at Chernobyl Nuclear Power Plant Unit 4 in 1986, there has been international recognition of the safety concerns posed by the operation of 67 Soviet-designed commercial nuclear reactors. These reactors are operated in eight countries from the former Soviet Union and its former satellite states in Central and Eastern Europe. The majority of these plants are in the Russian Federation (30 units) and Ukraine (14 units). New plants are in various stages of construction. U.S. support to improve the safety of Soviet-designed reactors over the past decade has been intended to enhance operational safety, provide for risk-reduction measures, and enhance regulatory capability. The U.S. approach to improving the safety of Soviet-designed reactors has matured into a large multi-year program known as the Soviet-Designed Reactor Safety Program that is managed by the U.S. Department of Energy (US DOE). The mission of the program is to implement a self-sustaining nuclear safety improvement program that would lead to internationally accepted safety practices at the plants. Those practices would create a safety culture that would be reflected in the operation, regulation, and professional attitudes of the designers, operators, and regulators of the nuclear facilities. A key component of this larger program has been the Plant Safety Evaluation Program, which supports in-depth safety assessments of VVER and RBMK plants. (author)

Perceived Benefits of Pre-Clinical Simulation-based Training on Clinical Learning Outcomes among Omani Undergraduate Nursing Students

Directory of Open Access Journals (Sweden)

Girija Madhavanprabhakaran

2015-01-01

Full Text Available Objectives: This study aimed to explore the benefits perceived by Omani undergraduate maternity nursing students regarding the effect of pre-clinical simulation-based training (PSBT on clinical learning outcomes. Methods: This non-experimental quantitative survey was conducted between August and December 2012 among third-year baccalaureate nursing students at Sultan Qaboos University in Muscat, Oman. Voluntary participants were exposed to faculty-guided PSBT sessions using low- and medium-fidelity manikins, standardised scenarios and skill checklists on antenatal, intranatal, postnatal and newborn care and assessment. Participants answered a purposely designed self-administered questionnaire on the benefits of PSBT in enhancing learning outcomes. Items were categorised into six subscales: knowledge, skills, patient safety, academic safety, confidence and satisfaction. Scores were rated on a four-point Likert scale. Results: Of the 57 participants, the majority (95.2% agreed that PSBT enhanced their knowledge. Most students (94.3% felt that their patient safety practices improved and 86.5% rated PSBT as beneficial for enhancing skill competencies. All male students and 97% of the female students agreed that PSBT enhanced their confidence in the safe holding of newborns. Moreover, 93% of participants were satisfied with PSBT. Conclusion: Omani undergraduate nursing students perceived that PSBT enhanced their knowledge, skills, patient safety practices and confidence levels in providing maternity care. These findings support the use of simulation training as a strategy to facilitate clinical learning outcomes in future nursing courses in Oman, although further research is needed to explore the objective impact of PSBT on learning outcomes.

Improving safety in mining

Energy Technology Data Exchange (ETDEWEB)

NONE

2007-08-15

AcuMine is a spin-out company from CRC Mining Australia and the University of Sydney's Australian Centre for Field Robotics (ACFR). Its focus is to provide safety and fatigue management in mining environments. The AcuLine Haul Check system was its first development. Of greater benefit to safety in mines will be the AcuMine Proximity System (APPS) developed to reliably detect and warn drivers when in proximity to other trucks and utility vehicles and to detect personnel near to those heavy vehicles. 6 figs.

Anti-Inflammatory Strategies in Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models.

Science.gov (United States)

Citro, Antonio; Cantarelli, Elisa; Pellegrini, Silvia; Dugnani, Erica; Piemonti, Lorenzo

2018-02-01

The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step toward a better management and outcome of pancreatic islet transplanted patients. Recently, we selected the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. Here, the most clinically used anti-inflammatory compounds (IL1-receptor antagonist, steroids, and TNF-α inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as a single agent and in combination with immunosuppression. No other anti-inflammatory compounds tested (IL1-receptor antagonist, steroids, and TNF-α inhibitor) alone or in combination with CXCR1/2 inhibitor improve islet engraftment and significantly delay graft rejection in the presence of MMF + FK-506 immunosuppressive treatment. These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.

Collaborative learning in pre-clinical dental hygiene education.

Science.gov (United States)

Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

2013-04-01

Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

New Safety rules

CERN Multimedia

Safety Commission

2008-01-01

The revision of CERN Safety rules is in progress and the following new Safety rules have been issued on 15-04-2008: Safety Procedure SP-R1 Establishing, Updating and Publishing CERN Safety rules: http://cern.ch/safety-rules/SP-R1.htm; Safety Regulation SR-S Smoking at CERN: http://cern.ch/safety-rules/SR-S.htm; Safety Regulation SR-M Mechanical Equipment: http://cern.ch/safety-rules/SR-M.htm; General Safety Instruction GSI-M1 Standard Lifting Equipment: http://cern.ch/safety-rules/GSI-M1.htm; General Safety Instruction GSI-M2 Standard Pressure Equipment: http://cern.ch/safety-rules/GSI-M2.htm; General Safety Instruction GSI-M3 Special Mechanical Equipment: http://cern.ch/safety-rules/GSI-M3.htm. These documents apply to all persons under the Director General’s authority. All Safety rules are available at the web page: http://www.cern.ch/safety-rules The Safety Commission

Preclinical discovery and development of maraviroc for the treatment of HIV.

Science.gov (United States)

Veljkovic, Nevena; Vucicevic, Jelica; Tassini, Sabrina; Glisic, Sanja; Veljkovic, Veljko; Radi, Marco

2015-06-01

Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.

An empirical assessment of near-source strong ground motion for a 6.6 m{sub b} (7.5 M{sub S}) earthquake in the Eastern United States

Energy Technology Data Exchange (ETDEWEB)

Campbell, Kenneth W

1984-06-01

To help assess the impact of the current U.S. Geological Survey position on the seismic safety of nuclear power plants in the Eastern United States (EUS), several techniques for estimating near-source strong ground motion for a Charleston size earthquake were evaluated. The techniques for estimating the near-source strong ground motion for a 6.6 m{sub b} (7.5 M{sub S}) in the Eastern United States which were assessed are methods based on site specific analyses, semi-theoretical scaling techniques, and intensity-based estimates. The first involves the statistical analysis of ground motion records from earthquakes and recording stations having the same general characteristics (earthquakes with magnitudes of 7.5 M{sub S} or larger, epicentral distances of 25 km or less, and sites of either soil or rock). Some recommendations for source and characterization scaling of the bias resulting primarily from an inadequate sample of near-source recordings from earthquakes of large magnitude are discussed. The second technique evaluated requires that semi-theoretical estimates of peak ground motion parameters for a 6.6 m{sub b} (7.5 M{sub S}) earthquake be obtained from scaling relations. Each relation uses a theoretical expression between peak acceleration magnitude and distance together with available strong motion data (majority coming from California) to develop a scaling relation appropriate for the Eastern United States. None of the existing ground motion models for the EUS include the potential effects of source or site characteristics. Adjustments to account for fault mechanisms, site topography, site geology, and the size and embedment of buildings are discussed. The final approach used relations between strong ground motion parameters and Modified Mercalli Intensity in conjunction with two methods to estimate peak parameters for a 6.6 m{sub s} (7.5 M{sub S}) earthquake. As with other techniques, adjustment of peak acceleration estimates are discussed. Each method

Benchmarking road safety of U.S. states: a DEA-based Malmquist productivity index approach.

