Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly

Science.gov (United States)

Durando, Paolo; Rosselli, Roberto; Cremonesi, Ilaria; Orsi, Andrea; Albanese, Erika; Barberis, Ilaria; Paganino, Chiara; Trucchi, Cecilia; Martini, Mariano; Marensi, Lorenzo; Turello, Valter; Study Group, the Ligurian Pneumococcal; Bregante, Alessandro; Cacciani, Roberto; Iudici, Rocco; La Marca, Diego; Pedano, Leonardo; Petrucci, Amadio Franco; Santolini, Maria; Sbisà, Valentina; Zacconi, Monica

2014-01-01

Background In September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years. Methods An observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs). Results No sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted

Fault-tolerant quantum computation for local non-Markovian noise

International Nuclear Information System (INIS)

Terhal, Barbara M.; Burkard, Guido

2005-01-01

We derive a threshold result for fault-tolerant quantum computation for local non-Markovian noise models. The role of error amplitude in our analysis is played by the product of the elementary gate time t 0 and the spectral width of the interaction Hamiltonian between system and bath. We discuss extensions of our model and the applicability of our analysis

Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson's disease.

Science.gov (United States)

Tolosa, E; Stern, M B

2012-02-01

Rasagiline, an MAO-B inhibitor, is indicated for the treatment of Parkinson's disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (≥70 years) and younger (Rasagiline: Efficacy and Safety on the Treatment of 'OFF' and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double-blind, placebo-controlled trials with the primary efficacy end-point being the reduction from baseline in daily OFF time. Secondary efficacy end-points included scores for Clinical Global Improvement (CGI)-Examiner during ON time, Unified Parkinson's Disease Rating Scale (UPDRS)-ADL during OFF time, UPDRS-Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. Rasagiline decreased daily OFF time versus placebo (Prasagiline but were not significant. Between-group comparisons (≥70 vs. efficacy was unaffected by age for all end-points (P>0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P>0.1). Adjunct rasagiline is efficacious and well tolerated in elderly non-demented patients (≥70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies

Directory of Open Access Journals (Sweden)

Schweizer A

2011-02-01

Full Text Available Anja Schweizer1, Sylvie Dejager2, James E Foley3, Wolfgang Kothny31Novartis Pharma AG, Basel, Switzerland; 2Novartis Pharma SAS, Rueil-Malmaison, France; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAAim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs, of vildagliptin based on a large pooled database of Phase II and III clinical trials.Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks' duration. AE profiles of vildagliptin (50 mg bid; N = 6116 were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210. Absolute incidence rates were calculated for all AEs, serious AEs (SAEs, discontinuations due to AEs, and deaths.Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively, whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators. The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas.Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.Keywords: type 2 diabetes, dipeptidyl peptidase-4, edema, safety, vildagliptin

Safety analysis of accident localization system

International Nuclear Information System (INIS)

1999-01-01

A complex safety analysis of accident localization system of Ignalina NPP was performed. Calculation results obtained, results of non-destruct ing testing and experimental data of reinforced concrete testing of buildings does not revealed deficiencies of buildings of accident localization system at unit 1 of Ignalina NPP. Calculations were performed using codes NEPTUNE, ALGOR, CONTAIN

Preliminary safety analysis of the PWR with accident-tolerant fuels during severe accident conditions

International Nuclear Information System (INIS)

Wu, Xiaoli; Li, Wei; Wang, Yang; Zhang, Yapei; Tian, Wenxi; Su, Guanghui; Qiu, Suizheng; Liu, Tong; Deng, Yongjun; Huang, Heng

2015-01-01

Highlights: • Analysis of severe accident scenarios for a PWR fueled with ATF system is performed. • A large-break LOCA without ECCS is analyzed for the PWR fueled with ATF system. • Extended SBO cases are discussed for the PWR fueled with ATF system. • The accident-tolerance of ATF system for application in PWR is illustrated. - Abstract: Experience gained in decades of nuclear safety research and previous nuclear accidents direct to the investigation of passive safety system design and accident-tolerant fuel (ATF) system which is now becoming a hot research point in the nuclear energy field. The ATF system is aimed at upgrading safety characteristics of the nuclear fuel and cladding in a reactor core where active cooling has been lost, and is preferable or comparable to the current UO 2 –Zr system when the reactor is in normal operation. By virtue of advanced materials with improved properties, the ATF system will obviously slow down the progression of accidents, allowing wider margin of time for the mitigation measures to work. Specifically, the simulation and analysis of a large break loss of coolant accident (LBLOCA) without ECCS and extended station blackout (SBO) severe accident are performed for a pressurized water reactor (PWR) loaded with ATF candidates, to reflect the accident-tolerance of ATF

Phase I safety, tolerability and pharmacokinetic study of recombinant human mannan-binding lectin

DEFF Research Database (Denmark)

Petersen, K.A.; Matthiesen, F.; Agger, T.

2006-01-01

(rhMBL) is in development as a novel therapeutic approach. To assess the safety, tolerability, and pharmacokinetics of rhMBL, a placebo-controlled double-blinded study was performed in MBL-deficient healthy male subjects. rhMBL was administered as both single intravenous (i.v.) infusions (0.01, 0...... mild and no serious adverse events were recorded. There were no clinically significant changes in laboratory evaluations, ECG or vital signs, and no anti-MBL antibodies were detected following rhMBL administration. After single i.v. doses of rhMBL the maximal plasma levels increased in a dose...... of the complement system without non-specific activation of the complement cascade.In conclusion, no safety or tolerability concern was raised following rhMBL administration no signs of immunogenicity detected, and an rhMBL plasma level judged sufficient to achieve therapeutic benefit (>1000 ng/mL) can be achieved....

A distributed fault tolerant architecture for nuclear reactor control and safety functions

International Nuclear Information System (INIS)

Hecht, M.; Agron, J.; Hochhauser, S.

1989-01-01

This paper reports on a fault tolerance architecture that provides tolerance to a broad scope of hardware, software, and communications faults which is being developed. This architecture relies on widely commercially available operating systems, local area networks, and software standards. Thus, development time is significantly shortened, and modularity allows for continuous and inexpensive system enhancement throughout the expected 20- year life. The fault containment and parallel processing capabilites of computers network are being exploited to provide a high performance, high availability network capable of tolerating a broad scope of hardware software, and operating system faults. The system can tolerate all but one known (and avoidable) single fault, two known and avoidable dual faults, and will detect all higher order fault sequences and provide diagnostics to allow for rapid manual recovery

REVIEW OF SAFETY AND TOLERANCE OF OMALIZUMAB

Directory of Open Access Journals (Sweden)

A.V. Emel'yanov

2008-01-01

Full Text Available The review of safety of monoclonal anti-ige-antibodies (xolair — a new medication for the treatment of severe allergic bronchial asthma is presented. Local and system adverse events, originating after injection of medicament in clinical studies and following administration in patients are discussed.Key words: children, bronchial asthma, monoclonal anti Ige antibodies.

Trust Index Based Fault Tolerant Multiple Event Localization Algorithm for WSNs

Science.gov (United States)

Xu, Xianghua; Gao, Xueyong; Wan, Jian; Xiong, Naixue

2011-01-01

This paper investigates the use of wireless sensor networks for multiple event source localization using binary information from the sensor nodes. The events could continually emit signals whose strength is attenuated inversely proportional to the distance from the source. In this context, faults occur due to various reasons and are manifested when a node reports a wrong decision. In order to reduce the impact of node faults on the accuracy of multiple event localization, we introduce a trust index model to evaluate the fidelity of information which the nodes report and use in the event detection process, and propose the Trust Index based Subtract on Negative Add on Positive (TISNAP) localization algorithm, which reduces the impact of faulty nodes on the event localization by decreasing their trust index, to improve the accuracy of event localization and performance of fault tolerance for multiple event source localization. The algorithm includes three phases: first, the sink identifies the cluster nodes to determine the number of events occurred in the entire region by analyzing the binary data reported by all nodes; then, it constructs the likelihood matrix related to the cluster nodes and estimates the location of all events according to the alarmed status and trust index of the nodes around the cluster nodes. Finally, the sink updates the trust index of all nodes according to the fidelity of their information in the previous reporting cycle. The algorithm improves the accuracy of localization and performance of fault tolerance in multiple event source localization. The experiment results show that when the probability of node fault is close to 50%, the algorithm can still accurately determine the number of the events and have better accuracy of localization compared with other algorithms. PMID:22163972

Trust Index Based Fault Tolerant Multiple Event Localization Algorithm for WSNs

Directory of Open Access Journals (Sweden)

Jian Wan

2011-06-01

Full Text Available This paper investigates the use of wireless sensor networks for multiple event source localization using binary information from the sensor nodes. The events could continually emit signals whose strength is attenuated inversely proportional to the distance from the source. In this context, faults occur due to various reasons and are manifested when a node reports a wrong decision. In order to reduce the impact of node faults on the accuracy of multiple event localization, we introduce a trust index model to evaluate the fidelity of information which the nodes report and use in the event detection process, and propose the Trust Index based Subtract on Negative Add on Positive (TISNAP localization algorithm, which reduces the impact of faulty nodes on the event localization by decreasing their trust index, to improve the accuracy of event localization and performance of fault tolerance for multiple event source localization. The algorithm includes three phases: first, the sink identifies the cluster nodes to determine the number of events occurred in the entire region by analyzing the binary data reported by all nodes; then, it constructs the likelihood matrix related to the cluster nodes and estimates the location of all events according to the alarmed status and trust index of the nodes around the cluster nodes. Finally, the sink updates the trust index of all nodes according to the fidelity of their information in the previous reporting cycle. The algorithm improves the accuracy of localization and performance of fault tolerance in multiple event source localization. The experiment results show that when the probability of node fault is close to 50%, the algorithm can still accurately determine the number of the events and have better accuracy of localization compared with other algorithms.

Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

Science.gov (United States)

Maiteki-Sebuguzi, Catherine; Jagannathan, Prasanna; Yau, Vincent M; Clark, Tamara D; Njama-Meya, Denise; Nzarubara, Bridget; Talisuna, Ambrose O; Kamya, Moses R; Rosenthal, Philip J; Dorsey, Grant; Staedke, Sarah G

2008-01-01

Background Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. Methods A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. Results Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1

Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

Directory of Open Access Journals (Sweden)

Kamya Moses R

2008-06-01

Full Text Available Abstract Background Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. Methods A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP, artesunate + amodiaquine (AS+AQ, or artemether-lumefantrine (AL. Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. Results Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years. At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7, or AS

Understanding local residents of Korea using nuclear effective safety

International Nuclear Information System (INIS)

Chung, Yun Hyung; Lee, Gey Hwi; Hah, Yeonhee; Kim, Beom Jun

2010-01-01

The risk perception gap between experts and lay people is based on the use of different concept on risk. It is getting increasingly important for nuclear practitioners to understand the lay people's subjective perception on nuclear safety. We proposed the nuclear effective safety index (NESI) which is based on data of the public survey of local inhabitants. We extracted the four factors for effective safety indicators; communication, trust, plant emergency response capability, and personal emergency coping skills. The latest NESI was 41.54, which was increased from 38.22 but still low. The three-year data of NESI showed the differences between genders and between sites as well as trend. The survey of antecedents of effective safety showed some meaningful events and profound differences between plant employees and local inhabitants. The NESI can be utilized as useful communication tool between the local inhabitants and nuclear practitioners. (authors)

Local tolerance testing of parenteral drugs: how to put into practice.

Science.gov (United States)

Jochims, Karin; Kemkowski, Joerg; Nolte, Thomas; Bartels, Thomas; Heusener, Alexander

2003-10-01

Notwithstanding that there are national and international guidelines about local tolerance testing of parenteral drugs in animals, in particular to mention CPMP/SWP/2145/00 (Note for Guidance on Non-Clinical Local Tolerance Testing of Medicinal Products), very heterogeneous study designs have been established in the past. A working group including experts of the leading pharmaceutical industry from German-language countries, named "Arbeitskreis Lokale Verträglichkeit," has been intensively discussing the experimental procedures in detail for a period of six years and has been considering their pros and cons. This team of experts now feels confident to give some recommendations for study conduct besides describing different materials and methods for this type of toxicological study. Special knowledge from toxicologists as well as pathologists from our working group has been taken into account. This paper deals with choice of species, number of animals used, controls, administration sites, volumes, rate and frequency, length of observation period, termination, clinical, macroscopic and histopathological examinations and, finally, overall assessment criteria and conclusion. Our purpose is that this paper may be of value for: *The study director who is inexperienced in the conduction of local tolerance testing and who may need a standard design as his first step into this new field. *The well-versed study director who would like to know how others have done in the past, who may examine self-critically his own practice and who is open to our team's recommendations, tips and tricks from practice. *The specialist at a regulatory authority who, finally, reviews study reports, assesses their format and content and, above all, decides on the approval of a drug product.

Local Safety Toolkit: Enabling safe communities of opportunity

CSIR Research Space (South Africa)

Holtmann, B

2010-08-31

Full Text Available remain inadequate to achieve safety. The Local Safety Toolkit supports a strategy for a Safe South Africa through the implementation of a model for a Safe Community of Opportunity. The model is the outcome of work undertaken over the course of the past...

The safety and tolerance of phytotherapies in menopausal medicine – a review of the literature

Directory of Open Access Journals (Sweden)

Piotr Czuczwar

2017-04-01

Full Text Available Phytoestrogens are polyphenol, non-steroidal substances of plant origin, resembling 17-estradiol in structure. These substances can act as either agonists or antagonists of oestrogen receptors  and . Phytoestrogens are widely used to alleviate menopausal symptoms, such as hot flushes and night sweats. Most of the currently available products of plant origin registered to soften climacteric symptoms consist of extracts obtained from soy, red clover, or black cohosh. Non-hormonal phytotherapy is a new alternative for patients suffering from menopausal symptoms. Active ingredients such as PI 82-GC FEM extract do not show any direct hormonal mechanisms of action typical for oestrogens and phytoestrogens. There are concerns about the safety and tolerability of phytoestrogens. In this review we summarise the current literature regarding the clinical aspect of safety and tolerance of different phytotherapies used to relieve menopausal symptoms.

Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study.

Science.gov (United States)

Nolan, Terry; Chotpitayasunondh, Tawee; Capeding, Maria Rosario; Carson, Simon; Senders, Shelly David; Jaehnig, Peter; de Rooij, Richard; Chandra, Richa

2016-01-04

Cell culture-derived inactivated influenza vaccines (TIVc) are necessary for scale and predictability of production to meet global demand. This study compared the safety and tolerability of TIVc with an egg-derived trivalent influenza vaccine (TIVf) in 4-17 yearolds. A Phase 3 observer blind, multicenter study enrolled 2055 healthy participants randomized 2:1 to receive either TIVc or TIVf, respectively (1372 TIVc and 683 TIVf evaluable subjects). Participants received one dose each on Days 1 and 28 (4-8 year-olds not previously vaccinated [NPV]) or one dose on Day 1 (4-8 and 9-17 yearolds previously vaccinated [PV]). Solicited adverse events (AEs) occurring within 7 days after each vaccination were assessed; participants were followed up for 6 months after their last dose for safety. Most solicited and unsolicited AEs were mild to moderate with vaccine-related SAEs were reported. TIVc and TIVf were similar in percentages of participants reporting solicited reactions in 4-8 years NPV group after the 1st dose: local reactions, TIVc: 48%, TIVf: 43%; systemic reactions, TIVc: 34%, TIVf: 32%; percentages were lower following the 2nd dose in TIVc; local reactions: TIVc: 40%; TIVf: 43%; systemic reactions: TIVc: 21%; TIVf: 22%. In 4-17 years PV group, solicited reactions were lower following TIVf, local reactions: TIVc: 53%; TIVf: 43%; systemic reactions: TIVc: 37%, TIVf: 30%. Injection-site pain was the most common solicited reaction, and was similar following TIVc and TIVf in 4-8 yearolds (TIVc: 56%; TIVf: 55%), and lower following TIVf in 9-17 years group (TIVc: 52%; TIVf: 42%). Reporting of unsolicited AEs was similar for TIVc and TIVf across the two age groups. TIVc was well tolerated and had a safety and reactogenicity profile similar to that of TIVf in healthy 4-17 yearolds (NCT01857206). Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

State and local safety program

Energy Technology Data Exchange (ETDEWEB)

Carlyle Thompson, G D [Utah State Division of Health, Salt Lake City, UT (United States)

1969-07-01

This paper will give emphasis to the need for an increasing role of the states, along with the Federal agencies, in the Plowshare Program in order to assure state and local confidence with respect to the safety of their residents as the Federal government seeks new methods to benefit society. First will be stressed the age-old principle of control at the source. Other factors to be discussed are monitoring; standards and their use; control action; public relations; predictions and the need to have certain advance knowledge of tests - even if security clearance is necessary for appropriate state representatives; the state and local government responsibility to their citizens; the isolation of national decision making from state and local concern and responsibility; cost assessments and their responsibility; and research as it relates to the ecological system as well a the direct short- or long-term effects of radioactivity on man. (author)

State and local safety program

International Nuclear Information System (INIS)

Carlyle Thompson, G.D.

1969-01-01

This paper will give emphasis to the need for an increasing role of the states, along with the Federal agencies, in the Plowshare Program in order to assure state and local confidence with respect to the safety of their residents as the Federal government seeks new methods to benefit society. First will be stressed the age-old principle of control at the source. Other factors to be discussed are monitoring; standards and their use; control action; public relations; predictions and the need to have certain advance knowledge of tests - even if security clearance is necessary for appropriate state representatives; the state and local government responsibility to their citizens; the isolation of national decision making from state and local concern and responsibility; cost assessments and their responsibility; and research as it relates to the ecological system as well a the direct short- or long-term effects of radioactivity on man. (author)

Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

Science.gov (United States)

Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

2010-01-01

Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

Reactor Safety Gap Evaluation of Accident Tolerant Components and Severe Accident Analysis

International Nuclear Information System (INIS)

Farmer, Mitchell T.; Bunt, R.; Corradini, M.; Ellison, Paul B.; Francis, M.; Gabor, John D.; Gauntt, R.; Henry, C.; Linthicum, R.; Luangdilok, W.; Lutz, R.; Paik, C.; Plys, M.; Rabiti, Cristian; Rempe, J.; Robb, K.; Wachowiak, R.

2015-01-01

The overall objective of this study was to conduct a technology gap evaluation on accident tolerant components and severe accident analysis methodologies with the goal of identifying any data and/or knowledge gaps that may exist, given the current state of light water reactor (LWR) severe accident research, and additionally augmented by insights obtained from the Fukushima accident. The ultimate benefit of this activity is that the results can be used to refine the Department of Energy's (DOE) Reactor Safety Technology (RST) research and development (R&D) program plan to address key knowledge gaps in severe accident phenomena and analyses that affect reactor safety and that are not currently being addressed by the industry or the Nuclear Regulatory Commission (NRC).

Reactor Safety Gap Evaluation of Accident Tolerant Components and Severe Accident Analysis

Energy Technology Data Exchange (ETDEWEB)

Farmer, Mitchell T. [Argonne National Lab. (ANL), Argonne, IL (United States); Bunt, R. [Southern Nuclear, Atlanta, GA (United States); Corradini, M. [Univ. of Wisconsin, Madison, WI (United States); Ellison, Paul B. [GE Power and Water, Duluth, GA (United States); Francis, M. [Argonne National Lab. (ANL), Argonne, IL (United States); Gabor, John D. [Erin Engineering, Walnut Creek, CA (United States); Gauntt, R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Henry, C. [Fauske and Associates, Burr Ridge, IL (United States); Linthicum, R. [Exelon Corp., Chicago, IL (United States); Luangdilok, W. [Fauske and Associates, Burr Ridge, IL (United States); Lutz, R. [PWR Owners Group (PWROG); Paik, C. [Fauske and Associates, Burr Ridge, IL (United States); Plys, M. [Fauske and Associates, Burr Ridge, IL (United States); Rabiti, Cristian [Idaho National Lab. (INL), Idaho Falls, ID (United States); Rempe, J. [Rempe and Associates LLC, Idaho Falls, ID (United States); Robb, K. [Argonne National Lab. (ANL), Argonne, IL (United States); Wachowiak, R. [Electric Power Research Inst. (EPRI), Knovville, TN (United States)

2015-01-31

The overall objective of this study was to conduct a technology gap evaluation on accident tolerant components and severe accident analysis methodologies with the goal of identifying any data and/or knowledge gaps that may exist, given the current state of light water reactor (LWR) severe accident research, and additionally augmented by insights obtained from the Fukushima accident. The ultimate benefit of this activity is that the results can be used to refine the Department of Energy’s (DOE) Reactor Safety Technology (RST) research and development (R&D) program plan to address key knowledge gaps in severe accident phenomena and analyses that affect reactor safety and that are not currently being addressed by the industry or the Nuclear Regulatory Commission (NRC).

Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

Science.gov (United States)

Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

2009-01-01

Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

Reliability analysis of repairable safety systems of a reprocessing plant allowing for tolerable system downtimes

International Nuclear Information System (INIS)

Schaefer, H.

1987-01-01

GRS has been engaged in safety analysises of the German Reprocessing Plant for several years. The development and verification of appropriate reliability analysis methods, the generation of data as well as the search for an adequate structural presentation of the results to form a basis of recommendations for technical or administrative measures or contributions to risk oriented evaluations have been or are in the process of being established. In contrast to NPP-studies, the reliability assessment of safety systems of a reprocessing plant is applied to repairable and often relatively small systems allowing for tolerable system downtimes. A sketch of the diverse cooling systems of a vessel containing a selfheating solution is given. The interruption of the cooling function for about one day might be tolerable before boiling will be reached. This interval is suitable for transfer of the solution to a spare vessel or for repairing the failed components, thus restoring the cooling function

Efficacy, safety and tolerability of simvastatin in children with familial hypercholesterolaemia - Rationale, design and baseline characteristics

NARCIS (Netherlands)

de Jongh, S.; Stalenhoef, A. F. H.; Tuohy, M. B.; Mercuri, M.; Bakker, H. D.; Kastelein, J. J. P.

2002-01-01

Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH). Methods: Patients were recruited from nine lipid clinics

Observational study on safety and tolerability of duloxetine in the treatment of female stress urinary incontinence in German routine practice

NARCIS (Netherlands)

Michel, Martin C.; Minarzyk, Anette; Schwerdtner, Inka; Quail, Deborah; Methfessel, Hans D.; Weber, Hans-Joachim

2013-01-01

To evaluate the safety and tolerability of duloxetine during routine clinical care in women with stress urinary incontinence (SUI) in Germany, and in particular, to identify previously unrecognized safety issues as uncommon adverse reactions, and the influence of confounding factors present in

Safety evaluation of accident-tolerant FCM fueled core with SiC-coated zircalloy cladding for design-basis-accidents and beyond DBAs

Energy Technology Data Exchange (ETDEWEB)

Chun, Ji-Han, E-mail: chunjh@kaeri.re.kr; Lim, Sung-Won; Chung, Bub-Dong; Lee, Won-Jae

2015-08-15

Highlights: • Thermal conductivity model of the FCM fuel was developed and adopted in the MARS. • Scoping analysis for candidate FCM FAs was performed to select feasible FA. • Preliminary safety criteria for FCM fuel and SiC/Zr cladding were set up. • Enhanced safety margin and accident tolerance for FCM-SiC/Zr core were demonstrated. - Abstract: The FCM fueled cores proposed as an accident tolerant concept is assessed against the design-basis-accident (DBA) and the beyond-DBA (BDBA) scenarios using MARS code. A thermal conductivity model of FCM fuel is incorporated in the MARS code to take into account the effects of irradiation and temperature that was recently measured by ORNL. Preliminary analyses regarding the initial stored energy and accident tolerant performance were carried out for the scoping of various cladding material candidates. A 16 × 16 FA with SiC-coated Zircalloy cladding was selected as the feasible conceptual design through a preliminary scoping analysis. For a selected design, safety analyses for DBA and BDBA scenarios were performed to demonstrate the accident tolerance of the FCM fueled core. A loss of flow accident (LOFA) scenario was selected for a departure-from-nucleate-boiling (DNB) evaluation, and large-break loss of coolant accident (LBLOCA) scenario for peak cladding temperature (PCT) margin evaluation. A control element assembly (CEA) ejection accident scenario was selected for peak fuel enthalpy and temperature. Moreover, a station blackout (SBO) and LBLOCA without a safety injection (SI) scenario were selected as a BDBA. It was demonstrated that the DBA safety margin of the FCM core is satisfied and the time for operator actions for BDBA s is evaluated.

A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis.

Science.gov (United States)

Shefner, Jeremy M; Watson, Mary Lou; Meng, Lisa; Wolff, Andrew A

2013-12-01

Abstract Tirasemtiv is a fast skeletal muscle activator that increases the sensitivity of the sarcomere to calcium, increasing the efficiency of muscle contraction when the muscle is stimulated at submaximal contraction frequencies. A previous study showed single doses of tirasemtiv to be well tolerated and associated with potentially important improvements in a variety of functional outcomes. This study determined safety of tirasemtiv when given at doses up to 500 mg daily for three weeks. Tirasemtiv was given as a single daily dose up to 375 mg for two weeks, with and without concomitant riluzole. In a separate cohort, an ascending dose protocol evaluated a total dose of 500 mg daily given in two divided doses. Safety and tolerability were assessed, as well as measures of function, muscle strength and endurance. Results showed that tirasemtiv was well tolerated, with dizziness the most common adverse event. Tirasemtiv approximately doubled the serum concentration of riluzole. Trends were noted for improvement in ALSFRS-R, Maximum Minute Ventilation, and Nasal Inspiratory Pressure. In conclusion, tirasemtiv is well tolerated and can be given safely with a reduced dose of riluzole. Positive trends in multiple exploratory outcome measures support the further study of this agent in ALS.