Science.gov (United States)

Egilmez, Gokhan; McAvoy, Deborah

2013-04-01

In this study, a DEA based Malmquist index model was developed to assess the relative efficiency and productivity of U.S. states in decreasing the number of road fatalities. Even though the national trend in fatal crashes has reached to the lowest level since 1949 (Traffic Safety Annual Assessment Highlights, 2010), a state-by-state analysis and comparison has not been studied considering other characteristics of the holistic national road safety assessment problem in any work in the literature or organizational reports. In this study, a DEA based Malmquist index model was developed to assess the relative efficiency and productivity of 50 U.S. states in reducing the number of fatal crashes. The single output, fatal crashes, and five inputs were aggregated into single road safety score and utilized in the DEA-based Malmquist index mathematical model. The period of 2002-2008 was considered due to data availability for the inputs and the output considered. According to the results, there is a slight negative productivity (an average of -0.2 percent productivity) observed in the U.S. on minimizing the number of fatal crashes along with an average of 2.1 percent efficiency decline and 1.8 percent technological improvement. The productivity in reducing the fatal crashes can only be attributed to the technological growth since there is a negative efficiency growth is occurred. It can be concluded that even though there is a declining trend observed in the fatality rates, the efficiency of states in utilizing societal and economical resources towards the goal of zero fatality is not still efficient. More effective policy making towards increasing safety belt usage and better utilization of safety expenditures to improve road condition are derived as the key areas to focus on for state highway safety agencies from the scope of current research. Published by Elsevier Ltd.

A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

Science.gov (United States)

Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

2014-03-15

Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. © 2013 UICC.

Long-term impact of a preclinical endovascular skills course on medical student career choices.

Science.gov (United States)

Lee, Jason T; Son, Ji H; Chandra, Venita; Lilo, Emily; Dalman, Ronald L

2011-10-01

Surging interest in the 0 + 5 integrated vascular surgery (VS) residency and successful recruitment of the top students in medical school requires early exposure to the field. We sought to determine the impact of a high-fidelity simulation-based preclinical endovascular skills course on medical student performance and ultimate career specialty choices. Fifty-two preclinical medical students enrolled in an 8-week VS elective course from 2007 to 2009. Students completed a baseline and postcourse survey and performed a renal angioplasty/stent procedure on an endovascular simulator (pretest). A curriculum consisting of didactic teaching covering peripheral vascular disease and weekly mentored simulator sessions concluded with a final graded procedure (posttest). Long-term follow-up surveys 1 to 3 years after course completion were administered to determine ultimate career paths of participants as well as motivating factors for career choice. Objective and subjective performance measured on the simulator and through structured global assessment scales improved in all students from pre- to posttest, particularly with regard to technical skill and overall procedural competency (P choices including surgical subspecialties (64%), radiology (10%), and cardiology (6%). Most respondents indicated major reasons for continued interest in VS were the ability to practice endovascular procedures on the simulator (92%) and mentorship from VS faculty (70%). Basic endovascular skills can be efficiently introduced through a simulation-based curriculum and lead to improved novice performance. Early exposure of preclinical medical students provides an effective teaching and recruitment tool for procedural-based fields, particularly surgical subspecialties. Mentored exposure to endovascular procedures on the simulator positively impacts long-term medical student attitudes toward vascular surgery and ultimate career choices. Copyright © 2011 Society for Vascular Surgery. Published by

Preclinical Pharmacokinetic/Pharmacodynamic Modeling and Simulation in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

OpenAIRE

Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen JMA; Raybon, Joseph

2015-01-01

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its...

China's approach to nuclear safety — From the perspective of policy and institutional system

International Nuclear Information System (INIS)

Mu, Ruimin; Zuo, Jian; Yuan, Xueliang

2015-01-01

Nuclear energy plays an important role in the energy sector in the world. It has achieved a rapid development during the past six decades and contributes to over 11% of the world's electricity supply. On the other side, nuclear accidents have triggered substantial debates with a growing public concern on nuclear facilities. Followed by the Fukushima nuclear accident, some developed countries decided to shut down the existing nuclear power plants or to abandon plans to build new ones. Given this background, accelerating the development of nuclear power on the basis of safety in China will make it a bellwether for other countries. China assigns the top priority to the nuclear safety in nuclear energy development and has maintained a good record in this field. The policy and institutional system provide the necessary guarantee for the nuclear energy development and safety management. Furthermore, China's approach to nuclear safety provides a benchmark for the safe development and utilization of nuclear power. This research draws an overall picture of the nuclear energy development and nuclear safety in China from the policy and institutional perspective. - Highlights: • China's Approach to Nuclear Safety. • Policy and Institutional System for Nuclear Energy Development. • A Benchmark for the Peaceful and Safe Utilization of Nuclear Power. • Further Efforts for Specific Laws and Administrative System

Image-guided drug delivery: preclinical applications and clinical translation

NARCIS (Netherlands)

Ojha, Tarun; Rizzo, Larissa; Storm, Gerrit; Kiessling, Fabian; Lammers, Twan Gerardus Gertudis Maria

2015-01-01

Image-guided drug delivery refers to the combination of drug targeting and imaging. Preclinically, image-guided drug delivery can be used for several different purposes, including for monitoring biodistribution, target site accumulation, off-target localization, drug release and drug efficacy.

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

OpenAIRE

Murthy, Vishakantha; Reyes, Santiago; Geng, Liyi; Gao, Yang; Brimijoin, Stephen

2016-01-01

Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains...

Index to Nuclear Safety: a technical progress review by chrology, permuted title, and author, Volume 11(1) through Volume 20(6)

Energy Technology Data Exchange (ETDEWEB)

Cottrell, W B; Passiakos, M

1980-06-01

This index to Nuclear Safety, a bimonthly technical progress review, covers articles published in Nuclear Safety, Volume II, No. 1 (January-February 1970), through Volume 20, No. 6 (November-December 1979). It is divided into three sections: a chronological list of articles (including abstracts) followed by a permuted-title (KWIC) index and an author index. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center (NSIC), covers all safety aspects of nuclear power reactors and associated facilities. Over 600 technical articles published in Nuclear Safety in the last ten years are listed in this index.

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

Science.gov (United States)

Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

2014-01-01

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

Criticality safety engineering at the Savannah River Site - the 1990s

International Nuclear Information System (INIS)

Chandler, J.R.; Apperson, C.E. Jr.

1996-01-01

The privatization and downsizing effort that is ongoing within the U.S. Department of Energy (DOE) is requiring a change in the management of criticality safety engineering resources at the Savannah River Site (SRS). Downsizing affects the number of criticality engineers employed by the prime contractor, Westinghouse Savannah River Company (WSRC), and privatization affects the manner in which business is conducted. In the past, criticality engineers at the SRS have been part of the engineering organizations that support each facility handling fissile material. This practice led to different criticality safety engineering organizations dedicated to fuel fabrication activities, reactor loading and unloading activities, separation and waste management operations, and research and development

Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry ...

African Journals Online (AJOL)

Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry. ... Nigerian Hospital Practice ... Abstract. Medical training provides an environment in which proper and professional attitudes towards psychiatric patients can be acquired.

Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.

Science.gov (United States)

Becker, P S; Taylor, J A; Trobridge, G D; Zhao, X; Beard, B C; Chien, S; Adair, J; Kohn, D B; Wagner, J E; Shimamura, A; Kiem, H-P

2010-10-01

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (Pgene-corrected cells in patients with FANCA.

Safety demonstration test (SR-3/S1C-3/S2C-3/SF-2) plan using the HTTR. Contract research

International Nuclear Information System (INIS)

Nakagawa, Shigeaki; Sakaba, Nariaki; Takamatsu, Kuniyoshi; Takada, Eiji; Tochio, Daisuke; Ohwada, Hiroyuki

2005-03-01

Safety demonstration tests using the HTTR are to be conducted from the FY2002 to verify the inherent safety features and to improve the safety design and evaluation technologies for HTGRs, as well as to contribute to not only the commercial HTGRs but also the research and development for the VHTR that is one of the Generation IV reactor candidates. This paper describes the reactivity insertion test (SR-3), the coolant flow reduction test by tripping of gas circulators (S1C-3, S2C-3), and the partial flow loss of coolant test (SF-2) planned in March 2005 with their detailed test method, procedure and results of pre-test analysis. From the analytical results, it was verified that the negative reactivity feedback effect of the core brings the reactor power safely to a stable level without a reactor scram. (author)

Resilience Safety Culture in Aviation Organisations

OpenAIRE

Akselsson, R.; Koornneef, F.; Stewart, S.; Ward, M.

2009-01-01

Chapter 2: Resilience Safety Culture in Aviation Organisations The European Commission HILAS project (Human Integration into the Lifecycle of Aviation Systems - a project supported by the European Commission’s 6th Framework between 2005-2009) was focused on using human factors knowledge and methodology to address key challenges for aviation (current and future) including a performance based approach for safety and fatigue management in the aviation sector, mainly inflight operations and maint...

Elective courses for medical students during the preclinical curriculum: a systematic review and evaluation

Directory of Open Access Journals (Sweden)

Ankit Agarwal

2015-05-01

Full Text Available Objective: Preclinical medical student electives are prevalent at medical schools across the United States, but the range of electives available and their impact on medical student education are not well described in the literature. The objective of this article is to review the literature relating to preclinical medical student electives and their impact on medical student educational outcomes. Methods: We reviewed studies that met the following criteria: English-language articles describing preclinical US-based medical electives. We used PubMed journal databases and limited our search for the time period 1999–2014. We excluded electives based in other countries or electives designed for third or fourth year students. Data abstracted included the topic of the elective, qualitative descriptions of the electives, and any associated surveys or exam data associated with the electives. Data were synthesized using descriptive tables sorting electives by broad topic. Reported outcomes and statistical methods were analyzed to assess study quality. Results: We found a wide range of subjects taught in the form of preclinical medical school electives. We identified electives in clinical skills, the humanities, student lifestyle, specialty-specific electives, and an assortment of other miscellaneous electives. Surveys and exams administered to students showed that the electives were universally well received by students. Of the 37 electives identified, 15 electives used quantitative objective assessments, such as knowledge exams, while the remaining tended to use student self-reported results. Conclusions: Preclinical medical student electives are prevalent at medical schools across the United States and have a significant impact on medical student education.

Biosafety preclinical trials of xenogenic, Allogeniec and autologous progenitor cells from fat tissue

OpenAIRE

Melikhova, Vs; Saburina, I.; Repin, V.; Novikova, N.; Murashev, A.; Orlov, A.

2008-01-01

Due to wide spread of new methods of regenerative medicine on basis of stem cells it has become increasingly necessary to establish standards of techniques using them. Preclinical trial of a new technology after receiving preliminary experiment results is a primary stage of its adoption. We carried out the experiments to assess biosafety of autogenous, allergenic and xenogeneic cultures of human and rat cells in models under standard preclinical experiments conditions used in a presentday pha...

Early bedside care during preclinical medical education: can technology-enhanced patient simulation advance the Flexnerian ideal?

Science.gov (United States)

Gordon, James A; Hayden, Emily M; Ahmed, Rami A; Pawlowski, John B; Khoury, Kimberly N; Oriol, Nancy E

2010-02-01

Flexner wanted medical students to study at the patient bedside-a remarkable innovation in his time-so that they could apply science to clinical care under the watchful eye of senior physicians. Ever since his report, medical schools have reserved the latter years of their curricula for such an "advanced" apprenticeship, providing clinical clerkship experiences only after an initial period of instruction in basic medical sciences. Although Flexner codified the segregation of preclinical and clinical instruction, he was committed to ensuring that both domains were integrated into a modern medical education. The aspiration to fully integrate preclinical and clinical instruction continues to drive medical education reform even to this day. In this article, the authors revisit the original justification for sequential preclinical-clinical instruction and argue that modern, technology-enhanced patient simulation platforms are uniquely powerful for fostering simultaneous integration of preclinical-clinical content in a way that Flexner would have applauded. To date, medical educators tend to focus on using technology-enhanced medical simulation in clinical and postgraduate medical education; few have devoted significant attention to using immersive clinical simulation among preclinical students. The authors present an argument for the use of dynamic robot-mannequins in teaching basic medical science, and describe their experience with simulator-based preclinical instruction at Harvard Medical School. They discuss common misconceptions and barriers to the approach, describe their curricular responses to the technique, and articulate a unifying theory of cognitive and emotional learning that broadens the view of what is possible, feasible, and desirable with simulator-based medical education.

Nuclear safety cooperation in Southeast Asia. Lessons from Asia's regional networks

International Nuclear Information System (INIS)

Trajano, Julius Cesar I.

2017-01-01

Debate has been ongoing among key stakeholders on whether South-east Asia should use or reject nuclear power. However, there are still significant regional concerns over nuclear safety and security in South-east Asia. As some ASEAN countries plan to pursue nuclear power, they need to create and maintain a pool of local nuclear professionals with actual relevant experience in the nuclear industry. While the IAEA does not influence a country's decision on introducing nuclear power, it supports Member States' efforts to evaluate all options towards making a knowledgeable decision. Nuclear safety is the responsibility of every nation that utilizes nuclear technology. National governments are responsible for regulations that govern how safety at nuclear facilities is maintained, as well as to reduce radiation risks, including emergency response and recovery actions. But nuclear energy has transboundary/ regional implications if nuclear safety in each member state is not strengthened. ASEAN countries share a common goal in achieving high level of public safety and confidence in nuclear and radiation related issues. Can regional cooperation help ASEAN Member-States strengthen nuclear safety? The paper examines the importance of regional cooperation on nuclear energy governance and the role of regional organisations in Asia in strengthening nuclear safety cooperation and emergency preparedness and response in Southeast Asia. (author)

Review of SKB's Safety Assessment SR-Can: Contributions in Support of SKI's and SSI's Review by External Consultants

Energy Technology Data Exchange (ETDEWEB)

2008-03-15

The Swedish Nuclear Fuel and Waste Management Co (SKB) plans to submit a license application for the construction of a repository for spent nuclear fuel in Sweden 2010. In support of this application SKB will present a safety report, SR-Site, on the repository's long-term safety and radiological consequences. As a preparation for SR-Site, SKB published the preliminary safety assessment SR-Can in November 2006. The purposes were to document a first evaluation of long-term safety for the two candidate sites at Forsmark and Laxemar and to provide feedback to SKB's future programme of work. An important objective of the authorities' review of SR-Can is to provide guidance to SKB on the complete safety reporting for the license application. The authorities have engaged external experts for independent modelling, analysis and review, with the aim to provide a range of expert opinions related to the sufficiency and appropriateness of various aspects of SR-Can. The conclusions and judgments in this report are those of the authors and may not necessarily coincide with those of SKI and SSI. The authorities own review will be published separately (SKI Report 2008:23, SSI Report 2008:04 E). This report compiles contributions from several specific research projects. The separate reviews cover topics regarding the engineered barrier system, the quality assurance, the climate evolution and its effects, and the ecosystems and environmental impacts. All contributions are in English apart from the review concerning ecosystems and environmental impacts, which is presented in Swedish

Crystal structure of the Hg4SiS6 and Hg4SiSe6 compounds

International Nuclear Information System (INIS)

Gulay, L.D.; Olekseyuk, I.D.; Parasyuk, O.V.

2002-01-01

The crystal structures of Hg 4 SiS 6 and Hg 4 SiSe 6 compounds were investigated using X-ray powder diffraction. These compounds crystallize in the monoclinic Cc space group with the lattice parameters a=1.23020(5), b=0.71031(4), c=1.22791(4) nm, β=109.721(3) deg. for Hg 4 SiS 6 and a=1.28110(4), b=0.74034(4), c=1.27471(1) nm, β=109.605(3) deg. for Hg 4 SiSe 6 . Atomic parameters were refined in the isotropic approximation (R I =0.0571 and R I =0.0555 for the Hg 4 SiS 6 and Hg 4 SiSe 6 , respectively)

Preclinical animal research on therapy dosimetry with dual isotopes

NARCIS (Netherlands)

M.W. Konijnenberg (Mark); M. de Jong (Marion)

2011-01-01

textabstractPreclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of

Subjective and Objective Evaluation of PBL Outcomes in Preclinical ...

African Journals Online (AJOL)

Subjective and Objective Evaluation of PBL Outcomes in Preclinical Medical Students. ... ABSTRACT: Problem based learning curriculum is widely recognized as a progressive, learner-centered, active learning approach and is currently used in the entire medical curriculum in over 10% of medical schools worldwide.

Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma

International Nuclear Information System (INIS)

Wang, Weining; Iyer, N. Gopalakrishna; Tay, Hsien Ts’ung; Wu, Yonghui; Lim, Tony K. H.; Zheng, Lin; Song, In Chin; Kwoh, Chee Keong; Huynh, Hung; Tan, Patrick O. B.; Chow, Pierce K. H.