75 FR 50700 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, and Drawbridge...

Science.gov (United States)

2010-08-17

...] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, and Drawbridge Operation... notice lists temporary safety zones, security zones, special local regulations, and drawbridge operation... responsive to the safety and security needs within their jurisdiction; therefore, District Commanders and...

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

Science.gov (United States)

Mano, Hiroyuki; Tanaka, Yoshinari

2017-12-01

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

Physicochemical, nutritive and safety evaluation of local cereal ...

African Journals Online (AJOL)

SARAH

2014-11-30

Nov 30, 2014 ... practices and good manufacturing processing should be considered. Such initiatives need to be carried amongst local cereal producers to help minimize food safety risk and ... potential for contamination and deterioration with.

76 FR 70342 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation...

Science.gov (United States)

2011-11-14

...] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation... published in the Federal Register. This notice lists temporary safety zones, security zones, special local... Commanders and Captains of the Port (COTP) must be immediately responsive to the safety and security needs...

EDRP public local inquiry, UKAEA/BNFL precognition on: Aspects of Dounreay safety and local liaison relevant to EDRP

International Nuclear Information System (INIS)

Blumfield, C.W.

1986-01-01

Aspects of safety at Dounreay Nuclear Establishment, including legislation, design safety, industrial safety and radiation monitoring procedures, are discussed. The arrangements for action in an emergency are outlined. Liaison between DNE and the local community, formal and informal, is summarised. (U.K.)

Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

Science.gov (United States)

Noh, G; Jang, E H

2014-01-01

Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

Water-safety strategies and local-scale spatial quality

NARCIS (Netherlands)

Nillesen, A.L.

2013-01-01

Delta regions throughout the world are subject to increasing flood risks. For protection, regional water safety strategies are being developed. Local-scale spatial qualities should be included in their evaluation. An experimental methodology has been developed for this purpose. This paper

Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant : Safety and Tolerability

NARCIS (Netherlands)

Bigaeva, Emilia; Doorn, Eva van; Liu, Heng; Hak, Eelko

2016-01-01

BACKGROUND AND OBJECTIVES: QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and

Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation

Science.gov (United States)

Sobieski, Courtney; Shu, Hong-Jin

2018-01-01

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID:29617444

Safety assessment of pipes with multiple local wall thinning defects under pressure and bending moment

International Nuclear Information System (INIS)

Peng Jian; Zhou Changyu; Xue Jilin; Dai Qiao; He Xiaohua

2011-01-01

The safety assessment of pipes with local wall thinning defects is highly important in engineering. Most attention has been paid on the safety assessment of pipe with single local wall thinning defect, while the studies about multiple local wall thinning defects are not nearly enough. However, the interaction of multiple local wall thinning defects in some conditions is great, and may have a great impact on the safety assessment. In the present standard API 579/ASME FFS, the safety assessment of pipes with multiple local wall thinning defects is given, while as well as the influence of load condition, the influences of arrangement and relative depth of defects are ignored, which may influence the safety assessment considerably. In this paper, the influence of the interaction between multiple local wall thinning defects on the remaining strength of pipes at different arrangements and depths of defects under different load conditions (pressure, tension-bending moment and compression-bending moment) are studied. A quantified index is defined to describe the interaction between defects quantitatively. For different arrangements and relative depths of defects, based on a limit value 0.05 of the quantified index of the interaction between defects, a relatively systematic safety assessment of pipes with multiple local wall thinning defects under different load conditions has been proposed.

Possible new roles for tolerable risk mediators

International Nuclear Information System (INIS)

O'Riordan, T.

1989-01-01

In his report on the Sizewell B Inquiry, the Inspector, Sir Frank Layfield, Q.C. introduced the term ''tolerable risk''. He regarded this as a better concept than the much abused and mis-interpreted phrase ''acceptable risk''. The application of tolerable risk implies that, even after regulation and incorporation of appropriate design safety criteria, there will always be a residual risk over which elements of the public will remain uneasy. They may tolerate, but they do not accept. They only tolerate because they have come to trust the process by which safety is assessed and delivered. This interpretation also implies that no safety target, the central theme of this meeting, should ever be regarded as stable or final. Such targets should continually be argued about and subject to regular searching review. Above all, such targets need to be re-justified to a doubting public so that they can be assured that the safety delivery process, namely the principles and management methods to ensure safety levels are actually met, is accountable and open for them to inspect. Thus the ''tolerable zone'' of nuclear plant safety is the product of procedures not simply assessments. These procedures need to be robust and adaptable. They need to be able to incorporate diversity of viewpoints and have a capacity to enable all who are involved to learn from each other's viewpoints and experience. In short the safety determination process needs to be more participatory and creative. (author)

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

Science.gov (United States)

Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

2017-01-01

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed

Personnel radiation safety. A case of hand lesion in a radiologist

International Nuclear Information System (INIS)

Pilipenko, M.Yi.; Kulyinyich, G.V.; Stadnik, L.L.

2012-01-01

The work featured the questions of norma and rules of radiation safety at work with ionizing radiation. The history of the question about the permissible doses is dabbler's. The changes in the skin when exceeding the tolerant dose are described. A case of severe local lesions of the hand caused by chronic occupational over irradiation, when the safety rules were neglected, is described

Preparing suitable climate scenario data to assess impacts on local food safety

NARCIS (Netherlands)

Liu, C.; Hofstra, N.; Leemans, R.

2015-01-01

Quantification of climate change impacts on food safety requires food safety assessment with different past and future climate scenario data to compare current and future conditions. This study presents a tool to prepare climate and climate change data for local food safety scenario analysis and

Local Road Safety Peer Exchange - Region 9 : An RSPCB Peer Exchange

Science.gov (United States)

2013-09-01

This report provides a summary of the proceedings of the Region 9 Local Road Safety Peer : Exchange held in Sacramento, California on September 17 and 18, 2013. The Federal Highway : Administration (FHWA) Office of Safety (HSA) sponsored the peer exc...

Safety and tolerability of once-daily tiotropium Respimat(®) as add-on to at least inhaled corticosteroids in adult patients with symptomatic asthma

DEFF Research Database (Denmark)

Dahl, Ronald; Engel, Michael; Dusser, Daniel

2016-01-01

BACKGROUND: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma. OBJECTIVE: To evaluate safety and tolerability of tiotro...

Toward a federal/state/local partnership in hazardous materials transportation safety

International Nuclear Information System (INIS)

1982-09-01

In recognition of the federal government's responsibility for initiating a national strategy for hazardous materials transportation safety, the Materials Transportation Bureau (MTB) prepared an internal strategy paper for creating a federal/state/local partnership in hazardous materials transportation safety in August 1981. The paper outlined the scope of the hazardous materials transportation problem and established MTB's approach for creating an intergovernmental partnership for its resolution. This paper represents an update and refinement of the original plan, and is designed to chart the direction of the emerging federal/state/local relationship. The cornerstone of the plan remains the establishment of a single national set of safety regulations. It is on achievement of this objective that MTB's plan for development of enforcement, training, and emergency response capabilities at all levels of government is based. Chapter I introduces the problem with a desription of the economic importance of hazardous materials and discusses its implications for public safety. Chapter II defines the appropriate role for each level of government in the areas of rulemaking, enforcement, emergency response, and education. Chapter III demonstrates the need for uniform national safety standards and describes the economic and safety benefits of this approach. Chapter IV contains a detailed description of MTB's program for developing a successful intergovernmental partnership in hazardous materials transportation safety

Tolerance and safety of superficial chemical peeling with salicylic acid in various facial dermatoses

Directory of Open Access Journals (Sweden)

Iqbal Zafar

2005-03-01

Full Text Available BACKGROUND: Chemical peeling is a skin-wounding procedure that may have some potentially undesirable side-effects. AIMS: The present study is directed towards safety concerns associated with superficial chemical peeling with salicylic acid in various facial dermatoses. METHODS: The study was a non-comparative and a prospective one. Two hundred and sixty-eight patients of either sex, aged between 10 to 60 years, undergoing superficial chemical peeling for various facial dermatoses (melasma, acne vulgaris, freckles, post-inflammatory scars/pigmentation, actinic keratoses, plane facial warts, etc. were included in the study. Eight weekly peeling sessions were carried out in each patient. Tolerance to the procedure and any undesirable effects noted during these sessions were recorded. RESULTS: Almost all the patients tolerated the procedure well. Mild discomfort, burning, irritation and erythema were quite common but the incidence of major side-effects was very low and these too, were easily manageable. There was no significant difference in the incidence of side-effects between facial dermatoses (melasma, acne and other pigmentary disorders. CONCLUSION: Chemical peeling with salicylic acid is a well tolerated and safe treatment modality in many superficial facial dermatoses.

A chloroplast-localized and auxin-induced glutathione S-transferase from phreatophyte Prosopis juliflora confer drought tolerance on tobacco.

Science.gov (United States)

George, Suja; Venkataraman, Gayatri; Parida, Ajay

2010-03-01

Plant growth and productivity are adversely affected by various abiotic stress factors. In our previous study, we used Prosopis juliflora, a drought-tolerant tree species of Fabaceae, as a model plant system for mining genes functioning in abiotic stress tolerance. Large-scale random EST sequencing from a cDNA library obtained from drought-stressed leaves of 2-month-old P. juliflora plants resulted in identification of three different auxin-inducible glutathione S-transferases. In this paper, we report the cellular localization and the ability to confer drought tolerance in transgenic tobacco of one of these GSTs (PjGSTU1). PjGSTU1 was overexpressed in Escherichia coli and GST and GPX activities in total protein samples were assayed and compared with controls. The results indicated that PjGSTU1 protein forms a functional homo-dimer in recombinant bacteria with glutathione transferase as well as glutathione peroxidase activities. PjGSTU1 transgenic tobacco lines survived better under conditions of 15% PEG stress compared with control un-transformed plants. In vivo localization studies for PjGSTU1 using GFP fusion revealed protein localization in chloroplasts of transgenic plants. The peroxidase activity of PjGSTU1 and its localization in the chloroplast indicates a possible role for PjGSTU1 in ROS removal. Copyright 2009 Elsevier GmbH. All rights reserved.

Evaluation of fire safety measures at local universities in Kenya with ...

African Journals Online (AJOL)

This study establishes fire safety measures in place in local universities in Kenya, and ... fire suppression systems, fire detection and alarm systems and fire Hydrants. ... response backed by university management endorsement and support. The Directorate of occupational safety and health services should also make the ...

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

Science.gov (United States)

Goday, A; Bellido, D; Sajoux, I; Crujeiras, A B; Burguera, B; García-Luna, P P; Oleaga, A; Moreno, B; Casanueva, F F

2016-09-19

Brackground:The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. Evaluating the short-term safety and tolerability of a VLCK diet (diet), and 44 to the standard low-calorie diet. No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both Pdiet group (Pdiet group declined at last follow-up. The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients.

Analysis of relationship between the local governments and the power companies through the changes of safety agreements

International Nuclear Information System (INIS)

Sugawara, Shin-etsu; Inamura, Tomoaki; Kimura, Hiroshi; Madarame, Haruki

2009-01-01

In Japan, safety of nuclear facilities is regulated by the central government and local governments are responsible for protecting the local public. To operate nuclear facilities in local communities, local governments would conclude safety agreements with power companies. In recent years, local governments have used the safety agreements as excuse for delaying the operations of nuclear facilities. The legal basis of the safety agreements was questioned by some who considered that this was the cause of the stranded relationship between local governments and power companies, and in some cases, the interrupted nature of electricity supply. To understand the sources of this difficult relationship, safety agreements must be analyzed, although these documents may have undergone revisions, and various regulations may have changed. By analyzing the safety agreements and revisions, we found that the relationship between local governments and power companies gradually changed over time, which can be divided into the following 3 stages: (1) in the early 70s, the dawn stage when local governments groped with the situation of nuclear facilities built in their communities; (2) from late 70s to 90s, the stage when local governments demanded information, and (3) from late 90s to present, the stage when local governments demand information and trustworthiness. This paper shows the results of analyzing the relationship changes between local governments and power companies. We conclude that viewpoints of local governments on nuclear power evolve, as social responsibilities of power companies stipulated in safety agreements also evolve over time. (author)

Local Road Safety Peer Exchange - Region 4 : An RSPCB Peer Exchange

Science.gov (United States)

2013-03-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Atlanta, Georgia on March 6th and 7th, 2013. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 4 Local Te...

Local Road Safety Peer Exchange - Region 7 : An RSPCB Peer Exchange

Science.gov (United States)

2012-05-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Denver, Colorado from May 31 to June 1, 2012. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 7 Local a...

The Fault Detection, Localization, and Tolerant Operation of Modular Multilevel Converters with an Insulated Gate Bipolar Transistor (IGBT Open Circuit Fault

Directory of Open Access Journals (Sweden)

Wei Li

2018-04-01

Full Text Available Reliability is one of the critical issues for a modular multilevel converter (MMC since it consists of a large number of series-connected power electronics submodules (SMs. In this paper, a complete control strategy including fault detection, localization, and tolerant operation is proposed for the MMC under an insulated gate bipolar transistor (IGBT open circuit fault. According to the output characteristics of the SM with the open-circuit fault of IGBT, a fault detection method based on the circulating current and output current observation is used. In order to further precisely locate the position of the faulty SM, a fault localization method based on the SM capacitor voltage observation is developed. After the faulty SM is isolated, the continuous operation of the converter is ensured by adopting the fault-tolerant strategy based on the use of redundant modules. To verify the proposed fault detection, fault localization, and fault-tolerant operation strategies, a 900 kVA MMC system under the conditions of an IGBT open circuit is developed in the Matlab/Simulink platform. The capabilities of rapid detection, precise positioning, and fault-tolerant operation of the investigated detection and control algorithms are also demonstrated.

A comparative analysis between France and Japan on local governments' involvement in nuclear safety governance

International Nuclear Information System (INIS)

Sugawara, Shin-etsu; Shiroyama, Hideaki

2011-01-01

This paper shows a comparative analysis between France and Japan on the way of the local governments' involvement in nuclear safety governance through some interviews. In France, a law came into force that requires related local governments to establish 'Commision Locale d'Information' (CLI), which means the local governments officially involve in nuclear regulatory activity. Meanwhile, in Japan, related local governments substantially involve in the operation of nuclear facilities through the 'safety agreements' in spite of the lack of legal authority. As a result of comparative analysis, we can point out some institutional input from French cases as follows: to clarify the local governments' roles in the nuclear regulation system, to establish the official channels of communication among nuclear utilities, national regulatory authorities and local governments, and to stipulate explicitly the transparency as a purpose of safety regulation. (author)

Variation in soil aluminium tolerance genes is associated with local adaptation to soils at the Park Grass Experiment.

Science.gov (United States)

Gould, Billie; McCouch, Susan; Geber, Monica

2014-12-01

Studies of the wild grass Anthoxanthum odoratum at the long-term Park Grass Experiment (PGE, Harpenden, UK) document a well-known example of rapid plant evolution in response to environmental change. Repeated fertilizer applications have acidified the soil in some experimental plots over the past 150+ years, and Anthoxanthum subpopulations have quickly become locally adapted. Early reciprocal transplants showed subpopulation differentiation specifically in response to soil aluminium (Al) toxicity across the experiment, even at small (30 m) spatial scales. Almost 40 years after its original measurement, we reassessed the degree of local adaptation to soil Al at the PGE using updated phenotyping methods and identified genes with variation linked to the tolerance trait. Root growth assays show that plants are locally adapted to soil Al at both the seedling and adult growth stages, but to a smaller extent than previously inferred. Among a large suite of candidate loci that were previously shown to have Al-sensitive expression differences between sensitive and tolerant plants, three loci contained SNPs that are associated with both Al tolerance and soil acidity: an Al-sensitive malate transporter (ALMT), a tonoplast intrinsic protein (TIP) and the putative homolog of the rice cell-wall modification gene STAR1. Natural genetic variation at these loci is likely to have contributed to the recent rapid evolution at PGE. Continued study of Al tolerance variants in Anthoxanthum will allow us to test hypotheses about the nature and source of genetic variation that enables some species to adapt to soil acidification and other types of rapid environmental change. © 2014 John Wiley & Sons Ltd.

An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

Science.gov (United States)

Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

2015-01-01

The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

Screening of diverse local germplasm of guar (cyamposis tetragonoloba (l.) taub.) for salt tolerance: A possible approach to utilize salt - affected soils

International Nuclear Information System (INIS)

Rasheed, M. J. Z.; Ahmad, K.; Qurainy, F. A.; Khan, S.; Athar, H. U. R.

2015-01-01

Lack of good quality water and soil salinity reduces crop productivity world-over. The development of salt stress tolerant cultivars/lines by screening and selection is of considerable value to enhance crop growth and yield. Though a number of breeding programs are underway to develop salt tolerant cultivars in wheat, barley, maize, and even grasses, a low amount of work done for improving salt tolerance in a potential leguminous forage crop guar widely grown in subcontinent due to rapid increase in its demand for its commercial use. Thus, the present study was focused on efforts to develop salt tolerant cultivars of guar. The growth responses of 31 accessions/lines/cultivars of a potential leguminous crop (Cyamopsis tetragonoloba) to salt stress were assessed at the vegetative growth stage. A considerable variation in salinity tolerance was found in a set of lines/cultivars of guar using agronomic traits. Under saline conditions, Khanewal Local2, Chiniot White, 27340, 24323, BWP-5589 produced the lowest shoot fresh and dry biomass in relative terms, while genotypes/lines 5597, 24288, Br 99, Khushab white, Sillanwali white and Mardan white had greater fresh and dry biomass. Klorkot white and 24323 had maximum plant height under non-saline conditions, whereas genotypes/line 5597 and 24288 was maximal in plant height under salt stress conditions. Moreover, genotypes/lines Khanewal Local2 followed by Chiniot White and 27340 were the lowest in plant height. Growth attributes and relative salt tolerance of guar genotypes were used to group genotypes/lines as salt tolerant, moderately tolerant and salt sensitive using Hierarchical Cluster method following squared Euclidean distance. It was found that genotypes/lines 41671, Khaushab White, 5597, 24320, 24288, Sillanwali White, 24321, Mardan White were the most salt tolerant, while Chiniot White, BWP-5589, Kalorkot White, Khanewal Local 2, 24323 were the most salt sensitive. The availability of considerable amount of

Fault-tolerant computing systems

International Nuclear Information System (INIS)

Dal Cin, M.; Hohl, W.

1991-01-01

Tests, Diagnosis and Fault Treatment were chosen as the guiding themes of the conference. However, the scope of the conference included reliability, availability, safety and security issues in software and hardware systems as well. The sessions were organized for the conference which was completed by an industrial presentation: Keynote Address, Reconfiguration and Recover, System Level Diagnosis, Voting and Agreement, Testing, Fault-Tolerant Circuits, Array Testing, Modelling, Applied Fault Tolerance, Fault-Tolerant Arrays and Systems, Interconnection Networks, Fault-Tolerant Software. One paper has been indexed separately in the database. (orig./HP)

Piper betle LEAVES EXTRACT PATCH: EVALUATION OF ANTIBACTERIAL ACTIVITY, RELEASE PROFILE OF EUGENOL, AND LOCAL TOLERANCE

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Mufrod Mufrod

2016-08-01

Full Text Available Piper betle leaf in extract form is more effective than crude drug. Eugenol is a component in the extract that has antibacterial activity but irritate. Patch of piper betle leaf extract was used on the mucosa to make oral cavity hygiene. Antibacterial activity was influenced by the release of eugenol from the patch. Release enhancer substances (RES such as glycerin, propylen glicol and tween 80 were added in patch formulation to increase the release of active substances. The aim of the research was to investigate the physicochemical properties, eugenol release profiles, and local tolerance test of the patch. Extract of piper betle leaf was made using infundation method. Patch was made according to the variation concentration of extract (1, 2 and 4% and RES (glycerine, propylen glycol and tween 80 using chitosan as vehicle. Patch produced solvent casting method. Patch obtained was tested for swelling index, folding endurance, surface pH, antibacterial activity, release of eugenol, and local tolerance. Data obtained were analyzed descriptively. The result showed that the addition of RES did not affect the surface pH but increase the water absorption with in inconsistent way except patch with tween 80. The flexibility (folding endurance value increased, and the highest amount of eugenol released was achieved by patch using propylen glicol. Patch with tween 80 and glycerin for all extract concentration and patch with 1% extract concentration using propylen glycol showed medium sensation (local tolerance, and patch with 2 and 4% extract using propylen glycol showed severe sensation.

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

Science.gov (United States)

Nel, Annalene M; Coplan, Paul; van de Wijgert, Janneke H; Kapiga, Saidi H; von Mollendorf, Claire; Geubbels, Eveline; Vyankandondera, Joseph; Rees, Helen V; Masenga, Gileard; Kiwelu, Ireen; Moyes, Jocelyn; Smythe, Shanique C

2009-07-31

To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Hypothesis Testing of Inclusion of the Tolerance Interval for the Assessment of Food Safety.

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Hungyen Chen

Full Text Available In the testing of food quality and safety, we contrast the contents of the newly proposed food (genetically modified food against those of conventional foods. Because the contents vary largely between crop varieties and production environments, we propose a two-sample test of substantial equivalence that examines the inclusion of the tolerance intervals of the two populations, the population of the contents of the proposed food, which we call the target population, and the population of the contents of the conventional food, which we call the reference population. Rejection of the test hypothesis guarantees that the contents of the proposed foods essentially do not include outliers in the population of the contents of the conventional food. The existing tolerance interval (TI0 is constructed to have at least a pre-specified level of the coverage probability. Here, we newly introduce the complementary tolerance interval (TI1 that is guaranteed to have at most a pre-specified level of the coverage probability. By applying TI0 and TI1 to the samples from the target population and the reference population respectively, we construct a test statistic for testing inclusion of the two tolerance intervals. To examine the performance of the testing procedure, we conducted a simulation that reflects the effects of gene and environment, and residual from a crop experiment. As a case study, we applied the hypothesis testing to test if the distribution of the protein content of rice in Kyushu area is included in the distribution of the protein content in the other areas in Japan.

The Efficacy, Safety and Tolerability of Retapamulin as a Treatment Option for Impetigo and Other Uncomplicated Superficial Skin Infections: A Meta-analysis

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Rudy Ciulianto

2015-04-01

Full Text Available BACKGROUND: The treatment of impetigo, secondarily infected dermatitis and infected traumatic lesions continue to develop as new generations of drugs are being formulated. Bacteria causing impetigo show growing resistance rates for commonly used antibiotics. Retapamulin being a new drug has been recently approved as topical antibiotic in children and adult. This study aimed to ascertain the efficacy, safety and tolerability of retapamulin as the treatment option for impetigo and other uncomplicated superficial skin infections. METHODS: A search for studies published from 2006-2014 was done in Pubmed, EBSCO, OVID, Science Direct, and Cochrane using the search strategy. The search was limited to studies conducted in human subjects and published in the English language. Randomized controlled trials evaluating the efficacy, safety and tolerability of retapamulin as treatment for impetigo and other uncomplicated superficial skin infections in children and adult were included and extracted independently and the qualities of the studies were appraised using critical appraisal tools. Data analysis was conducted by using RevMan 5. RESULTS: This study has high heterogeneity and found Retapamulin has no statistically significant difference in the clinical success after seven days and follow up among per-protocol-patients, bacteriogical confirmed patients and intention-to-treat patients with impetigo and other secondary infected traumatic lesions compared to other regimens. However, Retapamulin has beneficial effect in the clinical success, well tolerated and safe for children and adults. CONCLUSIONS: Retapamulin is comparably effective and safe as a treatment option for impetigo and other uncomplicated superficial skin infections. KEYWORDS: efficacy, safety, tolerability, retapamulin, impetigo, meta-analysis.

Safety and Tolerability of Hyperbaric Oxygen Therapy in Cats and Dogs.

Science.gov (United States)

Birnie, Gemma L; Fry, Darren R; Best, Matthew P

2018-05-14

This prospective clinical trial was designed to evaluate the safety of hyperbaric oxygen therapy (HBOT) in a population of cats and dogs with a variety of naturally occurring diseases. Seventy-eight dogs and twelve cats with various naturally occurring disease conditions, who had the potential to benefit from HBOT, were enrolled in the study. These patients were treated with HBOT in a monoplace hyperbaric oxygen chamber at 2 air pressure absolute for a treatment length of either 45 min or 60 min. There were 230 hyperbaric oxygen treatments performed during the study period. No major adverse effects were observed. There were 76 minor adverse effects recorded, which were not considered to be of clinical significance. Hyperbaric oxygen therapy was well tolerated and there were no major adverse effects recorded during treatment.

A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.

Science.gov (United States)

Rasmussen, Michael Højby; Olsen, Minna W Brændholt; Alifrangis, Lene; Klim, Søren; Suntum, Mette

2014-10-01

Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.