2015-01-01

-held notion that orthotopic PDX model is the gold standard preclinical model for HCC. The online version of this article (doi:10.1186/s12885-015-1814-8) contains supplementary material, which is available to authorized users

A generalizable pre-clinical research approach for orphan disease therapy

Directory of Open Access Journals (Sweden)

Beaulieu Chandree L

2012-06-01

Full Text Available Abstract With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.

Is medical students' moral orientation changeable after preclinical medical education?

Science.gov (United States)

Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

2012-03-01

Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors.

Science.gov (United States)

Tripathy, Debu; Bardia, Aditya; Sellers, William R

2017-07-01

The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Clin Cancer Res; 23(13); 3251-62. ©2017 AACR . ©2017 American Association for Cancer Research.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

Science.gov (United States)

Ng, Samuel Y; Yoshida, Noriaki; Christie, Amanda L; Ghandi, Mahmoud; Dharia, Neekesh V; Dempster, Joshua; Murakami, Mark; Shigemori, Kay; Morrow, Sara N; Van Scoyk, Alexandria; Cordero, Nicolas A; Stevenson, Kristen E; Puligandla, Maneka; Haas, Brian; Lo, Christopher; Meyers, Robin; Gao, Galen; Cherniack, Andrew; Louissaint, Abner; Nardi, Valentina; Thorner, Aaron R; Long, Henry; Qiu, Xintao; Morgan, Elizabeth A; Dorfman, David M; Fiore, Danilo; Jang, Julie; Epstein, Alan L; Dogan, Ahmet; Zhang, Yanming; Horwitz, Steven M; Jacobsen, Eric D; Santiago, Solimar; Ren, Jian-Guo; Guerlavais, Vincent; Annis, D Allen; Aivado, Manuel; Saleh, Mansoor N; Mehta, Amitkumar; Tsherniak, Aviad; Root, David; Vazquez, Francisca; Hahn, William C; Inghirami, Giorgio; Aster, Jon C; Weinstock, David M; Koch, Raphael

2018-05-22

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Utilization of blended learning to teach preclinical endodontics.

Science.gov (United States)

Maresca, Cristina; Barrero, Carlos; Duggan, Dereck; Platin, Enrique; Rivera, Eric; Hannum, Wallace; Petrola, Frank

2014-08-01

Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level.

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Directory of Open Access Journals (Sweden)

Cao Brian

2008-12-01

Full Text Available Abstract Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino-17-demethoxy geldanamycin (17AAG. Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2. These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

DEFF Research Database (Denmark)

Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

2016-01-01

Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

Gas-cooled fast reactor safety - and overview and status of the U.S. program

International Nuclear Information System (INIS)

Torri, A.; Buttemer, D.R.

1981-01-01

In the revised GCFR Safety Program Plan a quantitative risk limit line has been adopted to establish requirements for the safety related functions and systems. The risk limit line is derived from an interpretation of NRC established licensing requirements, including those for LMFBR's. Multiple barriers to the progression of accident sequences are defined in the form of six Lines of Protection (LOPs). LOPs-1 to 3 are dedicated to accident prevention and represent the normal operating systems, the dedicated safety systems and the inherent design features, respectively. LOPs-4 to 6 are dedicated to the mitigation of core melt accident consequences and include in-vessel accident containment, secondary containment integrity and radiological attenuation, respectively. Cumulative frequency limits and consequence limits are established for each LOP. Design features associated with each LOP are described and the results of supporting safety analyses are summarized. (author)

In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

OpenAIRE

Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

2017-01-01

Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

The interplay between academic performance and quality of life among preclinical students.

Science.gov (United States)

Shareef, Mohammad Abrar; AlAmodi, Abdulhadi A; Al-Khateeb, Abdulrahman A; Abudan, Zainab; Alkhani, Mohammed A; Zebian, Sanderlla I; Qannita, Ahmed S; Tabrizi, Mariam J

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

A Microdose PET Study of the Safety, Immunogenicity, Biodistribution, and Radiation Dosimetry of 18F-FB-A20FMDV2 for Imaging the Integrin αvβ6.

Science.gov (United States)

Keat, Nicholas; Kenny, Julia; Chen, Keguan; Onega, Mayca; Garman, Nadia; Slack, Robert J; Parker, Christine A; Lumbers, R Thomas; Hallett, Will; Saleem, Azeem; Passchier, Jan; Lukey, Pauline T

2018-06-01

The α v β 6 integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid α v β 6 -binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image α v β 6 levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of α v β 6 in humans. Methods: Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female) received a single microdose of 18 F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. Results: There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of 18 F-FB-A20FMDV2 was 8.7 ± 4.4 μg (range, 2.7-13.0 μg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. Conclusion: 18 F-FB-A20FMDV2 successfully

Fe-solubility of Ni7S6 and Ni9S8: Thermodynamic analysis

International Nuclear Information System (INIS)

Waldner, P.

2011-01-01

Experimental data on phase equilibria have been used for thermodynamic analysis of the iron solubility of the nickel sulfides Ni 7 S 6 and Ni 9 S 8 . For both compounds, a two-sublattice approach within the framework of the compound energy formalism has been applied to perform Gibbs free energy modelling at 0.1 MPa total pressure consistently embedded in recent thermodynamic assessment studies of other iron-nickel-sulfides. The predicted maxima of iron solubility around 3 at% of Ni 7 S 6 and 5.5 at% of Ni 9 S 8 are confirmed by experimental data. The calculations of complex ternary phase relations with Fe-bearing Ni 7 S 6 and Ni 9 S 8 gain further improvement. The first internally consistent description of all thermodynamically stable phases known in the literature for the iron-nickel-sulfur system is completed.

Pretest analysis document for Test S-FS-6

International Nuclear Information System (INIS)

Shaw, R.A.; Hall, D.G.

1985-05-01

This report documents the pretest analyses completed for Semiscale Test S-FS-6. This test will simulate a transient initiated by a 100% break in a steam generator bottom feedwater line downstream of the check valve. The initial conditions represent normal operating conditions for a C-E System 80 nuclear power plant. Predictions of transients resulting from feedwater line breaks in these plants have indicated that significant primary system overpressurization may occur. The enclosed analyses include a RELAP5/MOD2/CY21 code calculation and preliminary results from a facility hot, integrated test which was conducted to near S-FS-6 specifications. The results of these analyses indicate that the test objectives for Test S-FS-6 can be achieved. The primary system overpressurization will pose no threat to personnel or plant integrity

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

Science.gov (United States)

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Collaborating with Alexander Scriabine and the Miles Institute for Preclinical Pharmacology.

Science.gov (United States)

Janis, Ronald A

2015-11-15

This article represents a timely opportunity to express my affection, admiration and gratitude to Professor David Triggle. David was my Ph.D. advisor as well as a key consultant in the 1980s and early 1990s for research programs at Miles Institute for Preclinical Pharmacology in West Haven, CT, the U.S. research operation of Bayer AG, in the areas of Ca(2+) and K(+) channel ligands. The binding methodology developed in his laboratory was used to search for an endogenous ligand for L-type Ca(2+) channels. We did not find the substance that we were searching for, a genetically-determined, competitive inhibitor for the 1,4-dihydropyridine binding site, but instead isolated the endogenous ligand for the brain's own marijuana, anandamide. Devane, Mechoulam and coworkers first discovered that this compound was the endogenous ligand for delta-9-tetrahydrocannabinol, the active substance in cannabis. The endogenous endocannabinoid system is now the target of many exciting new approaches to drug discovery. Copyright © 2015 Elsevier Inc. All rights reserved.

Prediction of antibiotic resistance: time for a new preclinical paradigm?

DEFF Research Database (Denmark)

Sommer, Morten Otto Alexander; Munck, Christian; Toft-Kehler, Rasmus Vendler

2017-01-01

Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development. In this ......Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development....... In this Opinion article, we argue that the traditional procedures that are used for the prediction of antibiotic resistance today could be markedly improved by including a broader analysis of bacterial fitness, infection dynamics, horizontal gene transfer and other factors. This will lead to more informed...