Clinical efficacy, safety, and tolerability of fingolimod for the treatment of relapsing-remitting multiple sclerosis

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Gajofatto A

2015-12-01

Full Text Available Alberto Gajofatto,1,2 Marco Turatti,2 Salvatore Monaco,1,2 Maria Donata Benedetti2 1Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona, Italy; 2Division of Neurology B, Verona University Hospital, Verona, Italy Abstract: Fingolimod is a selective immunosuppressive agent approved worldwide for the treatment of relapsing-remitting multiple sclerosis (MS, a chronic and potentially disabling neurological condition. Randomized double-blind clinical trials have shown that fingolimod significantly reduces relapse rate and ameliorates a number of brain MRI measures, including cerebral atrophy, compared to both placebo and intramuscular interferon-1a. The effect on disability progression remains controversial, since one Phase III trial showed a significant benefit of treatment while two others did not. Although fingolimod has a very convenient daily oral dosing, the possibility of serious cardiac, ocular, infectious, and other rare adverse events justified the decision of the European Medicines Agency to approve the drug as a second-line treatment for MS patients not responsive to first-line therapy, or those with rapidly evolving course. In the United States, fingolimod is instead authorized as a first-line treatment. The aim of this review is to describe and discuss the characteristics of fingolimod concerning its efficacy, safety, and tolerability in the clinical context of multiple sclerosis management. Keywords: multiple sclerosis, fingolimod, safety, tolerability, efficacy

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

Science.gov (United States)

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

2016-01-01

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

Feasibility, safety and tolerability of accelerated dobutamine stress echocardiography

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Pavaci Herribert

2007-11-01

Full Text Available Abstract A continuous infusion of a single high dose of dobutamine has been, recently, suggested as a simple and effective protocol of stress echocardiography. The present study assesses the feasibility, safety, and tolerability of an accelerated dobutamine stress protocol performed in patients with suspected or known coronary artery disease. Two hundred sixty five consecutive patients underwent accelerated dobutamine stress echocardiography: the dobutamine was administered at a constant dose of 50 μg/kg/min for up to 10 minutes. The mean weight-adjusted cumulative dose of dobutamine used was 330 ± 105.24 μg/kg. Total duration of dobutamine infusion was 6.6 ± 2.1 min. Heart rate rose from 69.9 ± 12.1 to 123.1 ± 22.1 beats/min at peak with a concomitant change in systolic blood pressure (127.6 ± 18.1 vs. 167.6 ± 45.0 mmHg. Dobutamine administration produced a rapid increase in heart rate (9.4 ± 5.9 beats/min2. The side effects were similar to those described with the standard protocol; the most common were frequent premature ventricular complexes (21.5%, frequent premature atrial complexes (1.5% and non sustained ventricular tachycardia (1.5%; among non cardiac symptoms the most frequent were nausea (3.4%, headache (1.1% and symptomatic hypotension (1.1%. No major side effects were observed during the test. Our data demonstrate that a continous infusion of a single high dose of dobutamine is a safe and well tolerated method of performing stress echocardiography in patients with suspected or known coronary artery disease. This new protocol requires the administration of lower cumulative dobutamine dose than standard protocol and results in a significant reduction in test time.

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

Science.gov (United States)

Olde Rikkert, Marcel G M; Verhey, Frans R; Blesa, Rafael; von Arnim, Christine A F; Bongers, Anke; Harrison, John; Sijben, John; Scarpini, Elio; Vandewoude, Maurits F J; Vellas, Bruno; Witkamp, Renger; Kamphuis, Patrick J G H; Scheltens, Philip

2015-01-01

The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

77 FR 6007 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation...

Science.gov (United States)

2012-02-07

...] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation... they could be published in the Federal Register. This notice lists temporary safety zones, security... the safety and security needs within their jurisdiction; therefore, District Commanders and COTPs have...

Local Road Safety Peer Exchange - Regions 3 & 5 : An RSPCB Peer Exchange

Science.gov (United States)

2013-06-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Columbus, Ohio on June 12 and 13, 2013. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with the Region 3 & 5 Local...

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

NARCIS (Netherlands)

Sotgiu, Giovanni; Centis, Rosella; D'Ambrosio, Lia; Alffenaar, Jan-William C.; Anger, Holly A.; Caminero, Jose A.; Castiglia, Paolo; De Lorenzo, Saverio; Ferrara, Giovanni; Koh, Won-Jung; Schecter, Giesela F.; Shim, Tae S.; Singla, Rupak; Skrahina, Alena; Spanevello, Antonio; Udwadia, Zarir F.; Villar, Miquel; Zampogna, Elisabetta; Zellweger, Jean-Pierre; Zumla, Alimuddin; Migliori, Giovanni Battista

2012-01-01

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from

Road safety perspectives among employees of a multinational corporation in urban India: local context for global injury prevention.

Science.gov (United States)

Jacoby, Sara F; Winston, Flaura K; Richmond, Therese S

2017-12-01

In rapidly developing economies, like urban India, where road traffic injury rates are among the world's highest, the corporate workplace offers a non-traditional venue for road safety interventions. In partnership with a major multinational corporation (MNC) with a large Indian workforce, this study aimed to elicit local employee perspectives on road safety to inform a global corporate health platform. The safety attitudes and behaviours of 75 employees were collected through self-report survey and focus groups in the MNC offices in Bangalore and Pune. Analysis of these data uncovered incongruity between employee knowledge of safety strategies and their enacted safety behaviours and identified local preference for interventions and policy-level actions. The methods modelled by this study offer a straightforward approach for eliciting employee perspective for local road safety interventions that fit within a global strategy to improve employee health. Study findings suggest that MNCs can employ a range of strategies to improve the road traffic safety of their employees in settings like urban India including: implementing corporate traffic safety policy, making local infrastructure changes to improve road and traffic conditions, advocating for road safety with government partners and providing employees with education and access to safety equipment and safe transportation options.

Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance.

Science.gov (United States)

Mathieu, Chantal; Kozlovski, Plamen; Paldánius, Päivi M; Foley, James E; Modgill, Vikas; Evans, Marc; Serban, Carmen

2017-08-01

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

OpenAIRE

Holt, Jonathon D. S.; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

2015-01-01

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a...

[Tolerance, safety and efficacy of the one-day preparation of PEG3350 + bisacodyl compared to 2 days of PEG3350 + bisacodyl in pediatric patients].

Science.gov (United States)

Portillo Canizalez, Ligia Marcela; Blanco Rodriguez, Gerardo; Teyssier Morales, Gustavo; Penchyna Grub, Jaime; Trauernicht Mendieta, Sean; Zurita-Cruz, Jessie Nallely

Multiple intestinal preparations have been used in children undergoing colonoscopy, with variable limitation due to acceptance, tolerance, and proper cleaning. The objective of this study was to compare the tolerability, safety and efficacy of the colonoscopy preparation with 1 day with PEG 3350 (poliethylenglycol) (4g/kg/day) + bisacodyl compared to 2 days of preparation with PEG 3350 (2g/kg/day) + bisacodyl in pediatric patients. A clinical, randomized, and blind trial was performed. Patients aged 2 to 18 years scheduled for colonoscopy were included. Patients were randomized into two groups: 1 day of preparation with PEG 3350 4g/kg/day + bisacodyl and 2 days of preparation with PEG 3350 2g/kg/day + bisacodyl. Through a questionnaire, physical examination and endoscopic evaluation (Boston scale), the tolerance, safety and efficacy of the 2 preparations to be evaluated were determined. Student's t test was performed for quantitative variables and χ 2 for qualitative variables. There were no significant differences in compliance rates, adverse effects, and extent of colonoscopic evaluation. Tolerance and safety between the intestinal preparation for 1-day colonoscopy with PEG 3350 (4g/kg/day) + bisacodyl and the 2-day preparation with PEG 3350 (2g/kg/day) + bisacodyl were similar. The quality of cleanliness was good in both groups, being partially more effective in the 1-day group with PEG 3350 (4g/kg/day). Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Tolerance and safety evaluation of N, N-dimethylglycine, a naturally occurring organic compound, as a feed additive in broiler diets

NARCIS (Netherlands)

Kalmar, I.D.; Verstegen, M.W.A.; Maenner, K.; Zentek, J.; Meulemans, G.; Janssens, G.P.J.

2012-01-01

N, N-dimethylglycine (DMG) is a tertiary amino acid that naturally occurs as an intermediate metabolite in choline-to-glycine metabolism. The objective of the present trial was to evaluate tolerance, safety and bioaccumulation of dietary DMG in broilers when supplemented at 1 g and 10 g Na-DMG/kg. A

Feasibility, tolerability and safety of pediatric hyperpolarized {sup 129}Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis

Energy Technology Data Exchange (ETDEWEB)

Walkup, Laura L.; Watters, Erin; Ruppert, Kai [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); Thomen, Robert P.; Woods, Jason C. [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); Washington University in St. Louis, Department of Physics, St. Louis, MO (United States); Akinyi, Teckla G.; Cleveland, Zackary I. [Cincinnati Children' s Hospital Medical Center, Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati, OH (United States); University of Cincinnati, Biomedical Engineering Program, Cincinnati, OH (United States); Clancy, John P. [Cincinnati Children' s Hospital Medical Center, Division of Pulmonary Medicine, Cincinnati, OH (United States)

2016-11-15

Hyperpolarized {sup 129}Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized {sup 129}Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent {sup 129}Xe MRI, receiving up to three doses of {sup 129}Xe gas prepared by either a commercially available or a homebuilt {sup 129}Xe polarizer. Subject heart rate and SpO{sub 2} were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of {sup 129}Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO{sub 2} (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO{sub 2} values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following {sup 129}Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of {sup 129}Xe MRI has been assessed in a small group of children as young as 6 years. SpO{sub 2} changes were consistent with the expected physiological effects of a short anoxic breath

Intragastric Balloon for Obesity Treatment: Safety, Tolerance, and Efficacy

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Joana Ribeiro da Silva

2017-12-01

Full Text Available Background: Obesity is an increasing worldwide problem associated with a vast number of comorbidities. Decreasing body weight by only 5-10% has been shown to slow and even prevent the onset of obesity-related comorbidities. Between pharmacological therapy and bariatric surgery a great variety of endoscopic techniques are available, the most common being intragastric balloon (IGB. The purpose of this study was to assess the safety, tolerance, and kinetics of IGBs in weight loss. The kinetics of weight loss were evaluated in 2 different contexts and phases: after the IGB's removal and after follow-up that varied between 6 and 12 months. Successful weight loss was defined as ≥10% weight loss after 6-12 months. Methods: The study included 51 patients who had undergone Orbera® IGB placement between September 2014 and February 2016. Inclusion criteria were age between 18 and 65 years; body mass index (BMI 28-35 with severe obesity-related disorders; or BMI 35-40. The IGB was removed 6 months later. All patients were followed for a minimum period of 6-12 months. Results: Of 51 patients, 16 were excluded (7 due to intolerance and 35 patients entered the study, of which 83% were followed for more than 6-12 months. The average weight loss (WL and % excess WL (%EWL after 6 months of treatment were 11.94 kg and 42.16%, respectively. At 6-12 months, after removal of the IGB, the mean WL was 8.25 kg and %EWL was 30.27%. Nineteen patients attained a WL of ≥10% the baseline value at IGB removal and 12 maintained their weight below this threshold during the 6-12 following months. Conclusions: After temporary IGB implantation in overweight or obese individuals, a WL that was ≥10% of weight at baseline was achieved in 54.3% and sustained at 6-12 months in 41.4% of participants. IGBs are an attractive intermediate option between diet and exercise programs and bariatric surgery. In general, IGB placement is a safe and well-tolerated procedure.

Strengthening patient safety in transitions of care: an emerging role for local medical centres in Norway.

Science.gov (United States)

Kongsvik, Trond; Halvorsen, Kristin; Osmundsen, Tonje; Gjøsund, Gudveig

2016-08-30

Patient safety has gained less attention in primary care in comparison to specialised care. We explore how local medical centres (LMCs) can play a role in strengthening patient safety, both locally and in transitions between care levels. LMCs represent a form of intermediate care organisation in Norway that is increasingly used as a strategy for integrated care policies. The analysis is based on institutional theory and general safety theories. A qualitative design was applied, involving 20 interviews of nursing home managers, managers at local medical centres and administrative personnel. The LMCs mediate important information between care levels, partly by means of workarounds, but also as a result of having access to the different information and communications technology (ICT) systems in use. Their knowledge of local conditions is found to be a key asset. LMCs are providers of competence and training for the local level, as well as serving as quality assurers. As a growing organisational form in Norway, LMCs have to legitimise their role in the health care system. They represent an asset to the local level in terms of information, competence and quality assurance. As they have overlapping competencies, tasks and responsibilities with other parts of the health care system, they add to organisational redundancy and strengthen patient safety.

The Attitude of socio-harmony and Local Wisdom: an Indicator of the Development of Social Tolerance of High School Students

Directory of Open Access Journals (Sweden)

Adi Wijaya Deni

2018-01-01

Full Text Available This article discusses the dilematis aspect about the shift in traditional values-based local wisdom about the ecological aspects. Close to the learning in school emphasized the sides of cognitive ability and do not offset the granting of traditional values education. The purpose of this article is to promote tolerance of students to be more sensitive to the surroundings so as not to become individualists. Research results at the high school level, students are not given the attitude of socio-harmony in the form of tolerance. The purpose of this article is to enhance social tolerance that can deliver value to prevent the behavior concept asocial.

49 CFR 350.339 - What are tolerance guidelines?

Science.gov (United States)

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false What are tolerance guidelines? 350.339 Section 350... MOTOR CARRIER SAFETY ASSISTANCE PROGRAM Funding § 350.339 What are tolerance guidelines? Tolerance guidelines set forth the limited deviations from the FMCSRs allowed in your State's laws and regulations...

Recent Updates on the Systemic and Local Safety of Intranasal Steroids.

Science.gov (United States)

Jang, Tae Young; Kim, Young Hyo

2016-01-01

Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use. We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications. INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Evaluation of the Safety and Tolerability of Conjunctival Ring for Posterior Segment of the Eye.

Science.gov (United States)

Kinoshita, Satoshi; Ohguchi, Takeshi; Noda, Kousuke; Murata, Miyuki; Yasueda, Shin-Ichi; Obata, Haruka; Matsunaga, Toru; Fukushima, Tsutomu; Kanda, Atsuhiro; Ishida, Susumu

2017-08-01

To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye. In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases.

Pegylated Long-Acting Human Growth Hormone Possesses a Promising Once-Weekly Treatment Profile, and Multiple Dosing Is Well Tolerated in Adult Patients with Growth Hormone Deficiency

DEFF Research Database (Denmark)

Søndergaard, Esben; Klose, Marianne Christina; Hansen, Mette

2011-01-01

Background: Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration. Objectives......: Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD). Subjects and Methods: Thirty-three adult patients with GHD, age 20-65 yr, body mass index 18.5-35.0 kg/m(2), and glycated...... to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed. Results: NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed...

Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals

International Nuclear Information System (INIS)

Beyerle, Andrea; Nolte, Marc W.; Solomon, Cristina; Herzog, Eva; Dickneite, Gerhard

2014-01-01

Fibrinogen, a soluble 340 kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0 g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent. - Highlights: • A comprehensive series of pre-clinical investigations of human fibrinogen concentrate. • Human fibrinogen concentrate was shown to be pharmacodynamically active. • Human fibrinogen concentrate was well tolerated

Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals

Energy Technology Data Exchange (ETDEWEB)

Beyerle, Andrea, E-mail: andrea.beyerle@cslbehring.com [CSL Behring GmbH, Preclinical Research and Development, Marburg (Germany); Nolte, Marc W. [CSL Behring GmbH, Preclinical Research and Development, Marburg (Germany); Solomon, Cristina [CSL Behring GmbH, Medical Affairs, Marburg (Germany); Department of Anaesthesiology, Perioperative Medicine and General Intensive Care, Paracelsus Medical University, Salzburg (Austria); Herzog, Eva; Dickneite, Gerhard [CSL Behring GmbH, Preclinical Research and Development, Marburg (Germany)

2014-10-01

Fibrinogen, a soluble 340 kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0 g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent. - Highlights: • A comprehensive series of pre-clinical investigations of human fibrinogen concentrate. • Human fibrinogen concentrate was shown to be pharmacodynamically active. • Human fibrinogen concentrate was well tolerated

New engineering safety factors for Loviisa NPP core calculations

Energy Technology Data Exchange (ETDEWEB)

Kuopanportti, Jaakko; Saarinen, Simo; Lahtinen, Tuukka; Ekstroem, Karoliina [Fortum Power and Heat Ltd., Fortum (Finland)

2017-09-15

In Loviisa NPP, there are two limiting thermal margins called the enthalpy rise margin and the linear heat rate margin that are monitored during normal operation. Engineering safety factors are applied in determination of both of these factors. The factors take into account the effect of various manufacturing tolerances, impact of the irradiation and simulation uncertainties on the local heat rate and on the enthalpy of the coolant. The engineering factors were re-evaluated during 2015 and the factors were approved by the Finnish radiation and nuclear safety authority in 2016. The re-evaluation was performed by considering all of the identified phenomena that affect the local heat rate or the enthalpy of the coolant. This paper summarizes the work that was performed during the re-evaluation of the engineering safety factors and presents the results for each uncertainty component. The new engineering safety factors are 1.115 for the linear heat rate and 1.100 for the enthalpy rise margin when the old factors were 1.12 and 1.16, respectively. The new factors improve the fuel economy by about 1%.

Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder: a 52-week, open-label, multicenter study.

Science.gov (United States)

Marcus, Ronald N; Owen, Randall; Manos, George; Mankoski, Raymond; Kamen, Lisa; McQuade, Robert D; Carson, William H; Findling, Robert L

2011-09-01

Evaluate the long-term safety and tolerability of aripiprazole in the treatment of irritability in pediatric subjects (6-17 years) with autistic disorder. A 52-week, open-label, flexibly dosed (2-15 mg/d) study of the safety and tolerability of aripiprazole in outpatients with a DSM-IV-TR diagnosis of autistic disorder who either had completed 1 of 2 antecedent, 8-week randomized trials or were enrolled de novo (ie, not treated in the randomized trials). Safety and tolerability measures included incidences of adverse events, extrapyramidal symptoms, weight, metabolic measures, vital signs, and other clinical assessments. Subjects were enrolled between September 2006 and June 2009. Three hundred thirty subjects entered the treatment phase: 86 de novo, 174 prior aripiprazole, and 70 prior placebo. A total of 199 (60.3%) subjects completed 52 weeks of treatment. Adverse events were experienced by 286/330 subjects (86.7%). Common adverse events included weight increase, vomiting, nasopharyngitis, increased appetite, pyrexia, upper respiratory tract infection, and insomnia. Discontinuations due to adverse events occurred in 35/330 randomized subjects (10.6%)-most commonly aggression and weight increase. One patient discontinued from the study due to a laboratory-related adverse event (moderately increased alanine transaminase and aspartate transaminase). Nine subjects experienced serious adverse events-most frequently aggression. Extrapyramidal symptoms-related adverse events occurred in 48/330 subjects (14.5%)-most commonly tremor (3.0%), psychomotor hyperactivity (2.7%), akathisia (2.4%), and dyskinesia (not tardive, 2.4%). At > 9 months' aripiprazole exposure (n = 220), mean change in body weight z score was 0.33 and body mass index z score was 0.31. The percentages of subjects with clinically significant fasting metabolic abnormalities at > 9 months were 2% for glucose, 5% for total cholesterol, 7% for low-density lipoprotein cholesterol, 30% for high

A qualitative study of Southern U.S. consumers' top of the mind beliefs about the safety of local beef.

Science.gov (United States)

Telligman, Amy L; Worosz, Michelle R; Bratcher, Christy L

2017-02-01

Following the Reasoned Action Approach, the aim of this study was to explore consumers' top-of-mind food safety beliefs about local beef. Beef consumers recruited from farmers' markets (N = 101) and grocery stores (N = 174) across the state of Alabama participated in face-to-face intercept surveys. The survey included closed- and open-ended questions designed to elicit consumers' food safety beliefs about local beef. Results indicate that beef safety was not a top-of-mind concern for a majority of participants, however of the total number of participants familiar with the term "local beef" (n = 168, 61%), a majority (n = 105, 63%) associated local beef with improved food safety. Content analysis of verbatim text revealed that consumers believed local beef was safer because they possess greater knowledge about the product and less shipping was involved. Respondents also believe that locally processed meat is derived from small-scale operations which provided the assurance that local beef is more likely to meet U.S. regulatory standards and therefore be safer. Consumers believe they have more oversight of local beef due to both their relationships with supply chain actors and proximity which also provided food safety assurances. Copyright © 2016 Elsevier Ltd. All rights reserved.

Feasibility, tolerability and safety of pediatric hyperpolarized "1"2"9Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis

International Nuclear Information System (INIS)

Walkup, Laura L.; Watters, Erin; Ruppert, Kai; Thomen, Robert P.; Woods, Jason C.; Akinyi, Teckla G.; Cleveland, Zackary I.; Clancy, John P.

2016-01-01

Hyperpolarized "1"2"9Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized "1"2"9Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent "1"2"9Xe MRI, receiving up to three doses of "1"2"9Xe gas prepared by either a commercially available or a homebuilt "1"2"9Xe polarizer. Subject heart rate and SpO_2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of "1"2"9Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO_2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO_2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following "1"2"9Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of "1"2"9Xe MRI has been assessed in a small group of children as young as 6 years. SpO_2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

Science.gov (United States)

Bellantone, R; Bossola, M; Carriero, C; Malerba, M; Nucera, P; Ratto, C; Crucitti, P; Pacelli, F; Doglietto, G B; Crucitti, F

1999-01-01

After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen

Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera in healthy volunteers

Directory of Open Access Journals (Sweden)

Ashwinikumar A Raut

2012-01-01

Full Text Available Ashwagandha (Withania somnifera (WS, a "rasayana" drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30 were enrolled. After baseline investigations, they received WS capsules (Rx (aqueous extract, 8:1 daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day x10 days, 1 000 mg/day x 10 days, 1 250 mg/day x 10 days. Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar′s test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

Science.gov (United States)

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Tolerability, safety, and efficacy of PEG 3350 as a 1-day bowel preparation in children.

Science.gov (United States)

Walia, Ritu; Steffen, Rita; Feinberg, Lisa; Worley, Sarah; Mahajan, Lori

2013-02-01

The aim of the study was to evaluate the tolerability, safety, and efficacy of polyethylene glycol (PEG) 3350 without electrolytes as a 1-day bowel preparation for colonoscopy in children. A prospective study of 45 children undergoing colonoscopy prescribed PEG 3350 without electrolytes mixed with a commercial electrolyte beverage was performed. Patients PEG 3350 without electrolytes mixed in 32 ounces of Gatorade. Patients ≥ 45 kg were given 255 g of PEG 3350 without electrolytes in 64 ounces of Gatorade A basic metabolic panel was performed at the time of the clinic visit and just before colonoscopy. Patients completed a survey related to bowel preparation. Endoscopists graded bowel preparation and noted the proximal extent of the examination. A total of 44 patients (14 ± 3 years) completed the study. One patient was excluded due to protocol breach. All subjects reported the preparation was easy (61%) or tolerable (39%). Adverse events included nausea (34%), abdominal pain (23%), vomiting (16%), abdominal distension (20%), bloating (23%), and dizziness (7%). Although significant changes in serum glucose and CO2 were noted, no therapeutic interventions were indicated. Significant changes in sodium, potassium chloride, blood urea nitrogen, or creatinine did not occur. Colonic preparation was rated as excellent in 23%, good in 52%, fair in 23%, and poor in 2% of patients. Intubation of the ileum was successful in 100%. One-day bowel preparation with high dose PEG 3350 mixed with commercial electrolyte solution is tolerable, safe, and effective in children before colonoscopy.

Local Road Safety Peer Exchange - Region 1 : An RSPCB Peer Exchange

Science.gov (United States)

2012-10-01

This report provides a summary of the proceedings of the Local Road Safety Peer Exchange held in Piscataway, New Jersey October 10th and 11th, 2012. The Federal Highway Administration (FHWA) sponsored the Peer Exchange in coordination with Region 1 L...

Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project

Directory of Open Access Journals (Sweden)

F. Bertoldo

2011-06-01

Full Text Available Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestinal intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82 or placebo (70 underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (μCT analysis. 143 biopsies (76 zoledronic acid, 67 placebo had at least one μCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo. Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV, decreased trabecular separation (Tb.Sp, and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F by 63%, mineralizing surface (MS

Fault-tolerant design of local controller for the poloidal field converter control system on ITER

International Nuclear Information System (INIS)

Shen, Jun; Fu, Peng; Gao, Ge; He, Shiying; Huang, Liansheng; Zhu, Lili; Chen, Xiaojiao

2016-01-01

Highlights: • The requirements on the Local Control Cubicles (LCC) for ITER Poloidal Field Converter are analyzed. • Decoupled service-based software architecture is proposed to make control loops on LCC running at varying cycle-time. • Fault detection and recovery methods for the LCC are developed to enhance the system. • The performance of the LCC with or without fault-tolerant feature is tested and compared. - Abstract: The control system for the Poloidal Field (PF) on ITER is a synchronously networked control system, which has several kinds of computational controllers. The Local Control Cubicles (LCC) play a critical role in the networked control system for they are the interface to all input and output signals. Thus, some additional work must be done to guarantee the LCCs proper operation under influence of faults. This paper mainly analyzes the system demands of the LCCs and faults which have been encountered recently. In order to handle these faults, decoupled service-based software architecture has been proposed. Based on this architecture, fault detection and system recovery methods, such as redundancy and rejuvenation, have been incorporated to achieve a fault-tolerant private network with the aid of QNX operating system. Unlike the conventional method, this method requires no additional hardware and can be achieved relatively easily. To demonstrate effectiveness the LCCs have been successfully tested during the recent PF Converter Unit performance tests for ITER.

Fault-tolerant design of local controller for the poloidal field converter control system on ITER

Energy Technology Data Exchange (ETDEWEB)

Shen, Jun; Fu, Peng; Gao, Ge; He, Shiying; Huang, Liansheng, E-mail: huangls@ipp.ac.cn; Zhu, Lili; Chen, Xiaojiao

2016-11-15

Highlights: • The requirements on the Local Control Cubicles (LCC) for ITER Poloidal Field Converter are analyzed. • Decoupled service-based software architecture is proposed to make control loops on LCC running at varying cycle-time. • Fault detection and recovery methods for the LCC are developed to enhance the system. • The performance of the LCC with or without fault-tolerant feature is tested and compared. - Abstract: The control system for the Poloidal Field (PF) on ITER is a synchronously networked control system, which has several kinds of computational controllers. The Local Control Cubicles (LCC) play a critical role in the networked control system for they are the interface to all input and output signals. Thus, some additional work must be done to guarantee the LCCs proper operation under influence of faults. This paper mainly analyzes the system demands of the LCCs and faults which have been encountered recently. In order to handle these faults, decoupled service-based software architecture has been proposed. Based on this architecture, fault detection and system recovery methods, such as redundancy and rejuvenation, have been incorporated to achieve a fault-tolerant private network with the aid of QNX operating system. Unlike the conventional method, this method requires no additional hardware and can be achieved relatively easily. To demonstrate effectiveness the LCCs have been successfully tested during the recent PF Converter Unit performance tests for ITER.

Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder

Directory of Open Access Journals (Sweden)

Jan K Buitelaar

2009-08-01

Full Text Available Jan K Buitelaar1, J Antoni Ramos-Quiroga2, Miguel Casas2, J J Sandra Kooij3, Asko Niemelä4, Eric Konofal5, Joachim Dejonckheere6, Bradford H Challis7, Rossella Medori81Department of Psychiatry, University Medical Center, St. Radboud and Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands; 2Department of Psychiatry, Hospital Universitari Vall d’Hebron and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 3PsyQ, Psycho-Medical Programs, Program Adult ADHD, Den Haag, The Netherlands; 4Oulu University Hospital, Department of Psychiatry, Oulu, Finland; 5Groupe Hospitalier Pitie-Salpetriere, Paris, France; 6SGS Life Sciences, Mechelen, Belgium; 7Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA; 8Janssen-Cilag EMEA, Neuss, GermanyAbstract: The osmotic release oral system (OROS methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18–90 mg daily for the treatment of adults diagnosed with ADHD (N = 370. Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91% completed the seven-week treatment and the final dispensed dose was 18 mg (8%, 36 mg (29%, 54 mg (34%, 72 mg (20%, or 90 mg (9%. Adverse events were reported in 253 (68% patients and most were mild or moderate in severity; most frequently reported included headache (17%, decreased appetite (13%, and insomnia (11%. Adverse events were rarely serious (<1%; 2/370. Small mean increases in systolic and diastolic blood pressure (both 2.4 mmHg and pulse (3.2 bpm were observed. Body weight decreased

Overexpression of a Plasma Membrane-Localized SbSRP-Like Protein Enhances Salinity and Osmotic Stress Tolerance in Transgenic Tobacco

Directory of Open Access Journals (Sweden)

Avinash Mishra

2017-04-01

Full Text Available An obligate halophyte, Salicornia brachiata grows in salt marshes and is considered to be a potential resource of salt- and drought-responsive genes. It is important to develop an understanding of the mechanisms behind enhanced salt tolerance. To increase this understanding, a novel SbSRP gene was cloned, characterized, over-expressed, and functionally validated in the model plant Nicotiana tabacum. The genome of the halophyte S. brachiata contains two homologs of an intronless SbSRP gene of 1,262 bp in length that encodes for a stress-related protein. An in vivo localization study confirmed that SbSRP is localized on the plasma membrane. Transgenic tobacco plants (T1 that constitutively over-express the SbSRP gene showed improved salinity and osmotic stress tolerance. In comparison to Wild Type (WT and Vector Control (VC plants, transgenic lines showed elevated relative water and chlorophyll content, lower malondialdehyde content, lower electrolyte leakage and higher accumulation of proline, free amino acids, sugars, polyphenols, and starch under abiotic stress treatments. Furthermore, a lower build-up of H2O2 content and superoxide-radicals was found in transgenic lines compared to WT and VC plants under stress conditions. Transcript expression of Nt-APX (ascorbate peroxidase, Nt-CAT (catalase, Nt-SOD (superoxide dismutase, Nt-DREB (dehydration responsive element binding factor, and Nt-AP2 (apetala2 genes was higher in transgenic lines under stress compared to WT and VC plants. The results suggested that overexpression of membrane-localized SbSRP mitigates salt and osmotic stress in the transgenic tobacco plant. It was hypothesized that SbSRP can be a transporter protein to transmit the environmental stimuli downward through the plasma membrane. However, a detailed study is required to ascertain its exact role in the abiotic stress tolerance mechanism. Overall, SbSRP is a potential candidate to be used for engineering salt and osmotic

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

Directory of Open Access Journals (Sweden)

Solmi M

2017-06-01

-generation antipsychotics (SGAs ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry

Safety evaluation of the phosphinothricin acetyltransferase proteins encoded by the pat and bar sequences that confer tolerance to glufosinate-ammonium herbicide in transgenic plants.

Science.gov (United States)

Hérouet, Corinne; Esdaile, David J; Mallyon, Bryan A; Debruyne, Eric; Schulz, Arno; Currier, Thomas; Hendrickx, Koen; van der Klis, Robert-Jan; Rouan, Dominique

2005-03-01

Transgenic plant varieties, which are tolerant to glufosinate-ammonium, were developed. The herbicide tolerance is based upon the presence of either the bar or the pat gene, which encode for two homologous phosphinothricin acetyltransferases (PAT), in the plant genome. Based on both a review of published literature and experimental studies, the safety assessment reviews the first step of a two-step-approach for the evaluation of the safety of the proteins expressed in plants. It can be used to support the safety of food or feed products derived from any crop that contains and expresses these PAT proteins. The safety evaluation supports the conclusion that the genes and the donor microorganisms (Streptomyces) are innocuous. The PAT enzymes are highly specific and do not possess the characteristics associated with food toxins or allergens, i.e., they have no sequence homology with any known allergens or toxins, they have no N-glycosylation sites, they are rapidly degraded in gastric and intestinal fluids, and they are devoid of adverse effects in mice after intravenous administration at a high dose level. In conclusion, there is a reasonable certainty of no harm resulting from the inclusion of the PAT proteins in human food or in animal feed.

Safety aspects of genetically modified crops with abiotic stress tolerance

NARCIS (Netherlands)

Liang, C.; Prins, T.W.; Wiel, van de C.C.M.; Kok, E.J.

2014-01-01

Abiotic stress, such as drought, salinity, and temperature extremes, significantly reduce crop yields. Hence, development of abiotic stress-tolerant crops by modern biotechnology may contribute to global food security. Prior to introducing genetically modified crops with abiotic stress tolerance to

Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

Directory of Open Access Journals (Sweden)

Lewiecki EM

2011-12-01

Full Text Available E Michael LewieckiNew Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico, USAAbstract: Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL, a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture.Keywords: denosumab, osteoporosis, safety, risk, benefit, FDA

Safety of concurrent adjuvant radiotherapy and chemotherapy for locally advanced soft tissue sarcoma.

Science.gov (United States)

Greto, Daniela; Loi, Mauro; Saieva, Calogero; Muntoni, Cristina; Delli Paoli, Camilla; Becherini, Carlotta; Ciabatti, Cinzia; Perna, Marco; Campanacci, Domenico; Terziani, Francesca; Beltrami, Giovanni; Scoccianti, Guido; Bonomo, Pierluigi; Meattini, Icro; Desideri, Isacco; Simontacchi, Gabriele; Mangoni, Monica; Livi, Lorenzo

2018-04-01

This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2-21.1 years). Local DFS-recurrence-free survival, distant DFS-relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28-72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81-12.58, p = .002 and HR 4.83, CI 1.41-16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02-4.87, p = .045; HR 2.88, 95% CI 1.10-7.52, p = .031; HR 2.59, 95% CI 1.11-6.04, p = .028). Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Dams and Levees: Safety Risks

Science.gov (United States)

Carter, N. T.

2017-12-01

development of state levee safety programs. As of 2017, federal funding for work pursuant to these provisions has been limited. Key policy considerations include (1) whether the status quo regarding investment and responsibilities in dam and levee safety results in a tolerable level of risk nationally and locally, and (2) who bears those risks.

Safety and tolerability of combination therapy vs. standard treatment alone for patients with previously treated non-small cell lung cancer | Center for Cancer Research

Science.gov (United States)

Dr. James Gulley is leading a team to test the safety and tolerability of the combination of nivolumab and CV301 to see if it can improve the survival for patientis with metastatic non-small cell lung cancer.  Learn more...

Local food protection and safety infrastructure and capacity: a Maryland case study.

Science.gov (United States)

Kufel, Joanna Zablotsky; Resnick, Beth A; Fox, Mary; Frattaroli, Shannon; Gielen, Andrea; Burke, Thomas A

2011-01-01

In Maryland, county Food Protection Programs (FPP), housed within Environmental Public Health (EPH) Divisions, maintain responsibility for regular inspection of all food service facilities (FSF). With growing concerns about how our food supply is protected, it is important to determine the state and effectiveness of our food safety systems. This research elucidates the roles, responsibilities, strengths, and weaknesses of Food Safety and Protection Programs in Maryland. A 16-question survey tool, which addressed facets of the local food protection infrastructure, including FSF inspections, staffing, budget, and foodborne illness surveillance, was distributed to all 24 county FPP. The number of FSF in Maryland increased 97% from 2001 to 2006 and counties had an average inspection completion rate of 73%, with a 4% increase over the time period. Statewide, there were 4.1 EPH full-time employees (FTE) per 10 000 population and 1.6 FPP FTE per 10 000 population. EPH Division budgets increased 63% statewide, from $19.5 million in 2000 to $31.9 million in 2007. FPP budgets also increased 59% over the period, from $6.2 million in 2000 to $9.8 million in 2007. This study offers new quantitative measures of the demands, capacities, and performance of Food Protection and Safety Programs in Maryland. This assessment of local EPH and FPP capacity also offers insight into the strengths and weaknesses of the local food protection and safety infrastructure. Importantly, it reveals an infrastructure and dedicated food protection workforce that inspects the food supply and responds to foodborne illness outbreaks. Yet, resources vary substantially from county to county, impacting which services can be provided and how well they can be performed. This can, in turn, impact the potential risk of foodborne illness and the public's overall health.

Assessment of Tolerability and Safety of Monocomponent Complementary Food Products in the Diet of Infants With Risk for Allergic Diseases

Directory of Open Access Journals (Sweden)

L. S. Namazova-Baranova

2016-01-01

Full Text Available Background: Children with burdened allergological history and/or having preliminary allergy manifestations need the effective prevention of allergy from the first months of life.Objective: Our aim was to assess the tolerability, safety, and efficacy of monocomponent complementary food products in the diet of infants with high risk for allergic diseases.Methods: Tolerability, safety, and efficacy of monocomponent complementary food products (vegetable puree, fruit juices, and after 6 months — meat sauce were studied in a singlecentre, prospective, comparative study. The symptoms of indigestion, skin allergy symptoms were registered, the results of coprological research and immunogenicity of complementary food products were assessed.Results: The study included 200 children in the age from 5 months from the risk group of allergy developing. Children were divided into 4 groups of 50 people. It was found that complementary food products were well tolerated and assimilated by children, did not cause skin and gastrointestinal allergic reactions in healthy children with risk of allergy developing. Food antigens of complementary food components (pumpkin, rabbit meat, turkey meat, apples, pears, plums were characterized by low immunogenicity: the level of specific IgE to the specified products did not change in blood serum and remained at a low level at the beginning and at the end of the study (ranging from 0.01 to 0.03 kE/l.Conclusion: Studied complementary food products (vegetable-, fruit- and meat-based can be used in the diet of children with high risk for allergy.

Commonly used preparations for colonoscopy: Efficacy, tolerability and safety – A Canadian Association of Gastroenterology position paper

Science.gov (United States)

Barkun, Alan; Chiba, Naoki; Enns, Robert; Marcon, Margaret; Natsheh, Susan; Pham, Co; Sadowski, Dan; Vanner, Stephen

2006-01-01

INTRODUCTION: The increased demand for colonoscopy, coupled with the introduction of new bowel cleansing preparations and recent caution advisories in Canada, has prompted a review of bowel preparations by the Canadian Association of Gastroenterology. METHODS: The present review was conducted by the Clinical Affairs group of committees including the endoscopy, hepatobiliary/transplant, liaison, pediatrics, practice affairs and regional representation committees, along with the assistance of Canadian experts in the field. An effort was made to systematically assess randomized prospective trials evaluating commonly used bowel cleansing preparations in Canada. RESULTS: Polyethylene glycol (PEG)-; sodium phosphate (NaP)-; magnesium citrate (Mg-citrate)-; and sodium picosulphate, citric acid and magnesium oxide (PSMC)-containing preparations were reviewed. Regimens of PEG 2 L with bisacodyl (10 mg to 20 mg) or Mg-citrate (296 mL) are as effective as standard PEG 4 L regimens, but are better tolerated. NaP preparations appear more effective and better tolerated than standard PEG solutions. PSMC has good efficacy and tolerability but head-to-head trials with NaP solutions remain few, and conclusions equivocal. Adequate hydration during preparation and up to the time of colonoscopy is critical in minimizing side effects and improving bowel cleansing in patients receiving NaP and PSMC preparations. All preparations may cause adverse events, including rare, serious outcomes. NaP should not be used in patients with cardiac or renal dysfunction (PEG solution is preferable in these patients), bowel obstruction or ascites, and caution should be exercised when used in patients with pre-existing electrolyte disturbances, those taking medications that may affect electrolyte levels and elderly or debilitated patients. Health Canada’s recommended NaP dosing for most patients is two 45 mL doses 24 h apart. However, both safety and efficacy data on this dosing schedule are lacking

Local health department food safety and sanitation expenditures and reductions in enteric disease, 2000-2010.

Science.gov (United States)

Bekemeier, Betty; Yip, Michelle Pui-Yan; Dunbar, Matthew D; Whitman, Greg; Kwan-Gett, Tao

2015-04-01

In collaboration with Public Health Practice-Based Research Networks, we investigated relationships between local health department (LHD) food safety and sanitation expenditures and reported enteric disease rates. We combined annual infection rates for the common notifiable enteric diseases with uniquely detailed, LHD-level food safety and sanitation annual expenditure data obtained from Washington and New York state health departments. We used a multivariate panel time-series design to examine ecologic relationships between 2000-2010 local food safety and sanitation expenditures and enteric diseases. Our study population consisted of 72 LHDs (mostly serving county-level jurisdictions) in Washington and New York. While controlling for other factors, we found significant associations between higher LHD food and sanitation spending and a lower incidence of salmonellosis in Washington and a lower incidence of cryptosporidiosis in New York. Local public health expenditures on food and sanitation services are important because of their association with certain health indicators. Our study supports the need for program-specific LHD service-related data to measure the cost, performance, and outcomes of prevention efforts to inform practice and policymaking.

Reviewing the options for local estrogen treatment of vaginal atrophy

Directory of Open Access Journals (Sweden)

Lindahl SH

2014-03-01

Full Text Available Sarah H Lindahl Sutter East Bay Medical Foundation, SEBMF – Diablo Division, Castro Valley, CA, USA Background: Vaginal atrophy is a chronic condition with symptoms that include vaginal dryness, pain during sex, itching, irritation, burning, and discharge, as well as various urinary problems. Up to 45% of postmenopausal women may be affected, but it often remains underreported and undertreated. This article aims to review the current recommendations for treatment of vaginal atrophy, and current data on the effectiveness and safety of local vaginal estrogen therapies. Methods: Literature regarding vaginal atrophy (2007–2012 was retrieved from PubMed and summarized, with emphasis on data related to the treatment of vaginal atrophy with local vaginal estrogen therapy. Results: Published data support the effectiveness and endometrial safety of low-dose local estrogen therapies. These results further support the general recommendation by the North American Menopause Society that a progestogen is not needed for endometrial protection in patients using low-dose local vaginal estrogen. Benefits of long-term therapy for vaginal atrophy include sustained relief of symptoms as well as physiological improvements (eg, decreased vaginal pH and increased blood flow, epithelial thickness, secretions. Conclusion: Currently available local vaginal estrogen therapies are well tolerated and effective in relieving symptoms of vaginal atrophy. Recent data support the endometrial safety of low-dose regimens for up to 1 year. Keywords: menopause, estrogen, local estrogen therapy, vaginal atrophy

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women

NARCIS (Netherlands)

Nel, Annalene M.; Coplan, Paul; van de Wijgert, Janneke H.; Kapiga, Saidi H.; von Mollendorf, Claire; Geubbels, Eveline; Vyankandondera, Joseph; Rees, Helen V.; Masenga, Gileard; Kiwelu, Ireen; Moyes, Jocelyn; Smythe, Shanique C.

2009-01-01

To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa

Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial.

Directory of Open Access Journals (Sweden)

Emma-Jo Hayton

Full Text Available HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported.Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination.Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1 and predominantly transient (<48 hours. Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range of 633 (231-1533 post-vaccination, which is of no safety concern.These data demonstrate safety and good tolerability of the pSG2

Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis.

LENUS (Irish Health Repository)

Finucane, Francis M

2008-10-01

The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol production in pituitary disease. However, areas of uncertainty remain regarding its safety in older people, the optimal duration of the test and its performance in insulin resistant states. Whether basal cortisol concentration can reliably predict an adequate adrenal response to hypoglycaemia remains to be determined.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab in Healthy Volunteers

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David Monteith

2017-10-01

Full Text Available Background: Calcitonin gene-related peptide (CGRP is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742 binds to CGRP and may be effective in migraine prophylaxis.Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement.Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596 with single escalating and multiple subcutaneous (SC doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose or placebo (n = 2/dose were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF.Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1–600 mg SC and consecutive doses (150 mg SC. There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.

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

Science.gov (United States)

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

2009-01-01

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

Hysterosalpingo-foam sonography (HyFoSy): Tolerability, safety and the occurrence of pregnancy post-procedure.

Science.gov (United States)

Tanaka, Keisuke; Chua, Jackie; Cincotta, Robert; Ballard, Emma L; Duncombe, Gregory

2018-02-01

Fallopian tube patency testing is an essential part of infertility evaluation. Hysterosalpingo-contrast sonography (HyCoSy) has been described as reliable, well tolerated and safe compared to other modalities such as laparoscopy and a dye test or hysterosalpingography. Limited availability of the previously used contrast has led to the introduction of a foam contrast agent as an alternative. To assess the tolerability, safety and occurrence of pregnancy post-procedure of hysterosalpingo-foam sonography (HyFoSy). A retrospective cohort study of women who had a HyFoSy at Queensland Ultrasound for Women from March 2013 to February 2015. A questionnaire was sent to their referring doctor to identify any complications or subsequent pregnancies with or without artificial reproductive technology (ART) within six months of the HyFoSy. Of 200 women, four cases were abandoned due to difficulty introducing the intracervical catheter, severe discomfort or a vasovagal episode. Response from referring doctors for 155 women reported no post-procedural complication. One hundred and eleven women were followed up for at least six months. Twenty-four out of 59 women (40.7%) who had ART and 24 out of 52 women (46.2%) who did not have ART conceived. Fifty percent of women who were nulligravida at the time of investigation, found to have at least one patent fallopian tube, whose partner had a normal semen analysis, spontaneously conceived within the time of follow up. HyFoSy is well tolerated and safe. A preponderance of pregnancies in the first month after HyFoSy suggests that a therapeutic effect may exist. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

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Carolina L. Haass-Koffler

2017-12-01

Full Text Available The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled “Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers” (Haass-Koffler et al., 2017 [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73. Keywords: Glutamate receptor subtype 5 (mGlu5, Allosteric modulator, GET 73, Safety, Tolerability

Diagnosis and fault-tolerant control

CERN Document Server

Blanke, Mogens; Lunze, Jan; Staroswiecki, Marcel

2016-01-01

Fault-tolerant control aims at a gradual shutdown response in automated systems when faults occur. It satisfies the industrial demand for enhanced availability and safety, in contrast to traditional reactions to faults, which bring about sudden shutdowns and loss of availability. The book presents effective model-based analysis and design methods for fault diagnosis and fault-tolerant control. Architectural and structural models are used to analyse the propagation of the fault through the process, to test the fault detectability and to find the redundancies in the process that can be used to ensure fault tolerance. It also introduces design methods suitable for diagnostic systems and fault-tolerant controllers for continuous processes that are described by analytical models of discrete-event systems represented by automata. The book is suitable for engineering students, engineers in industry and researchers who wish to get an overview of the variety of approaches to process diagnosis and fault-tolerant contro...

Efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD: an open-label, pilot study

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Crawford Gordon M

2011-03-01

Full Text Available Abstract Background Escitalopram is licensed for use at doses up to 20 mg but is used clinically at higher doses. There is limited published data at higher doses and none in the treatment of Major Depressive Disorder (MDD. Methods This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in MDD. It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] ≤8 or failed to tolerate the dose. Results Forty-two patients (70% completed the study. Twenty-one patients (35% achieved remission with 8 of the 21 patients (38% needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20% patients had adverse events leading to discontinuation. The most common adverse events were headache (35%, nausea, diarrhoea and nasopharyngitis (all 25%. Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks. Conclusions Dose escalation with escitalopram above 20 mg may have a useful role in the management of patients with MDD, although further studies are needed to confirm this finding. Trial Registration ClinicalTrials.gov: NCT00785434

Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children.

Science.gov (United States)

Esposito, Susanna; Giavoli, Claudia; Trombetta, Claudia; Bianchini, Sonia; Montinaro, Valentina; Spada, Anna; Montomoli, Emanuele; Principi, Nicola

2016-01-02

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (pvaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (pvaccine administration (pchildren, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

DEFF Research Database (Denmark)

Steg, Ph Gabriel; Mehta, Shamir R; Jukema, J Wouter

2011-01-01

To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS)....

What is Fault Tolerant Control

DEFF Research Database (Denmark)

Blanke, Mogens; Frei, C. W.; Kraus, K.

2000-01-01

Faults in automated processes will often cause undesired reactions and shut-down of a controlled plant, and the consequences could be damage to the plant, to personnel or the environment. Fault-tolerant control is the synonym for a set of recent techniques that were developed to increase plant...... availability and reduce the risk of safety hazards. Its aim is to prevent that simple faults develop into serious failure. Fault-tolerant control merges several disciplines to achieve this goal, including on-line fault diagnosis, automatic condition assessment and calculation of remedial actions when a fault...... is detected. The envelope of the possible remedial actions is wide. This paper introduces tools to analyze and explore structure and other fundamental properties of an automated system such that any redundancy in the process can be fully utilized to enhance safety and a availability....

Infrastructural requirements for local implementation of safety policies: the discordance between top-down and bottom-up systems of action.

Science.gov (United States)

Timpka, Toomas; Nordqvist, Cecilia; Lindqvist, Kent

2009-03-09

Safety promotion is planned and practised not only by public health organizations, but also by other welfare state agencies, private companies and non-governmental organizations. The term 'infrastructure' originally denoted the underlying resources needed for warfare, e.g. roads, industries, and an industrial workforce. Today, 'infrastructure' refers to the physical elements, organizations and people needed to run projects in different societal arenas. The aim of this study was to examine associations between infrastructure and local implementation of safety policies in injury prevention and safety promotion programs. Qualitative data on municipalities in Sweden designated as Safe Communities were collected from focus group interviews with municipal politicians and administrators, as well as from policy documents, and materials published on the Internet. Actor network theory was used to identify weaknesses in the present infrastructure and determine strategies that can be used to resolve these. The weakness identification analysis revealed that the factual infrastructure available for effectuating national strategies varied between safety areas and approaches, basically reflecting differences between bureaucratic and network-based organizational models. At the local level, a contradiction between safety promotion and the existence of quasi-markets for local public service providers was found to predispose for a poor local infrastructure diminishing the interest in integrated inter-agency activities. The weakness resolution analysis showed that development of an adequate infrastructure for safety promotion would require adjustment of the legal framework regulating injury data exchange, and would also require rational financial models for multi-party investments in local infrastructures. We found that the "silo" structure of government organization and assignment of resources was a barrier to collaborative action for safety at a community level. It may therefore be

APPRAISAL OF NIMESULIDE EFFICIENCY, TOLERANCE AND SAFETY AMONG CHILDREN WITH JUVENILE ARTHRITIS

Directory of Open Access Journals (Sweden)

E.I. Alexeeva

2007-01-01

Full Text Available The article analyzes nimesulide application experience among children with juvenile arthritides against the insufficient efficiency of a therapy by other non steroid anti-inflammatory medications. The researchers show that nimesulide is an efficient non steroid anti-inflammatory medication for the patients, suffering from oligo- and limited poly arthritis of the I–II activity degree. Nimesulide also provided for the reliable regression of the clinical and laboratory activity manifestations of a disease and, what is more important, among most patients without applications of the local glucocorticosteroidbassisted therapy. Nimesulide is characterized by good tolerance and low toxicity, which is along with the permit to use it among children aged 2 and over, allows one to consider this drug as one of the medications to choose for the treatment of the inflammatory joint diseases among children.Key words: children, juvenile arthritis, nimesulide.

Safety of retransfusing shed blood after local infiltration analgesia in total knee arthroplasty

NARCIS (Netherlands)

Thomassen, B.J.; Pool, L.; Van Der Flier, R.; Stienstra, R.; in 't Veld, B.A.

2012-01-01

We investigated the safety of LIA (local infiltration analgesia) combined with retransfusion of drained blood. Total knee arthroplasty patients received two peri-articular injections during surgery followed by continuous infusion, both with ropivacaine (567 mg). Ropivacaine plasma concentrations

Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain.