Workplace safety: Let’s ask the right questions

CERN Multimedia

CERN Bulletin

2011-01-01

Since 2003, the International Labour Organization and the World Health Organization have been organising an annual event on 28 April called “World Day for Safety and Health at Work.” This year, CERN is taking part for the first time with campaigns organised by the Safety Unit of the BE Department and by the HSE Unit.   The HSE Unit and the Safety Unit of the BE Department invite you to find out about everyday health and safety questions by visiting the stands they will be setting up at the entrances to the different restaurants at lunchtime on Thursday, 28 April. "This will be a chance to think about safety not just in the workplace but also at home and in the context of leisure activities,” explains Charles-Edouard Sala, who came up with the idea for CERN's participation in the event. “Safety is, first and foremost, a matter of personal awareness of and sensitivity to risks. That is why we in the Safety Unit had the idea for a campaign with the mo...

Nuclear Safety R and D Programs and trend in the U. S. Utility Industry

International Nuclear Information System (INIS)

Kim, Jong Hyun

1992-01-01

First of all, the deterministic approach to safety analysis, which had dominated safety research in the earlier years, has given much ground to probabilistic approach. Secondly, human factors analysis has become an important part of safety research. Third, safety research relevant to reliability, or safety combined with reliability, are gradually taking place of purely safety-oriented or stand-alone safety research. More and more nuclear utilities in the U. S. are integrating safety with reliability. This evolution is in part due to the successful completion of major safety testing and analyses of deterministic nature, and partially due to the utility industry's desire to harvest synergistic nature, and partially due to the utility industry's desire to harvest synergistic results by combining safety with reliability, as the utility industry is more and more concerned about reducing operation and maintenance costs by enhancing reliability while maintaining plant safety. Nuclear safety is a complex and comprehensive concept, defying a simple categorization or interpretation. Thus, research and development in nuclear safety is necessarily diverse, and the program areas and trend presented in this paper are not meant to be all inclusive. For instance, there are some other active areas that were not mentioned, such as seismic risk assessment program and others. Nuclear safety research and development activities have undergone a perceptible shift of emphasis in recent years. They have become more focused and product-oriented. Also, except for the severe accident analysis, the emphasis on prevention and mitigation of accident, rather than analyzing the consequences of accident, is very much in evidence; that is, reliability-based technologies using PIRA methodology, and upgrading of instrumentation and control technologies are in the main stream of activities

Index to Nuclear Safety. A technical progress review by chronology, permuted title, and author. Vol. 11, No. 1--Vol. 17, No. 6

International Nuclear Information System (INIS)

Cottrell, W.B.; Klein, A.

1977-01-01

This index to Nuclear Safety covers articles in Nuclear Safety Vol. 11, No. 1 (Jan.-Feb. 1970), through Vol. 17, No. 6 (Nov.-Dec. 1976). The index includes a chronological list of articles (including abstract) followed by KWIC and Author Indexes. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center, covers all safety aspects of nuclear power reactors and associated facilities. The index lists over 350 technical articles in the last six years of publication

Index to Nuclear Safety. A technical progress review by chronology, permuted title, and author. Vol. 11, No. 1--Vol. 17, No. 6

Energy Technology Data Exchange (ETDEWEB)

Cottrell, W.B.; Klein, A.

1977-02-23

This index to Nuclear Safety covers articles in Nuclear Safety Vol. 11, No. 1 (Jan.-Feb. 1970), through Vol. 17, No. 6 (Nov.-Dec. 1976). The index includes a chronological list of articles (including abstract) followed by KWIC and Author Indexes. Nuclear Safety, a bimonthly technical progress review prepared by the Nuclear Safety Information Center, covers all safety aspects of nuclear power reactors and associated facilities. The index lists over 350 technical articles in the last six years of publication.

Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

LENUS (Irish Health Repository)

Polyzois, Ioannis

2011-05-01

The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson\\'s linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level.

Alberta Environment's weir safety program : options for rehabilitation to improve public safety : a case study of the Calgary weir

Energy Technology Data Exchange (ETDEWEB)

NONE

2010-07-01

Alberta Environment's water management operations (WMO) own and operates 46 dams and 800 km of canals. This presentation discussed a rehabilitation program designed to improve the safety of the WMO's Calgary weir which was built in 1908 to encourage settlement in the province. The weir includes a 32 m wide sluiceway, a 2.5 m concrete weir, and a fish ladder. A portage trail has been built to accommodate canoes, and signs are posted to indicate the hazards associated with the weir. The WMO has also launched an advertising campaign to outline hazards to the general public. The WMO has a contract with the Calgary fire department (CFD) to maintain a safety boom and provide rescue operations at the weir. The weir project aims to accommodate access and safety while enhancing flood conveyance capabilities of the weir. The project will allow upstream passage for patrol boats operated by the Calgary fire department's aquatic rescue service. The final design of the weir will include a series of drops constructed downstream of the weir to create pool and riffle structures that will eliminate hydraulic rollers. Notches will be cut in the weir to regulate flows moving through the new low and high flow channels. Case studies of other low-head dams operated by the WMO were also presented. tabs., figs.

Nuclear reactor safety program in U.S. Department of Energy and future perspectives

International Nuclear Information System (INIS)

Song, Y.T.

1987-01-01

The U.S. Department of Energy (DOE) establishes policy, issues orders, and assures compliance with requirements. The contractors who design, construct, modify, operate, maintain and decommission DOE reactors, set forth the assessment of the safety of cognizant reactors and impliment DOE orders. Teams of experts in the Depatment, through scheduled and unscheduled review programs, reassess the safety of reactors in every phases of their lives. As new technology develops, the safety programs are reevaluated and policies are modified to accommodate these new technologies. The diagnostic capabilities of the computer using multiple alarms to enhance detection of defects and control of a reactor have been greatly utilized in reactor operating systems. The application of artificial intelligence (AI) technologies for diagnostic and even for the decision making process in the event of reactor accidents would be one of the future trends in reactor safety programs. (author)

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

DEFF Research Database (Denmark)

Tiphaine, Adam de Beaumais; Hjalgrim, Lisa Lynqsie; Nersting, Jacob

2016-01-01

BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed...... and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal...... to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference...

EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms

International Nuclear Information System (INIS)

Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard; Dittmann, Klaus; Doerr, Wolfgang; Kasten-Pisula, Ulla; Rodemann, H. Peter

2007-01-01

Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with EGFR inhibitors. These include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Effects and mechanisms may differ for different classes of EGFR inhibitors, for different tumours and for normal tissues. The mechanisms underlying this heterogeneity are currently poorly understood, and predictive assays are not available yet. Importantly, mechanisms and predictors for the combined effects of radiation with EGFR inhibitors appear to be considerably different to those for application of EGFR inhibitors alone or in combination with chemotherapy. Therefore to further evaluate the efficacy and mechanisms of EGFR-inhibition in combined treatments, radiotherapy-specific preclinical research strategies, which include in vivo experiments using local tumour control as an endpoint, as well as animal studies on normal tissue toxicity are needed

Enhancing translation: guidelines for standard pre-clinical experiments in mdx mice.

Science.gov (United States)

Willmann, Raffaella; De Luca, Annamaria; Benatar, Michael; Grounds, Miranda; Dubach, Judith; Raymackers, Jean-Marc; Nagaraju, Kanneboyina

2012-01-01

Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy. Copyright © 2011 Elsevier B.V. All rights reserved.

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

Directory of Open Access Journals (Sweden)

Carlo Abbate

2014-01-01

Full Text Available Objective. We describe a case of dementia with Lewy bodies (DLB that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI- DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS. The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome.

Science.gov (United States)

Bagley, Mark C; Davis, Terence; Dix, Matthew C; Fusillo, Vincenzo; Pigeaux, Morgane; Rokicki, Michal J; Kipling, David

2010-09-01

The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use. Microwave irradiation using a stop-flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C-S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield. This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Science.gov (United States)

Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

2016-03-01

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

Science.gov (United States)

Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

2017-10-03

To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

Resilience Safety Culture in Aviation Organisations

NARCIS (Netherlands)

Akselsson, R.; Koornneef, F.; Stewart, S.; Ward, M.