Science.gov (United States)

Pergolizzi, Joseph V; Zampogna, Gianpietro; Taylor, Robert; Raffa, Robert B

2015-03-01

Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy(®), an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature.

Accurate 3D Localization Method for Public Safety Applications in Vehicular Ad-hoc Networks

KAUST Repository

Ansari, Abdul Rahim

2018-04-10

Vehicular ad hoc networks (VANETs) represent a very promising research area because of their ever increasing demand, especially for public safety applications. In VANETs vehicles communicate with each other to exchange road maps and traffic information. In many applications, location-based services are the main service, and localization accuracy is the main problem. VANETs also require accurate vehicle location information in real time. To fulfill this requirement, a number of algorithms have been proposed; however, the location accuracy required for public safety applications in VANETs has not been achieved. In this paper, an improved subspace algorithm is proposed for time of arrival (TOA) measurements in VANETs localization. The proposed method gives a closed-form solution and it is robust for large measurement noise, as it is based on the eigen form of a scalar product and dimensionality. Furthermore, we developed the Cramer-Rao Lower Bound (CRLB) to evaluate the performance of the proposed 3D VANETs localization method. The performance of the proposed method was evaluated by comparison with the CRLB and other localization algorithms available in the literature through numerous simulations. Simulation results show that the proposed 3D VANETs localization method is better than the literature methods especially for fewer anchors at road side units and large noise variance.

Pitavastatin demonstrates long-term efficacy, safety and tolerability in elderly patients with primary hypercholesterolaemia or combined (mixed) dyslipidaemia

DEFF Research Database (Denmark)

Stender, Steen; Budinski, Dragos; Hounslow, Neil

2013-01-01

Aims: To assess the long-term efficacy, safety and tolerability of pitavastatin (2 and 4 mg) in elderly patients (≥65 years of age) with primary hypercholesterolaemia or combined (mixed) dyslipidaemia.Design: Patients (n = 545) who had completed a 12-week double-blind comparative study (core study...... Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) targets for low-density lipoprotein cholesterol (LDL-C) was determined.Results: Of the patients enrolled, 539 received at least one dose of pitavastatin (safety population: men, 45.5%; Caucasian, 99.1%; mean age, 70.3 years; range, 65......-89 years). Only 17% of patients required up-titration to pitavastatin 4 mg. After 60 weeks, NCEP ATP III and EAS targets were attained by 93.8% and 89.0% of patients, respectively. Plasma LDL-C declined by 43.4% and high-density lipoprotein cholesterol increased by 9.6% versus core-study baseline values...

Development of Necessary Technology for localizing of Nuclear Safety Grade I and C System

International Nuclear Information System (INIS)

Kwon, Kee Choon; Jang, Tong Il; Kim, Jung Tack

2010-08-01

Through KNICS and Nu-Tech 2012, a MMIS(Man-Machine Interface System) package for nuclear plants was localized and is expected to be applied to SUN 1,2 plants. This study is aimed to support the application of the MMIS package including the following technologies that meet strengthened regulation requirements and enhanced utility's performance requirements to nuclear plants. - Dedication to safety-grade computers and real time operating systems - The broadband communication network for safety information - Application of the automatic test for safety systems - Application of programmable logic controllers to nuclear plants - Development strategy for an integrated SW development tool for control device

[Piezosurgery for surgically assisted rapid maxillary expansion under local anesthesia].

Science.gov (United States)

Sun, Hao; Li, Biao; Sun, Hao; Liu, Zhixu; Wang, Xudong

2014-08-01

This study evaluates piezosurgery for surgically assisted rapid maxillary expansion (SARME) under local anesthesia. SARME was performed on adults with maxillary transverse deficiency under local anesthesia with a piezosurgical device. Fourteen patients (six males and eight females) underwent lateral maxillary osteotomies, midpalatal osteotomies, and bilateral pterygomaxillary disjunction. The feelings of patients during the operation were determined through questionnaires. All patients underwent SARME in the out-patient operating room. The surgical procedures were completed under local anesthesia. All patients exhibited satisfactory tolerance. Ultrasonic bone-cutting surgery was recently introduced as a feasible alternative to the conventional tools of cranio-maxillofacial surgery for its technical characteristics of precision and safety. The device used was unique in that cutting action occurred when the tool was employed on mineralized tissues, but stoped on soft tissues. The results of the questionnaires showed that eight (57.14%) patients felt a mild sensation of ultrasonic vibration, tweleve (85.7 1%) felt mild tolerable pain and tooth soreness during surgery, and eleven (78.57%) felt little fear and hardly heard the ultrasonic sound. Preoperative and postoperative six months later measurements showed an evident effect of expansion. Piezosurgery enabled patients to undergo all the steps of SARME under local anesthesia, but more cases and longer follow-up are needed to verif ' the results.

Modifying locally the safety profile to improve the confinement of magnetic field lines in tokamak plasmas

International Nuclear Information System (INIS)

Constantinescu, D.; Firpo, M.-C.

2012-01-01

Using Hamiltonian models for the magnetic field lines, we propose a methodology to improve their confinement through the creation of transport barriers. A local modification of the safety profile creating a low-shear zone is shown to be sufficient to locally enhance drastically the regularity of the magnetic field lines without requesting a reversed shear. The optimal benefits of low-shear are obtained when the value q 0 of the safety profile in the low-shear zone is sufficiently far from the main resonance values m/n with low m and n, in the case of large enough values of those (m, n) mode amplitudes. A practical implementation in tokamak plasmas should involve electron cyclotron current drive to locally modify the magnetic shear. (paper)

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

Science.gov (United States)

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Management of health and safety in the organization of worktime at the local level.

Science.gov (United States)

Jeppesen, H J; Bøggild, H

1998-01-01

This study examined the consideration of health and safety issues in the local process of organizing worktime within the framework of regulations. The study encompassed all 7 hospitals in one region of Denmark. Twenty-three semi-structured interviews were carried out with 2 representatives from the different parties involved (management, cooperation committees, health and safety committees from each hospital, and 2 local unions). Furthermore, a questionnaire was sent to all 114 wards with day and night duty. The response rate was 84%. Data were collected on alterations in worktime schedules, responsibilities, reasons for the present design of schedules, and use of inspection reports. The organization of worktime takes place in single wards without external interference and without guidelines other than the minimum standards set in regulations. At the ward level, management and employees were united in a mutual desire for flexibility, despite the fact that regulations were not always followed. No interaction was found in the management of health and safety factors between the parties concerned at different levels. The demands for flexibility in combination with the absence of guidelines and the missing dynamics between the parties involved imply that the handling of health and safety issues in the organization of worktime may be accidental and unsystematic. In order to consider the health and safety of night and shift workers within the framework of regulations, a clarification of responsibilities, operational levels, and cooperation is required between the parties concerned.

Synthesis of Fault-Tolerant Embedded Systems with Checkpointing and Replication

DEFF Research Database (Denmark)

Izosimov, Viacheslav; Pop, Paul; Eles, Petru

2006-01-01

We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes are statically scheduled and communications are performed using the time...

75 FR 807 - Pesticide Tolerance Crop Grouping Program II; Revision to General Tolerance Regulations

Science.gov (United States)

2010-01-06

.... pubescens Ruiz & Pav., Capsicum spp.; (12) Roselle, Hibiscus sabdariffa L.; (13) Scarlet eggplant, Solanum..., specialty crop producers, pesticide registrants, the environment, or human health. No crop group tolerance... Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 1997) does not apply to this proposed rule...

Infrastructural requirements for local implementation of safety policies: the discordance between top-down and bottom-up systems of action

Directory of Open Access Journals (Sweden)

Lindqvist Kent

2009-03-01

Full Text Available Abstract Background Safety promotion is planned and practised not only by public health organizations, but also by other welfare state agencies, private companies and non-governmental organizations. The term 'infrastructure' originally denoted the underlying resources needed for warfare, e.g. roads, industries, and an industrial workforce. Today, 'infrastructure' refers to the physical elements, organizations and people needed to run projects in different societal arenas. The aim of this study was to examine associations between infrastructure and local implementation of safety policies in injury prevention and safety promotion programs. Methods Qualitative data on municipalities in Sweden designated as Safe Communities were collected from focus group interviews with municipal politicians and administrators, as well as from policy documents, and materials published on the Internet. Actor network theory was used to identify weaknesses in the present infrastructure and determine strategies that can be used to resolve these. Results The weakness identification analysis revealed that the factual infrastructure available for effectuating national strategies varied between safety areas and approaches, basically reflecting differences between bureaucratic and network-based organizational models. At the local level, a contradiction between safety promotion and the existence of quasi-markets for local public service providers was found to predispose for a poor local infrastructure diminishing the interest in integrated inter-agency activities. The weakness resolution analysis showed that development of an adequate infrastructure for safety promotion would require adjustment of the legal framework regulating injury data exchange, and would also require rational financial models for multi-party investments in local infrastructures. Conclusion We found that the "silo" structure of government organization and assignment of resources was a barrier to

Tolerability, safety and efficacy of Iloprost infusion without peristaltic pump in systemic sclerosis

Directory of Open Access Journals (Sweden)

S. Tosi

2011-09-01

Full Text Available Objective. To evaluate safety, tolerability and efficacy on Raynaud’s phenomenon (Rp of iloprost infusion without peristaltic pump in patients with systemic sclerosis (SSc. Patients and methods. The inclusion criteria were diagnosis of SSc, age between 18 and 65 years, presence of Rp, and absence of any controindication to the use of iloprost. The treatment was carried out in a day hospital setting and consisted first of 5 consecutive days of iloprost infusion (from an initial dose of 1.0 ng/Kg/min up to 2 ng/kg/min, and then of 2 days of infusions at the maximum possible dose every 45 days for one year. All of the adverse events were carefully recorded and the changes in the Rp were measured by a 5 grade scale (worsened, unmodified, slightly improved, very improved, disappeared. Results. Thirty-eight SSc patients (all females, mean age 49 years (range 18.5-65, disease duration 1.5 years (range 0.5-10.8 were enrolled in the study. During the first cycle of therapy, 14 avderse events occurred in 11 (28.9% patients and during the next cycles, 3 adverse events were seen in 3 (7.9% patients. In all of the cases they were mild and transient. Rp was considered very improved in 15 (39.5% patients, slightly improved in 13 (34.2%, unmodified in 8 (21% and worse in 2 (5.2%. Discussion. In this study intravenous iloprost without peristaltic pump proved to be safe, well tolerated, and as effective as traditional infusion through peristaltic pump in improving Rp in patients with SSc.

Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate

Directory of Open Access Journals (Sweden)

Waldy San Sebastian

2014-01-01

Full Text Available Aromatic L-amino acid decarboxylase (AADC deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of nonhuman primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3, or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.

Efficacy and tolerability of preservative-free eye drops containing a fixed combination of dorzolamide and timolol in glaucoma patients.

Science.gov (United States)

Renieri, Giulia; Führer, Katrin; Scheithe, Karl; Lorenz, Katrin; Pfeiffer, Norbert; Thieme, Hagen

2010-12-01

To evaluate the efficacy and tolerability of preservative-free eye drops (dorzolamide/timolol) in routine management of preservative-sensitive glaucoma patients. Data from 2,298 glaucoma patients requiring intraocular pressure (IOP) reduction and suffering from intolerance to benzalkonium chloride or active agents of previously used eye drops were valid for baseline and safety analysis in this prospective, open, noncomparative, multicenter, noninterventional study. Patients were treated with preservative-free dorzolamide/timolol eye drops for 12 weeks. Main efficacy endpoint was IOP reduction after 12 weeks of treatment. Two thousand forty-nine patients were considered for efficacy analysis. Tolerability was assessed by evaluating adverse drug reactions. Mean baseline IOP was 20.8 mmHg. Baseline IOP was reduced to 16.7 mmHg after 12 weeks of treatment corresponding to a mean absolute (percent) change of -4.1 mmHg (-17.3%). The proportion of patients with IOP ≤21 mmHg increased from 59.9% at baseline to 94.6% after 12 weeks. The most frequently reported ocular adverse drug reactions were burning eyes (2.4%) and hyperemia (0.9%). Local tolerability improved in 79.3% of patients compared to their previous glaucoma therapy. This observational study confirms the IOP lowering effect of preservative-free eye drops containing the fixed combination of dorzolamide/timolol in a large patient's population. The drug was well tolerated and improved the local tolerability in the vast majority of patients.

A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants.

Science.gov (United States)

Martinon-Torres, Federico; Gimenez-Sanchez, Francisco; Bernaola-Iturbe, Enrique; Diez-Domingo, Javier; Jiang, Qin; Perez, John L

2014-09-08

Neisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. This phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. Local reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. Due to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants. Copyright © 2014. Published by Elsevier Ltd.

Local Health Department Food Safety and Sanitation Expenditures and Reductions in Enteric Disease, 2000–2010

Science.gov (United States)

Yip, Michelle Pui-Yan; Dunbar, Matthew D.; Whitman, Greg; Kwan-Gett, Tao

2015-01-01

Objectives. In collaboration with Public Health Practice–Based Research Networks, we investigated relationships between local health department (LHD) food safety and sanitation expenditures and reported enteric disease rates. Methods. We combined annual infection rates for the common notifiable enteric diseases with uniquely detailed, LHD-level food safety and sanitation annual expenditure data obtained from Washington and New York state health departments. We used a multivariate panel time-series design to examine ecologic relationships between 2000–2010 local food safety and sanitation expenditures and enteric diseases. Our study population consisted of 72 LHDs (mostly serving county-level jurisdictions) in Washington and New York. Results. While controlling for other factors, we found significant associations between higher LHD food and sanitation spending and a lower incidence of salmonellosis in Washington and a lower incidence of cryptosporidiosis in New York. Conclusions. Local public health expenditures on food and sanitation services are important because of their association with certain health indicators. Our study supports the need for program-specific LHD service-related data to measure the cost, performance, and outcomes of prevention efforts to inform practice and policymaking. PMID:25689186

A controlled, randomized, head-to-head comparison of the Prolieve thermodilatation System versus the Targis System for benign prostatic hyperplasia: safety, procedural tolerability, and clinical results.

Science.gov (United States)

Shore, Neal D; Sethi, Parminder S

2010-09-01

Compare safety and tolerability of the Prolieve(®) System with the Targis(®) System using objective and subjective measures. Thirty-four men with symptomatic benign prostatic hyperplasia (BPH) were randomized to a single treatment with either the Prolieve or Targis system; 30 were treated and then followed for 6 months. After post-treatment bladder fill with ≥200 mL saline, patients were catheterized if they could not void after 2 hours or had a postvoid residual >150 mL. Catheter use, visual analog scale (VAS) tolerability scores, American Urological Association scores, and safety were assessed. After treatment, 15/16 (94%) Prolieve patients remained catheter-free compared with 3/14 (21%) Targis patients (P = 0.0001). Foley catheter indwelling time was 58.8 hours for the one Prolieve patient compared with 103.9 hrs (range 54-270 h) for the Targis patients (n = 9). Targis patients' catheterization requirements were: Seven Foley only, two intermittent self-catheters only, and two needing both. Intermittent self-catheterization continued for 1 month in two Targis patients. VAS tolerability scores were 24% to 50% lower during Prolieve treatment vs Targis (P 0.05). Overall, the incidence of device-related adverse events was 31% (Prolieve) compared with 64% (Targis) (P > 0.05)-most prevalently, urinary retention, dysuria, and hematuria. No device-related serious adverse events occurred. Prolieve provided enhanced near-term therapeutic benefit over Targis as assessed by catheterization, tolerability, and symptom relief, which may assist physician and patient decision-making when selecting an office-based transurethral microwave therapy option for patients.

Tolerance and safety of Lactobacillus paracasei ssp paracasei in combination with Bifidobacterium animalis ssp lactis in a prebiotic-containing infant formula: a randomised controlled trial

NARCIS (Netherlands)

Vlieger, Arine M.; Robroch, Afke; van Buuren, Stef; Kiers, Jeroen; Rijkers, Ger; Benninga, Marc A.; te Biesebeke, Rob

2009-01-01

The addition of probiotics to infant formula has been shown to be an efficient way to increase the number of beneficial bacteria in the intestine in order to promote a gut flora resembling that of breast-fed infants. The objective of the present study was to evaluate the safety and tolerance of a

Lithium safety and tolerability in mood disorders: a critical review

Directory of Open Access Journals (Sweden)

Ivan Aprahamian

2014-04-01

Full Text Available Background : Lithium is a first-line treatment for bipolar disorder in all phases, also indicated as add-on drug for unipolar depression and suicide prevention. This study encompasses a broad critical review on the safety and tolerability of lithium for mood disorders. Methods : A computerized search for English written human studies was made in MEDLINE, using the keywords “lithium” and “mood disorders”, starting from July 1993 through July 2013 (n = 416. This initial search aimed to select clinical trials, prospective data, and controlled design studies of lithium treatment for mood disorders reporting adverse effects (n = 36. The final selection yielded 91 studies. Results : The most common general side effects in patients on lithium treatment were thirst, frequent urination, dry mouth, weight gain, fatigue and cognitive complaints. Lithium users showed a high prevalence of hypothyroidism, hyperparathyroidism, and decrease in urinary concentration ability. Reduction of glomerular filtration rate in patients using lithium was also observed, but in a lesser extent. The evidence of teratogenicity associated with lithium use is not well established. Anti-inflammatory non-steroidal drugs, thiazide diuretics, angiotensin-converting enzyme inhibitors, and alprazolam may increase serum lithium and the consequent risk for intoxication. Discussion : Short-term lithium treatment is associated with mild side effects. Medium and long-term lithium treatment, however, might have effects on target organs which may be prevented by periodical monitoring. Overall, lithium is still a safe option for the treatment of mood disorders.

The safety basis of the integral fast reactor program

International Nuclear Information System (INIS)

Pedersen, D.R.; Seidel, B.R.

1990-01-01

The Integral Fast Reactor (IFR) and metallic fuel have emerged as the US Department of Energy reference reactor concept and fuel system for the development of an advanced liquid-metal reactor. This article addresses the basic elements of the IFR reactor concept and focuses on the safety advances achieved by the IFR Program in the areas of (1) fuel performance, (2) superior local faults tolerance, (3) transient fuel performance, (4) fuel-failure mechanisms, (5) performance in anticipated transients without scram, (6) core-melt mitigation, and (7) actinide recycle

Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

Science.gov (United States)

Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

2013-01-01

This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

Politicas de tolerancia cero (Zero Tolerance Policies). ERIC Digest.

Science.gov (United States)

McAndrews, Tobin

State legislatures and school boards are adopting a growing number of zero-tolerance polices toward weapons, guns, and violence. Zero-tolerance polices are rules intended to address specific school-safety issues. They have arisen in part as a response to the threat of the withdrawal of federal funds under the 1994 Gun-Free Schools Act, and…

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

NARCIS (Netherlands)

C.M.L. Herpen (Carla); F.A.L.M. Eskens (Ferry); M.J.A. de Jonge (Maja); I.M.E. Desar (Ingrid); L. Hooftman (Leon); E. Bone (Elisabeth); J.N.H. Timmerbonte (Johanna); J. Verweij (Jaap)

2010-01-01

textabstractBackground: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with

The tolerability of risk from nuclear power stations: a discussion of the HSE's guidelines

International Nuclear Information System (INIS)

Ryder, E.A.; Woods, P.B.

1989-01-01

The Health and Safety Executive's discussion document, ''The Tolerability of risk from nuclear power stations'', published just a year ago considers the concept of risk and the broad principles of risk assessment and proposes guidelines on the tolerable levels of individual and societal risks from normal operation and from accidents at nuclear power stations. This paper discusses how these guidelines might be applied in safety assessments so as to ensure an acceptable level of safety and considers some of the problems inherent in the estimation of risk from nuclear power stations. It shows how the tolerable risk levels of the Health and Safety Executive's document are related to the standards used by HM Nuclear Installations Inspectorate when licensing nuclear installations. Some of the uncertainties in the estimation of acceptable risk are discussed as are the acceptance criteria used by the Inspectorate in its assessments of both normal and accident situations. (author)

Determination of engineering safety factor -routine in Hungary (a methodology for the normal operation local power engineering safety factors)

International Nuclear Information System (INIS)

Szecsenyi, Z.; Korpas, L.; Bona, G.; Kereszturi, A.

2010-01-01

From the late nineties Paks Nuclear Power Plant-in collaboration with KFKI Atomic Energy Research Institute (KFKI AEKI)- is developing a system for determining the normal operation local power engineering safety factors. The system is based on a Monte Carlo sampling of the uncertain model input parameters. Additionally, the comparison of the calculation to the in-core measurements plays essential role for determining some important input parameters. By using new fuel types and the corresponding more recent detailed technological data, the applied method is being improved from time to time. Presently, the actually used and authorized engineering safety factors at Paks NPP are determined by using this method. In the paper, the system.s main properties are described (not going beyond the possible extent). The main points are as follows:-Mathematical definition of the engineering safety factor;-Sources of the uncertainties;-Input error propagation method constituting the basis of the system;-Flow-chart of the subsequent steps of the determination Finally, in the paper the engineering safety factors values of some selected parameters are presented as examples for demonstration of the capability of the method. (Authors)

Novel fault tolerant modular system architecture for I and C applications

International Nuclear Information System (INIS)

Kumar, Ankit; Venkatesan, A.; Madhusoodanan, K.

2013-01-01

Novel fault tolerant 3U modular system architecture has been developed for safety related and safety critical I and C systems of the reactor. Design innovatively utilizes simplest multi-drop serial bus called Inter-Integrated Circuits (I 2 C) Bus for system operation with simplicity, fault tolerance and online maintainability (hot swap). I 2 C bus failure modes analysis was done and system design was hardened for possible failure modes. System backplane uses only passive components, dual redundant I 2 C buses, data consistency checks and geographical addressing scheme to tackle bus lock ups/stuck buses and bit flips in data transactions. Dual CPU active/standby redundancy architecture with hot swap implements tolerance for CPU software stuck up conditions and hardware faults. System cards implement hot swap for online maintainability, power supply fault containment, communication buses fault containment and I/O channel to channel isolation and independency. Typical applications for pure hardwired (without real time software) Core Temperature Monitoring System for FBRs, as a Universal Signal Conditioning System for safety related I and C systems and as a complete control system for non nuclear safety systems have also been discussed. (author)

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours.

NARCIS (Netherlands)

Herpen, C.M.L. van; Eskens, F.A.; Jonge, M. de; Desar, I.M.E.; Hooftman, L.; Bone, E.A.; Timmer-Bonte, J.N.H.; Verweij, J.

2010-01-01

BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS:

Evaluation of efficacy, pharmacokinetics and tolerability of peptidomimetic aspartic proteinase inhibitors as cream formulation in experimental vaginal candidiasis.

Science.gov (United States)

De Bernardis, Flavia; Arancia, Silvia; Tringali, Giuseppe; Greco, Maria Cristina; Ragazzoni, Enzo; Calugi, Chiara; Trabocchi, Andrea; Sandini, Silvia; Graziani, Sofia; Cauda, Roberto; Cassone, Antonio; Guarna, Antonio; Navarra, Pierluigi

2014-08-01

It has been previously shown that the treatment with the two protease inhibitors APG12 and APG19 confers protection in a rat model of mucosal candidiasis; in this study, we examined whether these peptidomimetic inhibitors are also effective as a cream formulation in reducing Candida albicans vaginal infection. These efficacy studies were performed in a rat model of estrogen-dependent rat vaginitis by C. albicans on both azole-susceptible and azole-resistant C. albicans, and on both caspofungin-susceptible and caspofungin-resistant C. albicans strains. In vivo studies were also conducted in female albino rats and rabbits to obtain information about the safety, local tolerability and principal pharmacokinetics parameters of the two compounds. Both hit compounds showed remarkable results within the 48-h range as effective inhibitors of the infection, particularly causing rapid decay of vaginal C. albicans burden. Importantly, the two compounds showed marked acceleration of fungus clearance in the rats challenged with the fluconazole-resistant as well as with the capsofungin-resistant strain of C. albicans. Both compounds showed fast elimination rates when given by the intravenous route, and poor systemic absorption after intravaginal cream administration. Test drugs were also well tolerated in 7-day local tolerability experiments in the rabbit. © 2014 Royal Pharmaceutical Society.

76 FR 9646 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation...

Science.gov (United States)

2011-02-22

... DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Parts 100, 117, 147, and 165 [USCG-2010-0399] Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, Drawbridge Operation Regulations and Regulated Navigation Areas AGENCY: Coast Guard, DHS. ACTION: Notice of expired temporary rules...

Multicenter analysis of tolerance and clinical safety of the extracellular MR contrast agent gadobenate dimeglumine (MultiHance registered)

International Nuclear Information System (INIS)

Herborn, Christoph U.; Jaeger-Booth, I.; Goyen, M.; Lodemann, K.P.; Spinazzi, A.

2009-01-01

Purpose: Retrospective analysis of the occurrence of adverse events and the diagnostic efficacy of a paramagnetic contrast agent with weak intermittent protein binding and high relaxivity. Materials end methods: Postmarketing surveillance studies for gadobenate dimeglumine (MultiHance, BRACCO Altana Pharma, Constance) were conducted in Germany between 1998 and 2006 and then retrospectively analyzed. Demographic data, relevant comorbidities, and allergies were recorded. The safety and tolerability of MultiHance were logged on a standardized data sheet. Results: A total of 38568 patients were included in the study. 829 patients (2.1%) had a known intolerance against contrast media. The examined regions included the central nervous system, the liver, and the vascular bed. The injection rate with automated injectors (n = 10456) varied between 1.0 und 3.0 ml/sec in 86.5% of patients. Adverse events totaled 1.2%. 11 patients (0.03%) experienced serious adverse events. The most frequent findings were nausea, vomiting and a feeling of warmth. Conclusion: MultiHance is a safe and very well tolerated contrast agent for magnetic resonance imaging (MRI) with a profile and frequency of adverse events similar to other extracellular MR contrast materials. (orig.)

Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract

International Nuclear Information System (INIS)

Heinonen, Tuula; Gaus, Wilhelm

2015-01-01

Highlights: • Cross-matching of toxicological, clinical and other data improves risk analysis. • Induction of drug metabolism is linked to increased cell proliferation. • Rodents and man have differences in metabolism of Ginkgo biloba. • Controlled clinical data did not reveal any serious or specific adverse drug reaction. • Cross-matching of various sources gives strong evidence that G. biloba is safe. - Abstract: Ginkgo biloba is one of the most widely used herbal remedies in Europe and the US. It may be purchased in different types of formulations, but most of the clinical studies have been performed with the controlled G. biloba extract EGb761 ® . Indications include Alzheimers disease, cardiovascular disease, dementia, memory loss, and cerebral ischemia. The pharmacological modes of action cover antioxidant effects, radical scavenging, inhibition of platelet activating factor, alterations in membrane fluidity (signal transduction), and inhibition of glucocorticoid synthesis. Due to the widespread and long-term use of G. biloba – about a million doses of EGb761 ® are sold per day – tolerability and safety are a crucial issue. Based on broad and long-term clinical use of G. biloba extracts, it is regarded as well tolerated in man. Cross matching, a tool we introduced, combines different fields of knowledge and types of data to a consolidated result. In this article, we combine toxicological and clinical data and utilize other sources of information to assess tolerability and safety of G. biloba. It is well known that because of biological differences between animals and man or even between animal species, animal experiments do not necessarily mimic the effects in humans. Therefore, for adequate risk assessment, the relevance of non-clinical toxicological findings should be correlated with human data. The cross matching of toxicological data and results from clinical studies is possible because many toxicological and clinical studies are available

49 CFR 325.9 - Measurement tolerances.

Science.gov (United States)

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Measurement tolerances. 325.9 Section 325.9 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY... allowed to take into account the effects of the following factors: (1) The consensus standard practice of...

Safety and Tolerability of Transitioning from Cangrelor to Ticagrelor in Patients Who Underwent Percutaneous Coronary Intervention.

Science.gov (United States)

Badreldin, Hisham A; Carter, Danielle; Cook, Bryan M; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2017-08-01

The 3 phase 3 CHAMPION (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials collectively demonstrated the safety of transitioning from cangrelor, a potent, parenteral rapidly-acting P2Y 12 inhibitor, to clopidogrel in patients who underwent percutaneous coronary intervention (PCI). However, variation in timing of therapy, site-specific binding, and drug half-lives may theoretically complicate switching to other oral P2Y 12 inhibitors. Since regulatory approval, limited data are available regarding the "real-world" safety and tolerability of transitioning to these more potent oral P2Y 12 antagonists. From November 2015 to January 2017, we evaluated the clinical profiles and efficacy and safety outcomes in cangrelor-treated patients who underwent PCI transitioned to clopidogrel (n = 42) or ticagrelor (n = 82) at a large, tertiary care center. Most patients receiving cangrelor underwent PCI with a drug-eluting stent for acute coronary syndrome via a radial approach in the background of unfractionated heparin. Stent thrombosis within 48 hours was rare and occurred in 1 patient treated with ticagrelor. Global Use of Strategies to Open Occluded Coronary Arteries-defined bleeding occurred in 20% of patients switched to ticagrelor and 29% of patients switched to clopidogrel, but none were severe or life-threatening. In conclusion, rates of stent thrombosis and severe/life-threatening bleeding were low and comparable with those identified in the CHAMPION program, despite use of more potent oral P2Y 12 inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Coadministered Fat on the Tolerability, Safety, and Pharmacokinetic Properties of Dihydroartemisinin-Piperaquine in Papua New Guinean Children with Uncomplicated Malaria

OpenAIRE

Moore, B. R.; Benjamin, J. M.; Salman, S.; Griffin, S.; Ginny, E.; Page-Sharp, M.; Robinson, L. J.; Siba, P.; Batty, K. T.; Mueller, I.; Davis, T. M. E.

2014-01-01

Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/...

Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches.

Science.gov (United States)

Houzé, Bérengère; El-Khatib, Héjar; Arbour, Caroline

2017-10-03

Complementary and alternative medicine (CAM) therapies may be used as a non-pharmacological approach to chronic pain management. While hundreds of trials about individual CAM modality have been conducted, a comprehensive overview of their results is currently lacking for pain clinicians and researchers. This umbrella review synthesized the quality of meta-analytic evidence supporting the efficacy, tolerability and safety of CAM therapies for the management of chronic pain. MEDLINE, EMBASE, CINAHL, and CENTRAL were searched from October 1991 to November 2016. Reviews of clinical trials (randomized and non-randomized) with meta-analysis investigating the utility of any CAM modality for chronic pain were eligible. Pain relief post-intervention was the main outcome and secondary outcomes included patients' adherence and incidence of adverse effects during CAM protocol. Twenty-six reviews (207 clinical trials, >12,000 participants) about 18 CAM modalities, falling under natural products, mind and body practices or other complementary health approaches were included. Inhaled cannabis, graded motor imagery, and Compound Kushen injection (a form of Chinese medicine) were found the most efficient (with moderate-to-high effect sizes and low heterogeneity) and tolerable (≥80% of adherence to study protocols) for chronic pain relief. When reported, adverse effects related to these CAM were minor. Although several CAM were found effective for chronic pain relief, it remains unclear when these modalities are a reasonable choice against or in conjunction with mainstream treatments. In that sense, future research with a clear emphasis on concurrent evaluation of CAM overall efficacy and patient adherence/tolerance is needed. Copyright © 2017 Elsevier Inc. All rights reserved.

Fault-tolerant Actuator System for Electrical Steering of Vehicles

DEFF Research Database (Denmark)

Sørensen, Jesper Sandberg; Blanke, Mogens

2006-01-01

is needed that meets this requirement. This paper studies the fault-tolerance properties of an electrical steering system. It presents a fault-tolerant architecture where a dedicated AC motor design used in conjunction with cheap voltage measurements can ensure detection of all relevant faults......Being critical to the safety of vehicles, the steering system is required to maintain the vehicles ability to steer until it is brought to halt, should a fault occur. With electrical steering becoming a cost-effective candidate for electrical powered vehicles, a fault-tolerant architecture...

A Novel Real-Time Coal Miner Localization and Tracking System Based on Self-Organized Sensor Networks

Directory of Open Access Journals (Sweden)

Wang Yang

2010-01-01

Full Text Available With the development of information technology, we envision that the key of improving coal mine safety is how to get real-time positions of miners. In this paper, we propose a prototype system for real-time coal miner localization and tracking based on self-organized sensor networks. The system is composed of hardware and software platform. We develop a set of localization hardware devices with the Safety Certificate of Approval for Mining Products include miner node, wired fixed access station, and base with optical port. On the software side, we develop a layered software architecture of node application, server management, and information dissemination and broadcasting. We also develop three key localization technologies: an underground localization algorithm using received signal strength indication- (RSSI- verifying algorithm to reduce the influence of the severe environment in a coal mine; a robust fault-tolerant localization mechanism to improve the inherent defect of instability of RSSI localization; an accurate localization algorithm based on Monte Carlo localization (MCL to adapt to the underground tunnel structure. In addition, we conduct an experimental evaluation based on a real prototype implementation using MICA2 motes. The results show that our system is more accurate and more adaptive in general than traditional localization algorithms.

Mechanisms of food processing and storage-related stress tolerance in Clostridium botulinum.

Science.gov (United States)

Dahlsten, Elias; Lindström, Miia; Korkeala, Hannu

2015-05-01

Vegetative cultures of Clostridium botulinum produce the extremely potent botulinum neurotoxin, and may jeopardize the safety of foods unless sufficient measures to prevent growth are applied. Minimal food processing relies on combinations of mild treatments, primarily to avoid deterioration of the sensory qualities of the food. Tolerance of C. botulinum to minimal food processing is well characterized. However, data on effects of successive treatments on robustness towards further processing is lacking. Developments in genetic manipulation tools and the availability of annotated genomes have allowed identification of genetic mechanisms involved in stress tolerance of C. botulinum. Most studies focused on low temperature, and the importance of various regulatory mechanisms in cold tolerance of C. botulinum has been demonstrated. Furthermore, novel roles in cold tolerance were shown for metabolic pathways under the control of these regulators. A role for secondary oxidative stress in tolerance to extreme temperatures has been proposed. Additionally, genetic mechanisms related to tolerance to heat, low pH, and high salinity have been characterized. Data on genetic stress-related mechanisms of psychrotrophic Group II C. botulinum strains are scarce; these mechanisms are of interest for food safety research and should thus be investigated. This minireview encompasses the importance of C. botulinum as a food safety hazard and its central physiological characteristics related to food-processing and storage-related stress. Special attention is given to recent findings considering genetic mechanisms C. botulinum utilizes in detecting and countering these adverse conditions. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Insect Venom Immunotherapy: Analysis of the Safety and Tolerance of 3 Buildup Protocols Frequently Used in Spain.

Science.gov (United States)

Gutiérrez Fernández, D; Moreno-Ancillo, A; Fernández Meléndez, S; Domínguez-Noche, C; Gálvez Ruiz, P; Alfaya Arias, T; Carballada González, F; Alonso Llamazares, A; Marques Amat, L; Vega Castro, A; Antolín Amérigo, D; Cruz Granados, S; Ruiz León, B; Sánchez Morillas, L; Fernández Sánchez, J; Soriano Gomis, V; Borja Segade, J; Dalmau Duch, G; Guspi Bori, R; Miranda Páez, A

2016-01-01

Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk, as both local and systemic adverse reactions may occur, especially in the initial phases. We compared the tolerance to 3 VIT buildup protocols and analyzed risk factors associated with adverse reactions during this phase. We enrolled 165 patients divided into 3 groups based on the buildup protocol used (3, 4, and 9 weeks). The severity of systemic reactions was evaluated according to the World Allergy Organization model. Results were analyzed using exploratory descriptive statistics, and variables were compared using analysis of variance. Adverse reactions were recorded in 53 patients (32%) (43 local and 10 systemic). Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). The severity of the local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the onset of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association between severity of the local reaction and female gender. As for the risk factors associated with systemic reactions during the buildup phase, we found no significant differences in values depending on the protocol used or the insect responsible. The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied, patients undergoing the 9-week schedule presented no systemic reactions. Therefore, this protocol can be considered the safest approach.

Safety Study of Doxicycline in Broiler Chickens

Directory of Open Access Journals (Sweden)

Romeo Teodor Cristina

2010-05-01

Full Text Available Doxicycline is a structural isomer who meets the European reference standard (Ph.Eur. III 1997:0272 and respect EU Regulations for M.R.L. The good solubility permits high tissular absorption and distribution after administration in drinking water. The aim was to ascertain the clinical effects and tolerance consecutive to risen doses administration, as a part of safety study for this antibiotic in poultry in the respect of current drug testing methodology. The safety study revealed: good local and general tolerance to therapeutic doses (10 mg x kgb.w.-1 and to x2 dose, diarrhoea in lots which received x3 and x5 the therapeutic dose. Comparatively with the Control lot, haemoleucogram doesn’t suffer evident changes the registered values being between the references limits (exception of leucocitary formula. Also it was found an increased creatinin concentration consecutively to x3 and x5 greater doses administration and marked increasing of ASAT level and limited for ALAT’s, comparatively to control lot in the case of E4 lot, but light to reference values. Macro and microscopy revealed for the liver samples: hepatomegaly, diffuse hepatic degenerescence, nuclear heterochromatinization, vacuolar degenerescence; renal changes in nefrons and renal corpuscles, light splenomegaly, caecal sacs distension and brown-yellowish gaseous content to lots E3 and E4.

Analysis of fault tolerance and reliability in distributed real-time system architectures

International Nuclear Information System (INIS)

Philippi, Stephan

2003-01-01

Safety critical real-time systems are becoming ubiquitous in many areas of our everyday life. Failures of such systems potentially have catastrophic consequences on different scales, in the worst case even the loss of human life. Therefore, safety critical systems have to meet maximum fault tolerance and reliability requirements. As the design of such systems is far from being trivial, this article focuses on concepts to specifically support the early architectural design. In detail, a simulation based approach for the analysis of fault tolerance and reliability in distributed real-time system architectures is presented. With this approach, safety related features can be evaluated in the early development stages and thus prevent costly redesigns in later ones

Toward Human-Carnivore Coexistence: Understanding Tolerance for Tigers in Bangladesh.

Science.gov (United States)

Inskip, Chloe; Carter, Neil; Riley, Shawn; Roberts, Thomas; MacMillan, Douglas

2016-01-01

Fostering local community tolerance for endangered carnivores, such as tigers (Panthera tigris), is a core component of many conservation strategies. Identification of antecedents of tolerance will facilitate the development of effective tolerance-building conservation action and secure local community support for, and involvement in, conservation initiatives. We use a stated preference approach for measuring tolerance, based on the 'Wildlife Stakeholder Acceptance Capacity' concept, to explore villagers' tolerance levels for tigers in the Bangladesh Sundarbans, an area where, at the time of the research, human-tiger conflict was severe. We apply structural equation modeling to test an a priori defined theoretical model of tolerance and identify the experiential and psychological basis of tolerance in this community. Our results indicate that beliefs about tigers and about the perceived current tiger population trend are predictors of tolerance for tigers. Positive beliefs about tigers and a belief that the tiger population is not currently increasing are both associated with greater stated tolerance for the species. Contrary to commonly-held notions, negative experiences with tigers do not directly affect tolerance levels; instead, their effect is mediated by villagers' beliefs about tigers and risk perceptions concerning human-tiger conflict incidents. These findings highlight a need to explore and understand the socio-psychological factors that encourage tolerance towards endangered species. Our research also demonstrates the applicability of this approach to tolerance research to a wide range of socio-economic and cultural contexts and reveals its capacity to enhance carnivore conservation efforts worldwide.

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

Fault Tolerant Position-mooring Control for Offshore Vessels

DEFF Research Database (Denmark)

Blanke, Mogens; Nguyen, Trong Dong

2018-01-01

Fault-tolerance is crucial to maintain safety in offshore operations. The objective of this paper is to show how systematic analysis and design of fault-tolerance is conducted for a complex automation system, exemplified by thruster assisted Position-mooring. Using redundancy as required....... Functional faults that are only detectable, are rendered isolable through an active isolation approach. Once functional faults are isolated, they are handled by fault accommodation techniques to meet overall control objectives specified by class requirements. The paper illustrates the generic methodology...... by a system to handle faults in mooring lines, sensors or thrusters. Simulations and model basin experiments are carried out to validate the concept for scenarios with single or multiple faults. The results demonstrate that enhanced availability and safety are obtainable with this design approach. While...

Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy

Directory of Open Access Journals (Sweden)

Mary Elizabeth Cox

2010-01-01

Full Text Available Mary Elizabeth Cox1, Jennifer Rowell1, Leonor Corsino1, Jennifer B Green1,21Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition. Duke University Medical Center, Durham, NC, USA; 2Department of Medicine, Division of Endocrinology, Durham Veterans Affairs Medical Center, Durham, NC, USAAbstract: Although glycemic control is an important and effective way to prevent and minimize the worsening of diabetes-related complications, type 2 diabetes is a progressive disease which often proves difficult to manage. Most affected patients will eventually require therapy with multiple medications in order to reach appropriate glycemic targets. The dipeptidyl peptidase-4 (DPP-4 inhibitors constitute a relatively new class of oral medications for the treatment of type 2 diabetes, which has become widely incorporated into clinical practice. This review summarizes the available data on the efficacy, safety, and tolerability of these medications.Keywords: type 2 diabetes, pharmacotherapy, DPP-4 inhibitor, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin

Reirradiation tolerance of the rat heart

International Nuclear Information System (INIS)

Wondergem, Jan; Ravels, Frank J.M. van; Reijnart, Ivonne W.C.; Strootman, Erwin G.

1996-01-01

Purpose: To investigate the influence of reirradiation on the tolerance of the heart after a previous irradiation treatment. Methods and Materials: Female Wistar rats were locally irradiated to the thorax. Development of cardiac function loss was studied with the ex vivo working rat heart preparation. To compare the retreatment experiments, initial, and reirradiation doses were expressed as the percentage of the extrapolated tolerance dose (ETD). Results: Local heart irradiation with a single dose led to a dose-dependent and progressive decrease in cardiac function. The progressive nature of irradiation-induced heart disease is shown to affect the outcome of the retreatment, depending on both the time interval between subsequent doses and the size of the initial dose. The present data demonstrate that hearts are capable of repairing a large part of the initial dose of 10 Gy within the first 24 h. However, once biological damage as a result of the first treatment is fixed, the heart does not show any long-term recovery. At intervals up to 6 months between an initial treatment with 10 Gy and subsequent reirradiation, the reirradiation tolerance dose slightly decreased from 74% of the ETD ref (at 24-h interval) to 68% of the ETD ref (at 6-month interval). Between 6 and 9 months, reirradiation tolerance dose dropped more even to 43% of the ETD ref . Treatment of the heart with an initial dose of 17.5 Gy, instead of 10 Gy, 6 months prior to reirradiation, also led to a further decrease of the reirradiation tolerance dose ( ref ). Conclusions: The outcome of the present study shows a decreased tolerance of the heart to reirradiation at long time intervals (interval > 6 months). This has clinical implications for the estimation of reirradiation tolerance in patients whose mediastinum has to be reirradiated a long time after a first irradiation course

Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial.

Science.gov (United States)

Smilowitz, Jennifer T; Moya, Jackelyn; Breck, Melissa A; Cook, Chelsea; Fineberg, Annette; Angkustsiri, Kathleen; Underwood, Mark A

2017-05-30

Historically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001). Eighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 × 10 10  CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports. There were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log 10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 ± 2.8 SD) than for LS infants (3.5 ± 3.5 SD). Daily stool number was higher (p jaundice, number of illnesses, sick doctor visits, or diagnoses of eczema were different for the groups at any point. The B. infantis EVC001 supplement was safely consumed and well-tolerated. Stools were fewer and better formed in infants in the BiLS group compared with LS group. Adverse events were those expected in healthy infants and not different between groups. ClinicalTrials.gov NCT02457338 . Registered May 27, 2015.

Design Optimization of Time- and Cost-Constrained Fault-Tolerant Distributed Embedded Systems

DEFF Research Database (Denmark)

Izosimov, Viacheslav; Pop, Paul; Eles, Petru

2005-01-01

In this paper we present an approach to the design optimization of fault-tolerant embedded systems for safety-critical applications. Processes are statically scheduled and communications are performed using the time-triggered protocol. We use process re-execution and replication for tolerating...... transient faults. Our design optimization approach decides the mapping of processes to processors and the assignment of fault-tolerant policies to processes such that transient faults are tolerated and the timing constraints of the application are satisfied. We present several heuristics which are able...

Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quantitative review

Directory of Open Access Journals (Sweden)

Ana Katherine Gonçalves

2014-11-01

Full Text Available Recently, many studies have evaluated HPV vaccine safety and adverse effects. Two vaccines have been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co., Inc., Whitehouse Station, NJ. We have performed a systematic review of all randomized controlled trials in which HPV vaccines were compared with placebo regarding safety, tolerability and adverse effects. Studies were searched up to March 2013 in the databases: Pubmed, Embase, Scielo and Cancerlit. Odds Ratios (OR of most incident adverse effects were obtained. Twelve reports, involving 29,540 subjects, were included. In the HPV 16/18 group, the most frequently reported events related to the vaccine were pain (OR 3.29; 95% CI: 3.00–3.60, swelling (OR 3.14; 95% CI: 2.79–3.53 and redness (OR 2.41; 95% CI: 2.17–2.68. For the HPV 6/11/16/18 group the events were pain (OR 2.88; 95% CI: 2.42–3.43 and swelling (OR 2.65; 95% CI: 2.0–3.44. Concerning the HPV 16/18 vaccine, pain was the most common outcome detected. These effects can be due to a possible VLP-related inflammation process. Fatigue was the most relevant general effect observed followed by fever, gastrointestinal symptoms, and headache. In the HPV 6/11/16/18 group, only general symptoms, pain and swelling were observed. Pain and swelling were the most frequent. Comparing HPV 16/18 to HPV 6/11/16/18 vaccines, the former presented more adverse effects, perhaps because there are many more trials evaluating the bivalent vaccine. Other studies are needed to clarify this issue.

Toward Human-Carnivore Coexistence: Understanding Tolerance for Tigers in Bangladesh.

Directory of Open Access Journals (Sweden)

Chloe Inskip

Full Text Available Fostering local community tolerance for endangered carnivores, such as tigers (Panthera tigris, is a core component of many conservation strategies. Identification of antecedents of tolerance will facilitate the development of effective tolerance-building conservation action and secure local community support for, and involvement in, conservation initiatives. We use a stated preference approach for measuring tolerance, based on the 'Wildlife Stakeholder Acceptance Capacity' concept, to explore villagers' tolerance levels for tigers in the Bangladesh Sundarbans, an area where, at the time of the research, human-tiger conflict was severe. We apply structural equation modeling to test an a priori defined theoretical model of tolerance and identify the experiential and psychological basis of tolerance in this community. Our results indicate that beliefs about tigers and about the perceived current tiger population trend are predictors of tolerance for tigers. Positive beliefs about tigers and a belief that the tiger population is not currently increasing are both associated with greater stated tolerance for the species. Contrary to commonly-held notions, negative experiences with tigers do not directly affect tolerance levels; instead, their effect is mediated by villagers' beliefs about tigers and risk perceptions concerning human-tiger conflict incidents. These findings highlight a need to explore and understand the socio-psychological factors that encourage tolerance towards endangered species. Our research also demonstrates the applicability of this approach to tolerance research to a wide range of socio-economic and cultural contexts and reveals its capacity to enhance carnivore conservation efforts worldwide.

LFR safety approach and main ELFR safety analysis results

International Nuclear Information System (INIS)

Bubelis, E.; Schikorr, M.; Frogheri, M.; Mansani, L.; Bandini, G.; Burgazzi, L.; Mikityuk, K.; Zhang, Y.; Lo Frano, R.; Forgione, N.

2013-01-01

LFR safety approach: → A global safety approach for the LFR reference plant has been assessed and the safety analyses methodology has been developed. → LFR follows the general guidelines of the Generation IV safety concept recommendations. Thus, improved safety and higher reliability are recognized as an essential priority. → The fundamental safety objectives and the Defence-in-Depth (DiD) approach, as described by IAEA Safety Guides, have been preserved. → The recommendations of the Risk and Safety Working Group (RSWG) of GEN-IV IF has been taken into account: • safety is to be “built-in” in the fundamental design rather than “added on”; • full implementation of the Defence-in-Depth principles in a manner that is demonstrably exhaustive, progressive, tolerant, forgiving and well-balanced; • “risk-informed” approach - deterministic approach complemented with a probabilistic one; • adoption of an integrated methodology that can be used to evaluate and document the safety of Gen IV nuclear systems - ISAM. In particular the OPT tool is the fundamental methodology used throughout the design process

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

Directory of Open Access Journals (Sweden)

Benedikt Mahr

2017-12-01

Full Text Available The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long

Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

Science.gov (United States)

Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

2009-05-01

This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management

Directory of Open Access Journals (Sweden)

Luca Dalle Carbonare

2010-08-01

Full Text Available Luca Dalle Carbonare, Mirko Zanatta, Adriano Gasparetto, Maria Teresa ValentiClinic of Internal Medicine D, Department of Medicine, University of Verona, ItalyAbstract: Bisphosphonates (BPs are widely used in the treatment of postmenopausal ­osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively. The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis, and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes.Keywords: bisphosphonates, osteoporosis, safety, tolerability, zoledronic acid

Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long-acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials.

Science.gov (United States)

Majer, Istvan M; Gaughran, Fiona; Sapin, Christophe; Beillat, Maud; Treur, Maarten

2015-01-01

Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant

Intermediate probabilistic safety assessment approach for safety critical digital systems

International Nuclear Information System (INIS)

Taeyong, Sung; Hyun Gook, Kang

2001-01-01

Even though the conventional probabilistic safety assessment methods are immature for applying to microprocessor-based digital systems, practical needs force to apply it. In the Korea, UCN 5 and 6 units are being constructed and Korean Next Generation Reactor is being designed using the digital instrumentation and control equipment for the safety related functions. Korean regulatory body requires probabilistic safety assessment. This paper analyzes the difficulties on the assessment of digital systems and suggests an intermediate framework for evaluating their safety using fault tree models. The framework deals with several important characteristics of digital systems including software modules and fault-tolerant features. We expect that the analysis result will provide valuable design feedback. (authors)

78 FR 13252 - Pyroxasulfone; Pesticide Tolerances

Science.gov (United States)

2013-02-27

... moderately toxic to rats following a 4-week dermal exposure producing local inflammation and systemic effects...) method) is available to enforce the tolerance expression. The method may be requested from: Chief...

77 FR 15323 - Special Local Regulations and Safety Zone; War of 1812 Bicentennial Commemorations, Chesapeake...

Science.gov (United States)

2012-03-15

... National Technology Transfer and Advancement Act (NTTAA) (15 U.S.C. 272 note) directs agencies to use...] RIN 1625-AA08, AA00 Special Local Regulations and Safety Zone; War of 1812 Bicentennial Commemorations... Chesapeake Bay and Port of Baltimore, Maryland for War of 1812 Bicentennial Commemorations activities. This...

Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.