2009-01-01

Chapter 2: Resilience Safety Culture in Aviation Organisations The European Commission HILAS project (Human Integration into the Lifecycle of Aviation Systems - a project supported by the European Commission’s 6th Framework between 2005-2009) was focused on using human factors knowledge and

S-TEAMS: A Truly Multiprofessional Course Focusing on Nontechnical Skills to Improve Patient Safety in the Operating Theater.

Science.gov (United States)

Stewart-Parker, Emma; Galloway, Robert; Vig, Stella

Possessing adequate nontechnical skills (NTS) in operating theaters is of increasing interest to health care professionals, yet these are rarely formally taught. Teams make human errors despite technical expertise and knowledge, compromising patient safety. We designed a 1-day, multiprofessional, multidisciplinary course to teach, practice, and apply these skills through simulation. The course, "S-TEAMS," comprised a morning of lectures, case studies, and interactive teamworking exercises. The afternoon divided the group into multiprofessional teams to rotate around simulated scenarios. During the scenarios, teams were encouraged to focus on NTS, including communication strategies, situational awareness, and prompts such as checklists. A thorough debrief with experienced clinician observers followed. Data was collected through self-assessments, immediate and 6-month feedback to assess whether skills continued to be used and their effect on safety. In total, 68 health care professionals have completed the course thus far. All participants felt the course had a clear structure and that learning objectives were explicit. Overall, 95% felt the scenarios had good or excellent relevance to clinical practice. Self-assessments revealed a 55% increase in confidence for "speaking up" in difficult situations. Long-term data revealed 97% of the participants continued to use the skills, with 88% feeling the course had prevented them from making errors. Moreover, 94% felt the course had directly improved patient safety. There is a real demand and enthusiasm for developing NTS within the modern theater team. The simple and easily reproducible format of S-TEAMS is sustainable and inclusive, and crucially, the skills taught continue to be used in long term to improve patient safety and teamworking. Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Suggestion on the safety classification of spent fuel dry storage in China’s pressurized water reactor nuclear power plant

Science.gov (United States)

Liu, Ting; Qu, Yunhuan; Meng, De; Zhang, Qiaoer; Lu, Xinhua

2018-01-01

China’s spent fuel storage in the pressurized water reactors(PWR) is stored with wet storage way. With the rapid development of nuclear power industry, China’s NPPs(NPPs) will not be able to meet the problem of the production of spent fuel. Currently the world’s major nuclear power countries use dry storage as a way of spent fuel storage, so in recent years, China study on additional spent fuel dry storage system mainly. Part of the PWR NPP is ready to apply for additional spent fuel dry storage system. It also need to safety classificate to spent fuel dry storage facilities in PWR, but there is no standard for safety classification of spent fuel dry storage facilities in China. Because the storage facilities of the spent fuel dry storage are not part of the NPP, the classification standard of China’s NPPs is not applicable. This paper proposes the safety classification suggestion of the spent fuel dry storage for China’s PWR NPP, through to the study on China’s safety classification principles of PWR NPP in “Classification for the items of pressurized water reactor nuclear power plants (GB/T 17569-2013)”, and safety classification about spent fuel dry storage system in NUREG/CR - 6407 in the United States.

Criticality safety evaluation for TWR-S fuel assembly transportation using TK-S16 containers

International Nuclear Information System (INIS)

Pesic, M.P.; Steljic, M.M.; Antic, D.P.

2002-01-01

Criticality safety issues, concerning transportation of fresh high-enriched uranium fuel elements (TWR-S fuel assembly type) with Russian containers TK-S16, are objects of study in this paper. Three-dimensional (3D) models of fuel element and container were made, based upon their well-known geometry and material structure. The way to pack fuel elements in a bundle inside of the container is proposed. Calculations were done by MCNP4B2 computer code. This Monte Carlo criticality code determined the effective multiplication factor from the cross-section data and specific geometry data. This evaluation demonstrated the subcriticality of a single package and an array of packages during normal conditions of transport and various hypothetical accident conditions. (author)

Atomic Safety and Licensing Board Panel Biennial Report, Fiscal Years 1993--1994. Volume 6

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-08-01

In Fiscal Year 1993, the Atomic Safety and Licensing Board Panel (``the Panel``) handled 30 proceedings. In Fiscal Year 1994, the Panel handled 36 proceedings. The cases addressed issues in the construction, operation, and maintenance of commercial nuclear power reactors and other activities requiring a license form the Nuclear Regulatory Commission. This report sets out the Panel`s caseload during the year and summarizes, highlight, and analyzes how the wide- ranging issues raised in those proceedings were addressed by the Panel`s judges and licensing boards.

Differentiation of pork from beef, chicken, mutton and chevon ...

African Journals Online (AJOL)

Yomi

2012-04-19

Apr 19, 2012 ... 4Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang, Malaysia. ... 6Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, ..... Food Safety.

Regulatory Oversight of Safety Culture — Korea’s Experience

International Nuclear Information System (INIS)

Jung, S.J.; Choi, Y.S.; Kim, J.T.

2016-01-01

In Korea, a regulatory oversight program of safety culture was launched in 2012 to establish regulatory measures against several events caused by weak safety culture in the nuclear industry. This paper is intended to introduce the preliminary regulatory oversight framework, development and validation of safety culture components, pilot safety culture inspection results and lessons learned. The safety culture model should be based on a sound understanding of the national culture and industry characteristics where the model will be applied. The nuclear safety culture oversight model is being developed and built on the Korean regulatory system to independently assess the nuclear power operating organizations’ safety culture.

Impact of a Comprehensive Early Clinical Exposure Program for Preclinical Year Medical Students

Directory of Open Access Journals (Sweden)

Sumitra Govindarajan

2018-06-01

Full Text Available Purpose: To study the impact of an early clinical exposure program designed to provide a wide variety (cognitive, affective and psychomotor of learning experiences for the preclinical year students. Method: One hundred and fifty preclinical students were posted in small groups to selected departments – Transfusion medicine, Catheterization lab, Simulation lab, Radiology, Neurology, Nephrology, Respiratory medicine and General surgery. Each student had atleast ten hours  of clinical exposure under this program. The program was evaluated through a series of pre and post-test questionnaires, which were designed based on the learning objectives of each session. Students who wished to participate in the program evaluation gave informed consent, took up the pre / post test and were also asked to give their written open comments about the program. Results: There was a significant increase in the post-test scores (ranging from 9.14±2.67 to 36.65±6.62 when compared to the pre-test scores (ranging from 7.94±2.31 to 28.69±6.11 for all the sessions (p value <0.001, n=144. Analysis of the open feedback showed that the program had significant impact on the cognitive, psychomotor and affective domains. “Application of basic sciences in clinical practice”, “motivation to learn”, “got familiar with various specialties”, “insight about what the patient undergoes” were the themes identified from the open comments. Conclusion: The innovative use of early clinical exposure program to teach/learn clinical skills like phlebotomy and Basic Life Support had been well appreciated by the students. The present design involving a variety of learning experiences has been successful in introducing the various dimensions of medical profession like scientific, ethical, interpersonal, professional and social to the new entrants in addition to enhancing their motivation to learn. Keywords: Attitude, Learning, Simulation lab, Medical education, Curriculum

A 3S Risk ?3SR? Assessment Approach for Nuclear Power: Safety Security and Safeguards.

Energy Technology Data Exchange (ETDEWEB)

Forrest, Robert; Reinhardt, Jason Christian; Wheeler, Timothy A.; Williams, Adam David

2017-11-01

Safety-focused risk analysis and assessment approaches struggle to adequately include malicious, deliberate acts against the nuclear power industry's fissile and waste material, infrastructure, and facilities. Further, existing methods do not adequately address non- proliferation issues. Treating safety, security, and safeguards concerns independently is inefficient because, at best, it may not take explicit advantage of measures that provide benefits against multiple risk domains, and, at worst, it may lead to implementations that increase overall risk due to incompatibilities. What is needed is an integrated safety, security and safeguards risk (or "3SR") framework for describing and assessing nuclear power risks that can enable direct trade-offs and interactions in order to inform risk management processes -- a potential paradigm shift in risk analysis and management. These proceedings of the Sandia ePRA Workshop (held August 22-23, 2017) are an attempt to begin the discussions and deliberations to extend and augment safety focused risk assessment approaches to include security concerns and begin moving towards a 3S Risk approach. Safeguards concerns were not included in this initial workshop and are left to future efforts. This workshop focused on four themes in order to begin building out a the safety and security portions of the 3S Risk toolkit: 1. Historical Approaches and Tools 2. Current Challenges 3. Modern Approaches 4. Paths Forward and Next Steps This report is organized along the four areas described above, and concludes with a summary of key points. 2 Contact: rforres@sandia.gov; +1 (925) 294-2728

Nanotechnology and nuclear medicine; research and preclinical applications.

Science.gov (United States)

Assadi, Majid; Afrasiabi, Kolsoom; Nabipour, Iraj; Seyedabadi, Mohammad

2011-01-01

The birth of nanotechnology in human society was around 2000 years ago and soon found applications in various fields. In this article, we highlight the current status of research and preclinical applications and also future prospects of nanotechnology in medicine and in nuclear medicine. The most important field is cancer. A regular nanotechnology training program for nuclear medicine physicians may be welcome.

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

International Nuclear Information System (INIS)

Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.; Watson, Kenny J.; Collingwood, Steve; Charlton, Steven J.; Kent, Toby C.

2015-01-01

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED 50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M 2 muscarinic receptor occupancy, which predicted significantly higher M 2 receptor blockade at ED 50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED 50 doses for bronchoprotection we model systemic M 2 receptor occupancy. • Glycopyrrolate demonstrates lower M 2 occupancy at

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

Energy Technology Data Exchange (ETDEWEB)

Trifilieff, Alexandre; Ethell, Brian T. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Sykes, David A. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Watson, Kenny J.; Collingwood, Steve [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Charlton, Steven J. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Kent, Toby C., E-mail: tobykent@me.com [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom)

2015-08-15

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

Cookbooks in U.S. history: How do they reflect food safety from 1896 to 2014?

Science.gov (United States)

Almanza, Barbara A; Byrd, Karen S; Behnke, Carl; Ma, Jing; Ge, Li

2017-09-01

Historical cookbooks as a source of recipes and food preparation information would be expected to document advancements in food safety related to kitchen equipment, cleaning, foodborne illness knowledge, and consumer education materials. In turn, this food safety information might be expected to contribute to consumers' food safety behaviors. Using both quantitative and qualitative research methodology, this study assessed how food safety information in cookbooks changed and how quickly advancements were incorporated. Faster assimilation into cookbooks was associated with kitchen equipment, educational resources (hotlines and websites), and foodborne illness outbreaks. The rate of incorporation of education materials was moderate. Cleaning advances were the slowest to be incorporated. Modern cookbooks published after the 1980's rapidly evolved with advances in food safety knowledge. Copyright © 2017 Elsevier Ltd. All rights reserved.

Strategies to improve road safety : how to learn from Dutch experiences? Lecture held at the Seminar on Road Safety "Stategies to improve road safety: How to learn from Dutch experiences?", Ankara/Istanbul, Turkey, 6-7 November 2012. [a.k.a. as: Improving road safety : experiences from The Netherlands.

NARCIS (Netherlands)

Hagenzieker, M.P.

2016-01-01

On the occasion of the visit of the Dutch Prime Minister Mark Rutte to Turkey, The Netherlands embassy in Ankara and the consulate-general in Istanbul are organising a half-day seminar on the successful road safety strategy of the Netherlands on 6 and 7 November 2012. During these events road safety

Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies

International Nuclear Information System (INIS)

Amacher, David E.

2011-01-01

Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the 'two hit' theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R and D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

Science.gov (United States)

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding

(2aR*,5S*,6aS*,8aS*,E-Ethyl 5-hydroxy-7,7,8a-trimethyl-8-oxo-2,2a,6,6a,7,8,8a,8b-octahydro-1H-pentaleno[1,6-bc]oxepine-4-carboxylate

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Goverdhan Mehta

2012-12-01

Full Text Available The title compound, C17H24O5, featuring a 2-carbethoxy-3-oxepanone unit in its intramolecularly O—H...O hydrogen-bonded enol form, was obtained via [(CF3CO22Rh]2-catalysed intramolecular O—H bond insertion in the α-diazo-ω-hydroxy-β-ketoester, ethyl 4-[(1S,3aS,6R,6aS-6-hydroxy-2,2,3a-trimethyl-3-oxo-octahydropentalen-1-yl]-2-diazo-3-oxobutanoate. The seven-membered oxacyclic ring, thus constructed on a cis-fused diquinane platform, was found to adopt a distorted boat–sofa conformation.

A 6-month large-scale study into the safety of tamsulosin

Science.gov (United States)

Michel, M C; Bressel, H-U; Goepel, M; Rübben, H

2001-01-01

Aims Tamsulosin is an α1-adrenoceptor antagonist for the treatment of symptomatic benign prostatic hyperplasia with a tolerability similar to that of placebo in short-term, placebo-controlled studies with limited patient numbers. The present study was designed to test the safety of tamsulosin treatment in a large cohort of men during a prolonged period of time, particularly with regard to comedications. Methods A multicentre, open-label phase IIIb study with 1784 patients receiving 0.4 mg o.d. tamsulosin for 6 months was performed according to good clinical practice guidelines. The analysis was performed on an intention-to-treat basis and powered to detect adverse events (AE) occurring in 0.15% of patients with 95% confidence. Results During a total drug exposure time of 811 patient years, 386 AE were recorded in 253 patients (14.2%; 95% confidence intervals [CI] 12.0–15.2%). Twenty-nine patients suffered 44 serious AE including five fatal events (CI 0.12–0.73%) due to myocardial infarction (n = 3) and to pneumonia and a car accident (one each), but all deaths were judged to be unlikely to be related to study medication. The frequency of AE in patients without any comedication (n = 1095) was 13.0% (CI 11.3–14.9%). In a logistic regression analysis β-adrenoceptor blockers, converting enzyme inhibitors, antidiabetics and diuretics did not significantly affect the odds ratio for having AE. However, concomitant α-adrenoceptor antagonists (a protocol violation) and treatment with verapamil (which also has α-adrenoceptor antagonist activity) significantly enhanced the odds ratio for having AE to 3.87 (CI 1.52–9.85) and 3.17 (CI 1.52–6.58), respectively. Minor increases in the odds ratio, which did not reach statistical significance, were also observed for Ca2+ antagonists other than verapamil and for nitrates. Conclusions We conclude that tamsulosin has a good safety profile relative to AE rates in the placebo arms of previous studies on tamsulosin even in

Fluoro-norchloroepibatidine: Preclinical assessment of acute toxicity

International Nuclear Information System (INIS)

Molina, Patricia E.; Ding Yushin; Carroll, F. Ivy; Liang, F.; Volkow, Nora D.; Pappas, Naomi; Kuhar, Michael; Abumrad, Naji; Gatley, S. John; Fowler, Joanna S.

1997-01-01

18 Fluoro-norchloroepibatidine (exo-2-(6-fluoro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane [NFEP]), a labeled derivative of epibatidine, has shown promise for imaging brain nicotinic acetylcholine receptors with PET. We determined the dose-dependent effects of NFEP in conscious rats. NFEP (1.5 μg/kg; administered intravenously) resulted in 30% mortality. Neither 0.5 μg/kg or 0.25 μg/kg NFEP resulted in any significant changes in cardiorespiratory parameters, but plasma catecholamines increased (2- to 3-fold). Further studies are needed to determine the safety of NFEP that are specifically designed to assess the catecholamine response. Our results suggest that it is not advisable to initiate human PET studies with [ 18 F]-NFEP without further evidence supporting its safety

78 FR 16211 - Safety Zone, Corp. Event Finale UHC, St. Thomas Harbor; St. Thomas, U.S. Virgin Islands

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2013-03-14

... 1625-AA00 Safety Zone, Corp. Event Finale UHC, St. Thomas Harbor; St. Thomas, U.S. Virgin Islands... establish a temporary safety zone on the waters of St. Thomas Harbor in St. Thomas, U.S. Virgin Islands... through Friday, except federal holidays. The telephone number is 202-366-9329. See the ``Public...

Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma.