Science.gov (United States)

Ault, Alida; Tennant, Sharon M; Gorres, J Patrick; Eckhaus, Michael; Sandler, Netanya G; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E; Kao, Shing-Fen; Roederer, Mario; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F; Douek, Daniel C; Estes, Jacob D; Nabel, Gary J; Levine, Myron M; Rao, Srinivas S

2013-12-02

Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques. Copyright © 2013. Published by Elsevier Ltd.

Efficacy and tolerability of a local acting antiseptic agent in the treatment of vaginal dysbiosis during pregnancy.

Science.gov (United States)

Briese, Volker; Neumann, Gerd; Waldschläger, Juliane; May, Theodor W; Siebert, Jörg; Gerber, Bernd

2011-03-01

In the present study, the efficacy and tolerability of the local acting antiseptic octenidine hydrochloride/phenoxyethanol (OHP) for the treatment of vaginal dysbiosis (VD) and/or bacterial vaginosis (BV) in pregnancy and its potential influence on preterm births and low-weight newborns were examined. One-hundred nine pregnant women with increased pH values (>4.5) and BV characteristic symptoms were treated with OHP for 7 days and a second time in case of a recurrent pH increase. pH values were continuously controlled by women's self-measurements. pH decreased to ≤ 4.5 in 67.9% of patients. Seven of 12 women (58.3%) treated again with OHP due to a recurrent pH increase finally reached the pH target (pH ≤ 4.5). No preterm birth occurred in the OHP group; no newborn had a birth weight <2,000 g. Rates of preterm births and low-weight newborns were comparable between OHP group and pregnant women without VD/BV. OHP is effective and well tolerated in the treatment of VD/BV also in pregnancy without side effects and the occurrence of resistances. It could be an additional therapeutic option in the prevention of the multifactorial disease pattern 'preterm birth' with all their consequences.

Highway Safety Program Manual: Volume 3: Motorcycle Safety.

Science.gov (United States)

National Highway Traffic Safety Administration (DOT), Washington, DC.

Volume 3 of the 19-volume Highway Safety Program Manual (which provides guidance to State and local governments on preferred highway safety practices) concentrates on aspects of motorcycle safety. The purpose and specific objectives of a State motorcycle safety program are outlined. Federal authority in the highway safety area and general policies…

Three-year experience with the Sophono in children with congenital conductive unilateral hearing loss: tolerability, audiometry, and sound localization compared to a bone-anchored hearing aid.

Science.gov (United States)

Nelissen, Rik C; Agterberg, Martijn J H; Hol, Myrthe K S; Snik, Ad F M

2016-10-01

Bone conduction devices (BCDs) are advocated as an amplification option for patients with congenital conductive unilateral hearing loss (UHL), while other treatment options could also be considered. The current study compared a transcutaneous BCD (Sophono) with a percutaneous BCD (bone-anchored hearing aid, BAHA) in 12 children with congenital conductive UHL. Tolerability, audiometry, and sound localization abilities with both types of BCD were studied retrospectively. The mean follow-up was 3.6 years for the Sophono users (n = 6) and 4.7 years for the BAHA users (n = 6). In each group, two patients had stopped using their BCD. Tolerability was favorable for the Sophono. Aided thresholds with the Sophono were unsatisfactory, as they did not reach under a mean pure tone average of 30 dB HL. Sound localization generally improved with both the Sophono and the BAHA, although localization abilities did not reach the level of normal hearing children. These findings, together with previously reported outcomes, are important to take into account when counseling patients and their caretakers. The selection of a suitable amplification option should always be made deliberately and on individual basis for each patient in this diverse group of children with congenital conductive UHL.

Design Optimization of Time- and Cost-Constrained Fault-Tolerant Embedded Systems with Checkpointing and Replication

DEFF Research Database (Denmark)

Pop, Paul; Izosimov, Viacheslav; Eles, Petru

2009-01-01

We present an approach to the synthesis of fault-tolerant hard real-time systems for safety-critical applications. We use checkpointing with rollback recovery and active replication for tolerating transient faults. Processes and communications are statically scheduled. Our synthesis approach deci...

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.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

Science.gov (United States)

Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Vehicle Battery Safety Roadmap Guidance

Energy Technology Data Exchange (ETDEWEB)

Doughty, D. H.

2012-10-01

The safety of electrified vehicles with high capacity energy storage devices creates challenges that must be met to assure commercial acceptance of EVs and HEVs. High performance vehicular traction energy storage systems must be intrinsically tolerant of abusive conditions: overcharge, short circuit, crush, fire exposure, overdischarge, and mechanical shock and vibration. Fail-safe responses to these conditions must be designed into the system, at the materials and the system level, through selection of materials and safety devices that will further reduce the probability of single cell failure and preclude propagation of failure to adjacent cells. One of the most important objectives of DOE's Office of Vehicle Technologies is to support the development of lithium ion batteries that are safe and abuse tolerant in electric drive vehicles. This Roadmap analyzes battery safety and failure modes of state-of-the-art cells and batteries and makes recommendations on future investments that would further DOE's mission.

Local rollback for fault-tolerance in parallel computing systems

Science.gov (United States)

Blumrich, Matthias A [Yorktown Heights, NY; Chen, Dong [Yorktown Heights, NY; Gara, Alan [Yorktown Heights, NY; Giampapa, Mark E [Yorktown Heights, NY; Heidelberger, Philip [Yorktown Heights, NY; Ohmacht, Martin [Yorktown Heights, NY; Steinmacher-Burow, Burkhard [Boeblingen, DE; Sugavanam, Krishnan [Yorktown Heights, NY

2012-01-24

A control logic device performs a local rollback in a parallel super computing system. The super computing system includes at least one cache memory device. The control logic device determines a local rollback interval. The control logic device runs at least one instruction in the local rollback interval. The control logic device evaluates whether an unrecoverable condition occurs while running the at least one instruction during the local rollback interval. The control logic device checks whether an error occurs during the local rollback. The control logic device restarts the local rollback interval if the error occurs and the unrecoverable condition does not occur during the local rollback interval.

FAULT-TOLERANT DESIGN FOR ADVANCED DIVERSE PROTECTION SYSTEM

Directory of Open Access Journals (Sweden)

YANG GYUN OH

2013-11-01

Full Text Available For the improvement of APR1400 Diverse Protection System (DPS design, the Advanced DPS (ADPS has recently been developed to enhance the fault tolerance capability of the system. Major fault masking features of the ADPS compared with the APR1400 DPS are the changes to the channel configuration and reactor trip actuation equipment. To minimize the fault occurrences within the ADPS, and to mitigate the consequences of common-cause failures (CCF within the safety I&C systems, several fault avoidance design features have been applied in the ADPS. The fault avoidance design features include the changes to the system software classification, communication methods, equipment platform, MMI equipment, etc. In addition, the fault detection, location, containment, and recovery processes have been incorporated in the ADPS design. Therefore, it is expected that the ADPS can provide an enhanced fault tolerance capability against the possible faults within the system and its input/output equipment, and the CCF of safety systems.

Fault-tolerant system for catastrophic faults in AMR sensors

NARCIS (Netherlands)

Zambrano Constantini, A.C.; Kerkhoff, Hans G.

Anisotropic Magnetoresistance angle sensors are widely used in automotive applications considered to be safety-critical applications. Therefore dependability is an important requirement and fault-tolerant strategies must be used to guarantee the correct operation of the sensors even in case of

Fault-Tolerant Topology Selection for TTEthernet Networks

DEFF Research Database (Denmark)

Gavrilut, Voica Maria; Tamas-Selicean, Domitian; Pop, Paul

2015-01-01

Many safety-critical real-time applications are implemented using distributed architectures, composed of heterogeneous processing elements (PEs) interconnected in a network. In this paper, we are interested in the TTEthernet protocol, which is a deterministic, synchronized and congestion-free net......Many safety-critical real-time applications are implemented using distributed architectures, composed of heterogeneous processing elements (PEs) interconnected in a network. In this paper, we are interested in the TTEthernet protocol, which is a deterministic, synchronized and congestion......-free network protocol based on the IEEE 802.3 Ethernet standard and compliant with ARINC 664p7. TTEthernet supports three types of traffic: static time-triggered (TT) traffic and dynamic traffic, which is further subdivided into Rate Constrained (RC) traffic that has bounded end-to-end latencies, and Best...... a fault-tolerant network topology, consisting of redundant physical links and network switches, such that the architecture cost is minimized, the applications are fault-tolerant to a given number of permanent faults occurring in the communication network, and the timing constraints of the TT and RC...

Applications of a damage tolerance analysis methodology in aircraft design and production

Science.gov (United States)

Woodward, M. R.; Owens, S. D.; Law, G. E.; Mignery, L. A.

1992-01-01

Objectives of customer mandated aircraft structural integrity initiatives in design are to guide material selection, to incorporate fracture resistant concepts in the design, to utilize damage tolerance based allowables and planned inspection procedures necessary to enhance the safety and reliability of manned flight vehicles. However, validated fracture analysis tools for composite structures are needed to accomplish these objectives in a timely and economical manner. This paper briefly describes the development, validation, and application of a damage tolerance methodology for composite airframe structures. A closed-form analysis code, entitled SUBLAM was developed to predict the critical biaxial strain state necessary to cause sublaminate buckling-induced delamination extension in an impact damaged composite laminate. An embedded elliptical delamination separating a thin sublaminate from a thick parent laminate is modelled. Predicted failure strains were correlated against a variety of experimental data that included results from compression after impact coupon and element tests. An integrated analysis package was developed to predict damage tolerance based margin-of-safety (MS) using NASTRAN generated loads and element information. Damage tolerance aspects of new concepts are quickly and cost-effectively determined without the need for excessive testing.

Tolerance and withdrawal from prolonged opioid use in critically ill children.

Science.gov (United States)

Anand, Kanwaljeet J S; Willson, Douglas F; Berger, John; Harrison, Rick; Meert, Kathleen L; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J L; Prodhan, Parthak; Dean, J Michael; Nicholson, Carol

2010-05-01

After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis. Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

Understanding Risk Tolerance and Building an Effective Safety Culture

Science.gov (United States)

Loyd, David

2018-01-01

Estimates range from 65-90 percent of catastrophic mishaps are due to human error. NASA's human factors-related mishaps causes are estimated at approximately 75 percent. As much as we'd like to error-proof our work environment, even the most automated and complex technical endeavors require human interaction... and are vulnerable to human frailty. Industry and government are focusing not only on human factors integration into hazardous work environments, but also looking for practical approaches to cultivating a strong Safety Culture that diminishes risk. Industry and government organizations have recognized the value of monitoring leading indicators to identify potential risk vulnerabilities. NASA has adapted this approach to assess risk controls associated with hazardous, critical, and complex facilities. NASA's facility risk assessments integrate commercial loss control, OSHA (Occupational Safety and Health Administration) Process Safety, API (American Petroleum Institute) Performance Indicator Standard, and NASA Operational Readiness Inspection concepts to identify risk control vulnerabilities.

Function and safety assessment of Lactococus lactis subsp. lactis ...

African Journals Online (AJOL)

the characterizations of the strain, such as acid-tolerance, bile-tolerance, antimicrobial activity, antibiotic sensitivity and safety were also examined. The serum total cholesterol, triglyceride and bile acid levels significantly decreased of mice given a high-cholesterol diet supplemented with yogurt fermented by Lactococus ...

SafetyAnalyst : software tools for safety management of specific highway sites

Science.gov (United States)

2010-07-01

SafetyAnalyst provides a set of software tools for use by state and local highway agencies for highway safety management. SafetyAnalyst can be used by highway agencies to improve their programming of site-specific highway safety improvements. SafetyA...

Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial.

Directory of Open Access Journals (Sweden)

Moeko Noguchi-Shinohara

Full Text Available The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state and Study 2 (fed state]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.

Mine-hoist active fault tolerant control system and strategy

Energy Technology Data Exchange (ETDEWEB)

Wang, Z.; Wang, Y.; Meng, J.; Zhao, P.; Chang, Y. [China University of Mining and Technology, Xuzhou (China)] wzjsdstu@163.com

2005-06-01

Based on fault diagnosis and fault tolerant technologies, the mine-hoist active fault-tolerant control system (MAFCS) is presented with corresponding strategies, which includes the fault diagnosis module (FDM), the dynamic library (DL) and the fault-tolerant control model (FCM). When a fault is judged from some sensor by the FDM, FCM reconfigures the state of the MAFCS by calling the parameters from all sub libraries in DL, in order to ensure the reliability and safety of the mine hoist. The simulating result shows that MAFCS is of certain intelligence, which can adopt the corresponding control strategies according to different fault modes, even when there is quite a difference between the real data and the prior fault modes. 7 refs., 5 figs., 1 tab.

Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.

Science.gov (United States)

Biton, Victor; Gil-Nagel, Antonio; Brodie, Martin J; Derossett, Sarah E; Nohria, Virinder

2013-11-01

Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG. Copyright © 2013 Elsevier B.V. All rights reserved.

Electrical Steering of Vehicles - Fault-tolerant Analysis and Design

DEFF Research Database (Denmark)

Blanke, Mogens; Thomsen, Jesper Sandberg

2006-01-01

solutions and still meet strict requirements to functional safety. The paper applies graph-based analysis of functional system structure to find a novel fault-tolerant architecture for an electrical steering where a dedicated AC-motor design and cheap voltage measurements ensure ability to detect all......The topic of this paper is systems that need be designed such that no single fault can cause failure at the overall level. A methodology is presented for analysis and design of fault-tolerant architectures, where diagnosis and autonomous reconfiguration can replace high cost triple redundancy...

Viral Infection: A Potent Barrier to Transplantation Tolerance

Directory of Open Access Journals (Sweden)

David M. Miller

2008-01-01

Full Text Available Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

Safety and Tolerability of Essential Oil from Cinnamomum zeylanicum Blume Leaves with Action on Oral Candidosis and Its Effect on the Physical Properties of the Acrylic Resin

Directory of Open Access Journals (Sweden)

Julyana de Araújo Oliveira

2014-01-01

Full Text Available The anti-Candida activity of essential oil from Cinnamomum zeylanicum Blume, as well as its effect on the roughness and hardness of the acrylic resin used in dental prostheses, was assessed. The safety and tolerability of the test product were assessed through a phase I clinical trial involving users of removable dentures. Minimum inhibitory concentration (MIC and minimum fungicidal concentrations (MFC were determined against twelve Candida strains. Acrylic resin specimens were exposed to artificial saliva (GI, C. zeylanicum (GII, and nystatin (GIII for 15 days. Data were submitted to ANOVA and Tukey posttest (α=5%. For the phase I clinical trial, 15 healthy patients used solution of C. zeylanicum at MIC (15 days, 3 times a day and were submitted to clinical and mycological examinations. C. zeylanicum showed anti-Candida activity, with MIC = 625.0 µg/mL being equivalent to MFC. Nystatin caused greater increase in roughness and decreased the hardness of the material (P<0.0001, with no significant differences between GI and GII. As regards the clinical trial, no adverse clinical signs were observed after intervention. The substance tested had a satisfactory level of safety and tolerability, supporting new advances involving the clinical use of essential oil from C. zeylanicum.

Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

Science.gov (United States)

Maloney, Jennifer; Berman, Gary; Gagnon, Remi; Bernstein, David I; Nelson, Harold S; Kleine-Tebbe, Jörg; Kaur, Amarjot; Li, Qing; Nolte, Hendrik

2016-01-01

Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Newly Identified Wild Rice Accessions Conferring High Salt Tolerance Might Use a Tissue Tolerance Mechanism in Leaf

Science.gov (United States)

Prusty, Manas R.; Kim, Sung-Ryul; Vinarao, Ricky; Entila, Frederickson; Egdane, James; Diaz, Maria G. Q.; Jena, Kshirod K.

2018-01-01

+ sequestration in leaf might be occurring independent of tonoplast-localized OsNHX1. The newly isolated wild rice accessions will be valuable materials for both rice improvement to salinity stress and the study of salt tolerance mechanism in plants. PMID:29740456

Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared with prior prostaglandin therapy

Directory of Open Access Journals (Sweden)

J Charles Henry

2008-10-01

Full Text Available J Charles Henry1, James H Peace2, Jeanette A Stewart3,4, William C Stewart3,41Little Rock Eye Clinic, Little Rock, AR, USA; 2Diabetic Eye Medical Clinic, Inglewood, CA, USA; 3PRN Pharmaceutical Research Network, LLC, Dallas,TX, USA; 4Carolina Eye Institute, University of South Carolina, School of Medicine, Columbia, SC, USAPurpose: To evaluate the efficacy, safety and tolerability of changing to travoprost BAK-free from prior prostaglandin therapy in patients with primary open-angle glaucoma or ocular hypertension.Design: Prospective, multi-center, historical control study.Methods: Patients treated with latanoprost or bimatoprost who needed alternative therapy due to tolerability issues were enrolled. Patients were surveyed using the Ocular Surface Disease Index (OSDI to evaluate OSD symptoms prior to changing to travoprost BAK-free dosed once every evening. Patients were re-evaluated 3 months later.Results: In 691 patients, travoprost BAK-free demonstrated improved mean OSDI scores compared to either latanoprost or bimatoprost (p < 0.0001. Patients having any baseline OSD symptoms (n = 235 demonstrated significant improvement after switching to travoprost BAK-free (p < 0.0001. In 70.2% of these patients, symptoms were reduced in severity by at least 1 level. After changing medications to travoprost BAK-free, mean intraocular pressure (IOP was significantly decreased (p < 0.0001. Overall, 72.4% preferred travoprost BAK-free (p < 0.0001, travoprost BAK-free vs prior therapy. Travoprost BAK-free demonstrated less conjunctival hyperemia than either prior therapy (p < 0.0001.Conclusions: Patients previously treated with a BAK-preserved prostaglandin analog who are changed to travoprost BAK-free have clinically and statistically significant improvement in their OSD symptoms, decreased hyperemia, and equal or better IOP control.Keywords: glaucoma, prostaglandin analog, travoprost, latanoprost, bimatoprost, preservative, benzalkonium chloride

Enhanced Accident Tolerant LWR Fuels National Metrics Workshop Report

Energy Technology Data Exchange (ETDEWEB)

Lori Braase

2013-01-01

The U.S. Department of Energy Office of Nuclear Energy (DOE-NE), in collaboration with the nuclear industry, has been conducting research and development (R&D) activities on advanced Light Water Reactor (LWR) fuels for the last few years. The emphasis for these activities was on improving the fuel performance in terms of increased burnup for waste minimization and increased power density for power upgrades, as well as collaborating with industry on fuel reliability. After the events at the Fukushima Nuclear Power Plant in Japan in March 2011, enhancing the accident tolerance of LWRs became a topic of serious discussion. In the Consolidated Appropriations Act, 2012, Conference Report 112-75, the U.S. Congress directed DOE-NE to: • Give “priority to developing enhanced fuels and cladding for light water reactors to improve safety in the event of accidents in the reactor or spent fuel pools.” • Give “special technical emphasis and funding priority…to activities aimed at the development and near-term qualification of meltdown-resistant, accident-tolerant nuclear fuels that would enhance the safety of present and future generations of light water reactors.” • Report “to the Committee, within 90 days of enactment of this act, on its plan for development of meltdown-resistant fuels leading to reactor testing and utilization by 2020.” Fuels with enhanced accident tolerance are those that, in comparison with the standard UO2-zirconium alloy system currently used by the nuclear industry, can tolerate loss of active cooling in the reactor core for a considerably longer time period (depending on the LWR system and accident scenario) while maintaining or improving the fuel performance during normal operations, and operational transients, as well as design-basis and beyond design-basis events. The overall draft strategy for development and demonstration is comprised of three phases: Feasibility Assessment and Down-selection; Development and Qualification; and

A prospective clinical study to evaluate the safety and performance of wireless localization of nonpalpable breast lesions using radiofrequency identification technology.

Science.gov (United States)

Dauphine, Christine; Reicher, Joshua J; Reicher, Murray A; Gondusky, Christina; Khalkhali, Iraj; Kim, Michelle

2015-06-01

The purpose of this study was to evaluate the safety and performance of localizing nonpalpable breast lesions using radiofrequency identification technology. Twenty consecutive women requiring preoperative localization of a breast lesion were recruited. Subjects underwent placement of both a hook wire and a radiofrequency identification tag immediately before surgery. The radiofrequency identification tag was the primary method used by the operating surgeon to localize each lesion during excision, with the hook wire serving as backup in case of tag migration or failed localization. Successful localization with removal of the intended lesion was the primary outcome measured. Tag migration and postoperative infection were also noted to assess safety. Twenty patients underwent placement of a radiofrequency identification tag, 12 under ultrasound guidance and eight with stereotactic guidance. In all cases, the radiofrequency identification tag was successfully localized by the reader at the level of the skin before incision, and the intended lesion was removed along with the radiofrequency identification tag. There were no localization failures and no postoperative infections. Tag migration did not occur before incision, but in three cases, occurred as the lesion was being retracted with fingers to make the final cut along the deep surface of the specimen. In this initial clinical study, radiofrequency tags were safe and able to successfully localize nonpalpable breast lesions. Radiofrequency identification technology may represent an alternative method to hook wire localization.

78 FR 20277 - Safety Zones & Special Local Regulations; Recurring Marine Events in Captain of the Port Long...

Science.gov (United States)

2013-04-04

.... Regulatory History and Information The Coast Guard promulgated safety zones and special local regulations for... first week of July. Location: Waters of the Connetquot River off Snapper Inn Restaurant, Oakdale, NY in...: Waters of Patchogue Bay off ``Lombardi's On the Bay'' restaurant, Patchogue, NY in approximate position...

Simulation of a G-tolerance curve using the pulsatile cardiovascular model

Science.gov (United States)

Solomon, M.; Srinivasan, R.

1985-01-01

A computer simulation study, performed to assess the ability of the cardiovascular model to reproduce the G tolerance curve (G level versus tolerance time) is reported. A composite strength duration curve derived from experimental data obtained in human centrifugation studies was used for comparison. The effects of abolishing automomic control and of blood volume loss on G tolerance were also simulated. The results provide additional validation of the model. The need for the presence of autonomic reflexes even at low levels of G is pointed out. The low margin of safety with a loss of blood volume indicated by the simulation results underscores the necessity for protective measures during Shuttle reentry.

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.

Science.gov (United States)

Eckburg, Paul B; Ge, Yigong; Hafkin, Barry

2017-04-01

A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections. Copyright © 2017 American Society for Microbiology.

Safety, tolerability, and biomarkers of the treatment of mice with aerosolized toll-like receptor ligands

Directory of Open Access Journals (Sweden)

Victoria eAlfaro

2014-02-01

Full Text Available We have previously discovered a synergistically therapeutic combination of two Toll-like receptor (TLR ligands, an oligodeoxynucleotide (ODN and Pam2CSK4. Aerosolization of these ligands stimulates innate immunity within the lungs to prevent pneumonia from bacterial and viral pathogens. Here we examined the safety and tolerability of this treatment in mice, and characterized the expression of biomarkers of innate immune activation. We found that neutrophils appeared in lung lavage fluid 4 hours after treatment, reached a peak at 48 hours, and resolved by 7 days. The peak of neutrophil influx was accompanied by a small increase in lung permeability. Despite the abundance of neutrophils in lung lavage fluid, only rare neutrophils were visible histopathologically in the interstitium surrounding bronchi and veins and none were visible in alveolar airspaces. The cytokines IL-6, TNF and CXCL2 rose several hundred-fold in lung lavage fluid 4 hours after treatment in a dose-dependent and synergistic manner, providing useful biomarkers of lung activation. IL-6 rose five-fold in serum with delayed kinetics compared to its rise in lavage fluid, and might serve as a systemic biomarker of immune activation of the lungs. The dose-response relationship of lavage fluid cytokines was preserved in mice that underwent myeloablative treatment with cytosine arabinoside to model the treatment of hematologic malignancy. There were no overt signs of distress in mice treated with ODN/Pam2CSK4 in doses up to 8-fold the therapeutic dose, and no changes in temperature, respiratory rate, or behavioral signs of sickness including sugar water preference, food disappearance, cage exploration or social interaction, though there was a small degree of transient weight loss. We conclude that treatment with aerosolized ODN/Pam2CSK4 is well tolerated in mice, and that innate immune activation of the lungs can be monitored by the measurement of inflammatory cytokines in lung lavage

Columbus safety and reliability

Science.gov (United States)

Longhurst, F.; Wessels, H.

1988-10-01

Analyses carried out to ensure Columbus reliability, availability, and maintainability, and operational and design safety are summarized. Failure modes/effects/criticality is the main qualitative tool used. The main aspects studied are fault tolerance, hazard consequence control, risk minimization, human error effects, restorability, and safe-life design.

Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program

DEFF Research Database (Denmark)

See, William A; Wirth, Manfred P; McLeod, David G

2002-01-01

We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer.......We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer....

Distress tolerance as a predictor of risky and aggressive driving.

Science.gov (United States)

Beck, Kenneth H; Ali, Bina; Daughters, Stacey B

2014-01-01

The purpose of this investigation was to determine the relationship between distress tolerance and risky and aggressive driving. Distress tolerance, defined as an individual's capability to experience and endure negative emotional states, was hypothesized to be related negatively to aggressive driving and risky driving. An anonymous, web-based survey of 769 college students was conducted at a large East Coast university. After controlling for age, gender, race, ethnicity, year in school, grade point average, and driving frequency, distress tolerance was significantly inversely related to reported risky driving and aggressive driving. College drivers who have a diminished capacity to endure frustration without experiencing negative emotional states (i.e., low distress tolerance) tend to drive aggressively and in a risky manner. Traditional deterrence-based approaches to highway safety may benefit from inclusion of a wider array of prevention strategies that focus on emotion regulation while driving.