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Nakayama, Robert; Zhang, Yi-Xiang; Czaplinski, Jeffrey T; Anatone, Alex J; Sicinska, Ewa T; Fletcher, Jonathan A; Demetri, George D; Wagner, Andrew J

2016-03-29

Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.

Use of a clinical PET/MR scanner for preclinical research with first results

International Nuclear Information System (INIS)

Chary, Karthik; Teuho, Jarmo; Virta, Jenni; Sipilä, Hannu; Saunavaara, Virva; Roivainen, Anne; Teräs, Mika

2014-01-01

This study was performed to evaluate the feasibility of preclinical imaging in a clinical PET/MR system. Preliminary sequences were evaluated for establishing preclinical protocols for rat brain and rabbit knee. Rats were placed in a stereotactic holder, allowing a 30 minute scan time before re-administration of anesthesia. In-house developed warm-water heating system was used to maintain the body temperature at 37.5°C, monitored using an MR-compatible rectal probe. Brain imaging was performed with a dedicated 4 channel phased array receive coil (RAPID Biomedical GmbH, Germany). High resolution coronal images were acquired using conventional T1-SE (0.30x0.30x1.2mm) and T2-TSE (0.23x0.23x0.7mm) with a total scan time of 30 min. PET/MR imaging was performed on two white rabbits. The rabbits were imaged in a custom wooden holder. PET/MR protocol had a total duration of 45 minutes. No external heating was used. MR protocol consisted of anatomical T1, T2 and PDW of the knees, using a SENSE Flex-S coil. MR attenuation correction (MRAC) was acquired with 3D T1-FFE using three-class segmentation. A dynamic 30 minute PET acquisition was started on injection of 33.8MBq of Ga-68. Animal coils enabled high resolution images to be acquired in reasonable acquisition time with regards to animal handling and anesthesia. T1 and T2 images provided good differentiation of anatomy in the rat brain with high contrast. T1, T2 and PDW images of the rabbit knee had high resolution and differentiation of anatomical structures. MRAC was able to distinguish the knees and the body contour. Image fusion of PET and MR was able to localize the infection, which was confirmed by a physician. Pre-clinical imaging with the Ingenuity TF was deemed feasible, although PET imaging is limited by the resolution of the scanner. The preliminary sequences were successfully implemented for future studies on the Ingenuity TF.

Use of a clinical PET/MR scanner for preclinical research with first results

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Chary, Karthik; Teuho, Jarmo; Virta, Jenni; Sipilä, Hannu; Saunavaara, Virva; Roivainen, Anne; Teräs, Mika [Turku PET Centre, Turku University Hospital, Turku (Finland)

2014-07-29

This study was performed to evaluate the feasibility of preclinical imaging in a clinical PET/MR system. Preliminary sequences were evaluated for establishing preclinical protocols for rat brain and rabbit knee. Rats were placed in a stereotactic holder, allowing a 30 minute scan time before re-administration of anesthesia. In-house developed warm-water heating system was used to maintain the body temperature at 37.5°C, monitored using an MR-compatible rectal probe. Brain imaging was performed with a dedicated 4 channel phased array receive coil (RAPID Biomedical GmbH, Germany). High resolution coronal images were acquired using conventional T1-SE (0.30x0.30x1.2mm) and T2-TSE (0.23x0.23x0.7mm) with a total scan time of 30 min. PET/MR imaging was performed on two white rabbits. The rabbits were imaged in a custom wooden holder. PET/MR protocol had a total duration of 45 minutes. No external heating was used. MR protocol consisted of anatomical T1, T2 and PDW of the knees, using a SENSE Flex-S coil. MR attenuation correction (MRAC) was acquired with 3D T1-FFE using three-class segmentation. A dynamic 30 minute PET acquisition was started on injection of 33.8MBq of Ga-68. Animal coils enabled high resolution images to be acquired in reasonable acquisition time with regards to animal handling and anesthesia. T1 and T2 images provided good differentiation of anatomy in the rat brain with high contrast. T1, T2 and PDW images of the rabbit knee had high resolution and differentiation of anatomical structures. MRAC was able to distinguish the knees and the body contour. Image fusion of PET and MR was able to localize the infection, which was confirmed by a physician. Pre-clinical imaging with the Ingenuity TF was deemed feasible, although PET imaging is limited by the resolution of the scanner. The preliminary sequences were successfully implemented for future studies on the Ingenuity TF.

Risk-informed approach for safety, safeguards, and security (3S) by design

International Nuclear Information System (INIS)

Suzuki, Mitsutoshi; Burr, Tom; Howell, John

2011-01-01

Over several decades the nuclear energy society worldwide has developed safety assessment methodology based on probabilistic risk analysis for incorporating its benefit into design and accident prevention for nuclear reactors. Although safeguards and security communities have different histories and technical aspects compared to safety, risk assessment as a supplement to their current requirements could be developed to promote synergism between Safety, Safeguards, and Security (3S) and to install effective countermeasures in the design of complex nuclear fuel cycle facilities. Since the 3S initiative was raised by G8 countries at Hokkaido Toyako-Summit in 2008, one approach to developing synergism in a 3S By Design (3SBD) process has been the application of risk-oriented assessment methodology. In the existing regulations of safeguards and security, a risk notion has already been considered for inherent threat and hazard recognition. To integrate existing metrics into a risk-oriented approach, several mathematical methods have already been surveyed, with attention to the scarcity of intentional acts in the case of safeguards and the sparseness of actual event data. A two-dimensional probability distribution composed of measurement error and incidence probabilities has been proposed to formalize inherent difficulties in the International Atomic Energy Agency (IAEA) safeguards criteria. In particular, the incidence probability that is difficult to estimate has been explained using a Markov model and game theory. In this work, a feasibility study of 3SBD is performed for an aqueous reprocessing process, and synergetic countermeasures are presented for preliminary demonstration of 3SBD. Although differences and conflicts between individual 'S' communities exist, the integrated approach would be valuable for optimization and balance between the 3S design features as well as for effective and efficient implementation under existing regulation frameworks. In addition

Preclinical stress research: where are we headed? An early career investigator's perspective.

Science.gov (United States)

Gururajan, Anand; Kos, Aron; Lopez, Juan Pablo

2018-03-07

Stress is a major risk factor in the development of various psychiatric disorders such as depression, anxiety and post-traumatic stress disorder. The use of stress paradigms in preclinical contexts is essential to advance our understanding of the pathophysiology of these disorders. However, they are not without their limitations and in this commentary, we have examined some of the practical issues associated with their use. We also highlight some of the latest techniques to identify their neuromolecular correlates as well as the potentially important and integrative role of computational neuroscience. Finally, we share our perspective on future directions in the field of preclinical stress research.

Polarization and pressure effects in caesium 6S-8S two-photon spectroscopy

International Nuclear Information System (INIS)

Lee, Yi-Chi; Tsai, Chin-Chun; Chui, Hsiang-Chen; Chang, Yi-Hsiu; Chen, Ying-Yu

2010-01-01

This work analyses the effects of polarization and pressure in caesium 6S-8S two-photon spectroscopy. The linewidth was broadened and the frequency was shifted by a change of polarization states. The frequency shift and the linewidth broadening of the caesium 6S-8S two-photon transition were measured as a function of laser power using one single-frequency Ti:sapphire ring cavity laser, two caesium cells and two quarter-wave plates to ensure polarization states of light, and we showed that the linewidth cannot be evaluated just by fitting data to a Lorentzian shape. As determined by fitting the data to a Voigt profile, the natural linewidth is independent of the polarization states of the pump beams, the laser power and the pressure. Caesium 6S-8S two-photon transitions pumped by a circularly polarized beam have narrower linewidths and smaller shifts than those pumped by a linearly polarized beam. The light shift obtained by pumping with the circularly polarized beam is -6.75(57) Hz (mW mm -2 ) -1 , and that obtained by pumping with a linearly polarized beam is -7.25(45) Hz (mW mm -2 ) -1 . These results agree closely with theoretical calculations. The pressure shift is -588(387) Hz mPa -1 . This work shows how to evaluate two-photon transitions with a Voigt profile, and then helps us to understand two-photon transitions with different polarization states, and improve the signal quality obtained when they are used as frequency markers.

Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa.

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