Evaluation of local tolerance of the antiretroviral spermicide (WHI-07)-loaded gel-microemulsion in the porcine female reproductive tract.

Science.gov (United States)

D'Cruz, Osmond J; Uckun, Fatih M

2008-04-01

The local tolerance of the antiretroviral spermicide, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate)-loaded gel-microemulsion was evaluated in a physiologically relevant and sensitive porcine model. Gilts (Duroc) in nonestrus stages of the reproductive cycle received either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for 6 days. Cervicovaginal lavage (CVL) fluid was obtained for up to 72 h after a single exposure and the cellular profile and levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) were quantitated by flow cytometry and chemiluminescence-based multiplex immunoassay, respectively. The reproductive tract (vagina, cervix, uteri and Fallopian tubes) harvested on day 7 was scored histologically for evidence of mucosal irritation using a new scoring criterion for ten histological endpoints that reflect pathological changes in the epithelial/ subepithelial and vascular/perivascular compartments. When compared with irritant reactions caused by the detergent-type spermicide, benzalkonium chloride (BZK), the scatter profile of CVL immune cells and basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) in CVL fluid were unaffected by intravaginal exposure to 2% WHI-07. Unlike BZK, endpoint histology of the proximal and distal regions of the reproductive tract from gilts treated with 2.0% WHI-07 via gel-microemulsion for 6 days did not result in mucosal irritation or alteration in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues and underlying/surrounding muscles. Based on surrogate markers for inflammation, leukocyte profile and histologic data for local tolerance, repeated intravaginal administration of WHI-07 via gel-microemulsion as a prophylactic contraceptive is unlikely to cause vaginal irritation.

Fault-Tolerant Consensus of Multi-Agent System With Distributed Adaptive Protocol.

Science.gov (United States)

Chen, Shun; Ho, Daniel W C; Li, Lulu; Liu, Ming

2015-10-01

In this paper, fault-tolerant consensus in multi-agent system using distributed adaptive protocol is investigated. Firstly, distributed adaptive online updating strategies for some parameters are proposed based on local information of the network structure. Then, under the online updating parameters, a distributed adaptive protocol is developed to compensate the fault effects and the uncertainty effects in the leaderless multi-agent system. Based on the local state information of neighboring agents, a distributed updating protocol gain is developed which leads to a fully distributed continuous adaptive fault-tolerant consensus protocol design for the leaderless multi-agent system. Furthermore, a distributed fault-tolerant leader-follower consensus protocol for multi-agent system is constructed by the proposed adaptive method. Finally, a simulation example is given to illustrate the effectiveness of the theoretical analysis.

Risk assessment of safety data link and network communication in digital safety feature control system of nuclear power plant

International Nuclear Information System (INIS)

Lee, Sang Hun; Son, Kwang Seop; Jung, Wondea; Kang, Hyun Gook

2017-01-01

Highlights: • Safety data communication risk assessment framework and quantitative scheme were proposed. • Fault-tree model of ESFAS unavailability due to safety data communication failure was developed. • Safety data link and network risk were assessed based on various ESF-CCS design specifications. • The effect of fault-tolerant algorithm reliability of safety data network on ESFAS unavailability was assessed. - Abstract: As one of the safety-critical systems in nuclear power plants (NPPs), the Engineered Safety Feature-Component Control System (ESF-CCS) employs safety data link and network communication for the transmission of safety component actuation signals from the group controllers to loop controllers to effectively accommodate various safety-critical field controllers. Since data communication failure risk in the ESF-CCS has yet to be fully quantified, the ESF-CCS employing data communication systems have not been applied in NPPs. This study therefore developed a fault tree model to assess the data link and data network failure-induced unavailability of a system function used to generate an automated control signal for accident mitigation equipment. The current aim is to provide risk information regarding data communication failure in a digital safety feature control system in consideration of interconnection between controllers and the fault-tolerant algorithm implemented in the target system. Based on the developed fault tree model, case studies were performed to quantitatively assess the unavailability of ESF-CCS signal generation due to data link and network failure and its risk effect on safety signal generation failure. This study is expected to provide insight into the risk assessment of safety-critical data communication in a digitalized NPP instrumentation and control system.

Efficacy, tolerability, and safety of hypnosis in adult irritable bowel syndrome: systematic review and meta-analysis.

Science.gov (United States)

Schaefert, Rainer; Klose, Petra; Moser, Gabriele; Häuser, Winfried

2014-06-01

To assess the efficacy, tolerability, and safety of hypnosis in adult irritable bowel syndrome by a meta-analysis of randomized controlled trials. Studies were identified by a literature search of the databases Allied and Complementary Medicine Database, Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PubMed, PsycINFO, and Scopus (from inception to June 30, 2013). Primary outcomes were adequate symptom relief, global gastrointestinal score, and safety. Summary relative risks (RRs) with number needed to treat (NNT) and standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated using random-effects models. Eight randomized controlled trials with a total of 464 patients and a median of 8.5 (7-12) hypnosis sessions over a median of 12 (5-12) weeks were included into the analysis. At the end of therapy, hypnosis was superior to control conditions in producing adequate symptom relief (RR, 1.69 [95% CI = 1.14-2.51]; NNT, 5 [3-10]) and in reducing global gastrointestinal score (SMD, 0.32 [95% CI = -0.56 to -0.08]). At long-term follow-up, hypnosis was superior to controls in adequate symptom relief (RR, 2.17 [95% CI = 1.22-3.87]; NNT, 3 [2-10]), but not in reducing global gastrointestinal score (SMD, -0.57 [-1.40 to 0.26]). One (0.4%) of 238 patients in the hypnosis group dropped out due to an adverse event (panic attack). This meta-analysis demonstrated that hypnosis was safe and provided long-term adequate symptom relief in 54% of patients with irritable bowel syndrome refractory to conventional therapy.

Entry limitations and heterogeneous tolerances in a Schelling-like segregation model

International Nuclear Information System (INIS)

Radi, Davide; Gardini, Laura

2015-01-01

In this paper we consider a Schelling-type segregation model with two groups of agents that differ in some aspects, such as religion, political affiliation or color of skin. The first group is identified as the local population, while the second group is identified as the newcomers, whose members want to settle down in the city or country, or more generally a system, already populated by members of the local population. The members of the local population have a limited tolerance towards newcomers. On the contrary, some newcomers, but not all of them, may stand the presence of any amount of members of the local population. The heterogeneous, and partially limited, levels of tolerance trigger an entry and exit dynamics into and from the system of the members of the two groups based on their satisfaction with the number of members of the other group into the system. This entry/exit dynamics is described by a continuous piecewise-differentiable map in two dimensions. The dynamics of the model is characterized by smooth bifurcations as well as by border collision bifurcations. A combination of analytical results and numerical analysis are the main tools used to describe the quite complicated local and global dynamics of the model. The investigation reveals that two factors are the main elements that preclude integration. The first one is a low level of tolerance of the members of the two populations. The second one is an excessive and unbalanced level of tolerance between the two populations. In this last case, to facilitate the integration between members of the two groups, we impose an entry-limitation policy represented by the imposition of a maximum number of newcomers allowed to enter the system. The investigation of the dynamics reveals that the entry-limitation policy is useful to promote integration as it limits the negative effects due to excessive and unbalanced levels of tolerance.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

Science.gov (United States)

Kendall, Richard; Lenoir, Joke; Gerrard, Stephen; Scheuerle, Rebekah L; Slater, Nigel K H; Tuleu, Catherine

2017-04-01

Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women.

Science.gov (United States)

Hughes, T E; Kim, D D; Marjason, J; Proietto, J; Whitehead, J P; Vath, J E

2013-09-01

Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. Thirty-one obese (mean BMI 38 kg/m2) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in β-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin. Copyright © 2013 The Obesity Society.

Child Work Safety on the Farms of Local Agricultural Market Producers: Parent and Child Perspectives.

Science.gov (United States)

Summers, Phillip; Quandt, Sara A; Spears Johnson, Chaya R; Arcury, Thomas A

2018-01-01

Agriculture is a hazardous industry, yet there are few regulations on the ages at which children may engage in farm work. Local agricultural market producers (LAMPs) are a growing subset of farmers within "sustainable agriculture" who engage in direct-to-consumer and direct-to-retailer enterprises. This study explores the occupational health and safety perceptions of parents and children for children who work on their families' LAMP farms. In-depth interviews were conducted with 12 parent-child dyads from LAMP farms in Illinois and North Carolina. Four themes emerged from these 24 interviews; parents and children perceived that: (1) the nature of small farms makes them safer than industrial agricultural operations; (2) child safety on farms is common sense; (3) avoiding hazardous tasks keeps children safe; and (4) parents know best (compared to regulations) about ways to keep their children safe. Some of these themes echo the results of earlier studies conducted with more conventional farms. Further research is needed to develop programs to improve child occupational safety on LAMP farms.

Public 'in'tolerance of technological hazards and risk policy

International Nuclear Information System (INIS)

Simmons, P.; Walker, G.; Irwin, A.; Wynne, B.

1998-01-01

Full text of publication follows: it has been recognised that the notion that there is an 'acceptable' level of risk to the public from technological hazards is in many cases inappropriate. UK government policy on major industrial hazards is informed by the principle of 'tolerability' of risk (TOR). In the paper we examine this principle and how it relates to the views of people who live day-to-day with such hazards. The analysis of public views is based on the results of a Q-method study carried out in the course of recent research funded by the UK Health and Safety Executive. The Q-method study distinguishes between different bases of public toleration - and lack of toleration - of risk. The study found lack a toleration to be based on a single cluster of factors, whereas the bases for public toleration of risk were far more differentiated. The results are outlined in the paper. In the concluding section of the paper we examine the implications of these results for policy, in particular for the application of the TOR principle when setting risk criteria. (authors)

Safety and tolerability of repetitive transcranial magnetic stimulation in patients with pathologic positive sensory phenomena: a review of literature

Science.gov (United States)

Muller, Paul A; Pascual-Leone, Alvaro; Rotenberg, Alexander

2013-01-01

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is emerging as a valuable therapeutic and diagnostic tool. rTMS appears particularly promising for disorders characterized by positive sensory phenomena attributable to alterations in sensory cortex excitability. Among these are tinnitus, auditory and visual hallucinations, and pain syndromes. OBJECTIVE Despite studies addressing rTMS efficacy in suppression of positive sensory symptoms, the safety of stimulation of potentially hyperexcitable cortex has not been fully addressed. We performed a systematic literature review and metanalysis to describe the rTMS safety profile in these disorders. METHODS Using the PubMed database, we performed an English-language literature search from January 1985 to April 2011 to review all pertinent publications. Per study, we noted and listed pertinent details. From these data we also calculated a crude per-subject risk for each adverse event. RESULTS 106 publications (n = 1815 subjects) were identified with patients undergoing rTMS for pathologic positive sensory phenomena. Adverse events associated with rTMS were generally mild and occurred in 16.7% of subjects. Seizure was the most serious adverse event, and occurred in three patients with a 0.16% crude per-subject risk. The second most severe adverse event involved aggravation of sensory phenomena, occurring in 1.54%. CONCLUSIONS The published data suggest rTMS for the treatment or diagnosis of pathologic positive sensory phenomena appears to be a relatively safe and well-tolerated procedure. However, published data are lacking in systematic reporting of adverse events, and safety risks of rTMS in these patient populations will have to be addressed in future prospective trials. PMID:22322098

CORAL REEFS. Genomic determinants of coral heat tolerance across latitudes.

Science.gov (United States)

Dixon, Groves B; Davies, Sarah W; Aglyamova, Galina A; Meyer, Eli; Bay, Line K; Matz, Mikhail V

2015-06-26

As global warming continues, reef-building corals could avoid local population declines through "genetic rescue" involving exchange of heat-tolerant genotypes across latitudes, but only if latitudinal variation in thermal tolerance is heritable. Here, we show an up-to-10-fold increase in odds of survival of coral larvae under heat stress when their parents come from a warmer lower-latitude location. Elevated thermal tolerance was associated with heritable differences in expression of oxidative, extracellular, transport, and mitochondrial functions that indicated a lack of prior stress. Moreover, two genomic regions strongly responded to selection for thermal tolerance in interlatitudinal crosses. These results demonstrate that variation in coral thermal tolerance across latitudes has a strong genetic basis and could serve as raw material for natural selection. Copyright © 2015, American Association for the Advancement of Science.

Radiation tolerance of the vaginal mucosa

International Nuclear Information System (INIS)

Hintz, b.L.; Kagan, A.R.; Chan, P.; Gilbert, H.A.; Nussbaum, H.; Rao, A.R.; Wollin, M.

1980-01-01

Sixteen patients with cancer of the vagina that were controlled locally for a minimum of eighteen months after teletherpay (T) or brachytherapy (B) or both (T and B), were analyzed for radiation tolerance of the vaginal mucosa. The site of vaginal necrosis did not always coincide with the site of the tumor. The posterior wall appeared more vulnerable than the anterior or lateral walls. For the distal vaginal mucosa, necrosis requiring surgical intervention occurred following combined T and B, if summated rad exceeded9800. The upper vagina tolerated higher dosages. No patient surgery for upper vaginal necrosis even though summated (T and B) dosage up to 14,000 rad was applied. Placing radioactive needles on the surface of the vaginal cylinder with or without interstitial perincal needles should be avoided. Further accumulation of data is needed to define these vaginal mucosa tolerance limits more closely

Artificial sweeteners and mixture of food additives cause to break oral tolerance and induce food allergy in murine oral tolerance model for food allergy.

Science.gov (United States)

Yamashita, H; Matsuhara, H; Miotani, S; Sako, Y; Matsui, T; Tanaka, H; Inagaki, N

2017-09-01

Processed foods are part of daily life. Almost all processed foods contain food additives such as sweeteners, preservatives and colourants. From childhood, it is difficult to avoid consuming food additives. It is thought that oral tolerance for food antigens is acquired during early life. If tolerance fails, adverse immune responses to food proteins may occur. We hypothesized that food additives prevent acquisition of oral tolerance and aimed to verify the safety of food additives. We induced experimental oral tolerance in mice for ovalbumin (OVA), a food antigen, by previous oral treatment with OVA before sensitization with OVA injections. Food additives were administered at the induction of oral tolerance, and food allergy was induced by repeated administration of OVA. Symptoms of food allergy were defined as a change in body temperature and allergic diarrhoea. Saccharin sodium and a mixture of food additives inhibited acquisition of oral tolerance. Hypothermia and allergic diarrhoea with elevation of OVA-specific IgE were induced in the murine model of oral tolerance. Analyses of antigen-presenting cells in mesenteric lymph nodes showed that food additives affected their manner of migration. Additionally, food additives decreased the proportion of CD25 hi regulatory T cells among CD4 + T cells in the mesenteric lymph nodes. A large amount of food additives may prevent acquisition of oral tolerance. Intake of food additives in early life may increase the risk of food allergies. © 2017 John Wiley & Sons Ltd.

The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction.

Science.gov (United States)

Ventimiglia, Eugenio; Capogrosso, Paolo; Montorsi, Francesco; Salonia, Andrea

2016-01-01

Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well-tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated.

Safety, Tolerability, and Immunogenicity of Interferons

Directory of Open Access Journals (Sweden)

Michael G. Tovey

2010-04-01

Full Text Available Interferons (IFNs are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are “flu-like” symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1 and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFN�

A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.

Science.gov (United States)

Dean, Emma; Banerji, Udai; Schellens, Jan H M; Krebs, Matthew G; Jimenez, Begona; van Brummelen, Emilie; Bailey, Chris; Casson, Ed; Cripps, Diana; Cullberg, Marie; Evans, Stephen; Foxley, Andrew; Lindemann, Justin; Rugman, Paul; Taylor, Nigel; Turner, Guy; Yates, James; Lawrence, Peter

2018-05-01

AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet. Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and C max ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2). In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and C max were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later t max and lower C max after food versus overnight fast. Fed and fasted AUCτ and C max ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states. PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Safety and tolerability of tegaserod in patients with chronic constipation: pooled data from two phase III studies.

LENUS (Irish Health Repository)

Quigley, Eamonn M M

2012-02-03

BACKGROUND & AIMS: Studies show that tegaserod effectively relieves the symptoms of chronic constipation\\/idiopathic constipation (CC). This pooled analysis assessed the safety and tolerability of tegaserod in a large dataset of CC patients. METHODS: Adverse event (AE) data were pooled from 2 double-blind, placebo-controlled phase III trials of 12 weeks\\' duration. Post hoc analysis was conducted for the most frequent AEs (incidence, >or=3%). RESULTS: Eight hundred eighty-one, 861, and 861 patients received tegaserod 6 mg twice a day, 2 mg twice a day, or placebo, respectively. Most AEs were mild\\/moderately severe. AE incidence was similar for the tegaserod 6 mg and 2 mg twice a day (57.1% and 56.3%, respectively) and placebo groups (59.6%) and most frequent in the gastrointestinal system (tegaserod 6 mg twice a day, 25.8%; 2 mg twice a day, 22.5%; placebo, 24.6%). Headache, the most common AE, was slightly more frequent in the placebo group (tegaserod 6 mg twice a day, 11.0%; 2 mg twice a day, 10.1%; placebo, 13.2%). Diarrhea (generally transient and resolved with continued treatment) was the only AE with a statistically significant difference between groups (tegaserod 6 mg twice a day 6.6% vs placebo 3.0%, P=.0005). Serious AE incidence (1.4% overall) was comparable across treatment groups, although abdominal surgery was less common in the combined tegaserod (0.5%) than the placebo group (1.0%). Discontinuation as a result of AEs was slightly higher in tegaserod 6 mg twice a day patients (5.7%; 2 mg twice a day, 3.3%; placebo, 3.7%), mainly because of diarrhea. Laboratory and electrocardiogram parameters were comparable across groups. CONCLUSIONS: Tegaserod is well tolerated by patients with CC during 12 weeks of treatment.

Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs: a blind, randomized, placebo-controlled study.

Science.gov (United States)

Maina, E; Pelst, M; Hesta, M; Cox, E

2017-01-18

Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healthy dogs before testing it in food allergic dogs. Eight experimental healthy beagle dogs, never orally exposed to peanut, were randomized in two groups to receive SLIT with peanut or placebo for 4 months. Subjects were monitored daily for local and systemic adverse effects. Blood samples for complete blood count and serum biochemistry, and urine for urinalysis were collected and the dogs' body weight was recorded at day 0, 35 and 119 of the SLIT treatment. Sera for the determination of peanut-specific IgG and IgE were collected at day 0, 35, 49, 70, 91, 105 and 119. Intradermal tests were performed before (day 0) and after (day 119) the experiment. The content of each dispenser used to administer treatment or placebo was tested for sterility after usage. In order to assess the presence or absence of sensitization, dogs were challenged 6 months after the end of the study with 2000 μg of peanut extract daily for 7 to 14 days. All dogs completed the study. The treatment did not provoke either local or systemic side-effects. Peanut-specific IgG significantly increased in treatment group. Even though a significant increase in peanut-specific IgE was also seen, intradermal tests were negative in all dogs before and after the experiment, and the challenge test did not trigger any adverse reactions in the treated dogs, which shows the protocol did not cause sensitization to peanut, but nevertheless primed the immune system as indicated by the humoral immune response. All dispenser solutions

Tolerance

DEFF Research Database (Denmark)

Tønder, Lars

is linked to a different set of circumstances than the ones suggested by existing models in contemporary democratic theory. Reorienting the discussion of tolerance, the book raises the question of how to disclose new possibilities within our given context of affect and perception. Once we move away from......Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...

Task Migration for Fault-Tolerance in Mixed-Criticality Embedded Systems

DEFF Research Database (Denmark)

Saraswat, Prabhat Kumar; Pop, Paul; Madsen, Jan

2009-01-01

In this paper we are interested in mixed-criticality embedded applications implemented on distributed architectures. Depending on their time-criticality, tasks can be hard or soft real-time and regarding safety-criticality, tasks can be fault-tolerant to transient faults, permanent faults, or have...... processors, such that the faults are tolerated, the deadlines for the hard real-time tasks are satisfied and the QoS for soft tasks is maximized. The proposed online adaptive approach has been evaluated using several synthetic benchmarks and a real-life case study....... no dependability requirements. We use Earliest Deadline First (EDF) scheduling for the hard tasks and the Constant Bandwidth Server (CBS) for the soft tasks. The CBS parameters determine the quality of service (QoS) of soft tasks. Transient faults are tolerated using checkpointing with roll- back recovery...

Rapeseed with tolerance to the non selective herbicide glufosinate ammonium

Energy Technology Data Exchange (ETDEWEB)

Rasche, E. [Hoechst Schering AgrEvo GmbH, Frankfurt am Main (Germany)

1998-12-31

Weed control with herbicides is essential to grow rapeseed. Glufosinate Ammonium is used as a non selective herbicide successfully in many countries for over 10 years. It conforms well with ever increasing safety standards for human beings, animals and the environment. The tolerance of rapeseed and other crop plants was achieved by genetic modification. A resistance gene (PAT or BAR) was transfered into previously susceptible rapeseed plants. This new approach allowed the development of Glufosinate Ammonium as an almost ideal selective herbicide. In cooperation with major seed companies and by own breeding programmes new Glufosinate tolerant rapeseed varieties and hybrids are developed. Data on metabolism, toxicity, residues, efficacy etc. were generated to get registration for the selective herbicide use. In addition various studies were done for safety assessments of the PAT gene and the modified rapeseed. In spring 1995 Canadian authorities granted worldwide the first approvals for the selective use of Glufosinate Ammonium (trademark Liberty) and Glufosinate tolerant (trademark and logo Liberty Link) spring rapeseed (Canola). After a successful launch in 1995 about 150.000 ha of Liberty Link Canola were grown and treated with Liberty in 1996. The Liberty Link Canola growers were very well satisfied. In a grower survey 84% stated that they will definitely use the Liberty Link System again. In Europe registrations for Glufosinate Ammonium as a selective herbicide and for the first Glufosinate tolerant rapeseed varieties are expected in the course of 1997. The Liberty Link System will be launched in rapeseed most probably in 1998. (orig.)

[Systemic approach to ecologic safety at objects with radiation jeopardy, involved into localization of low and medium radioactive waste].

Science.gov (United States)

Veselov, E I

2011-01-01

The article deals with specifying systemic approach to ecologic safety of objects with radiation jeopardy. The authors presented stages of work and algorithm of decisions on preserving reliability of storage for radiation jeopardy waste. Findings are that providing ecologic safety can cover 3 approaches: complete exemption of radiation jeopardy waste, removal of more dangerous waste from present buildings and increasing reliability of prolonged localization of radiation jeopardy waste at the initial place. The systemic approach presented could be realized at various radiation jeopardy objects.

Accident tolerant fuel analysis

International Nuclear Information System (INIS)

2014-01-01

Safety is central to the design, licensing, operation, and economics of Nuclear Power Plants (NPPs). Consequently, the ability to better characterize and quantify safety margin holds the key to improved decision making about light water reactor design, operation, and plant life extension. A systematic approach to characterization of safety margins and the subsequent margins management options represents a vital input to the licensee and regulatory analysis and decision making that will be involved. The purpose of the Risk Informed Safety Margin Characterization (RISMC) Pathway research and development (R&D) is to support plant decisions for risk-informed margins management by improving economics and reliability, and sustaining safety, of current NPPs. Goals of the RISMC Pathway are twofold: (1) Develop and demonstrate a risk-assessment method coupled to safety margin quantification that can be used by NPP decision makers as part of their margin recovery strategies. (2) Create an advanced ''RISMC toolkit'' that enables more accurate representation of NPP safety margin. In order to carry out the R&D needed for the Pathway, the Idaho National Laboratory is performing a series of case studies that will explore methods- and tools-development issues, in addition to being of current interest in their own right. One such study is a comparative analysis of safety margins of plants using different fuel cladding types: specifically, a comparison between current-technology Zircaloy cladding and a notional ''accident-tolerant'' (e.g., SiC-based) cladding. The present report begins the process of applying capabilities that are still under development to the problem of assessing new fuel designs. The approach and lessons learned from this case study will be included in future Technical Basis Guides produced by the RISMC Pathway. These guides will be the mechanism for developing the specifications for RISMC tools and for defining how plant

Variation in genotoxic stress tolerance among frog populations exposed to UV and pollutant gradients

International Nuclear Information System (INIS)

Marquis, Olivier; Miaud, Claude; Ficetola, Gentile Francesco; Bocher, Aurore; Mouchet, Florence; Guittonneau, Sylvie; Devaux, Alain

2009-01-01

Populations of widely distributed species can be subjected to unequal selection pressures, producing differences in rates of local adaptation. We report a laboratory experiment testing tolerance variation to UV-B and polycyclic aromatic hydrocarbons (PAHs) among common frog (Rana temporaria) populations according to their natural exposure level in the field. Studied populations were naturally distributed along two gradients, i.e. UV-B radiation with altitude and level of contamination by PAHs with the distance to emitting sources (road traffic). Tadpoles from eight populations were subjected to (1) no or high level of artificial UV-B; (2) four concentrations of benzo[a]pyrene (BaP) (0, 50, 250, 500 μg L -1 ); (3) simultaneously to UV-B and BaP. Since both stressors are genotoxic, the number of micronucleated erythrocytes (MNE) in circulating red blood cells was used as a bioindicator of tadpole sensitivity. High-altitude populations appear to be locally adapted to better resist UV-B genotoxicity, as they showed the lowest MNE numbers. Conversely, no correlation was observed between levels of PAH contamination in the field and tadpole tolerance to BaP in the laboratory, indicating the absence of local adaptation for BaP tolerance in these populations. Nevertheless, the decrease of MNE formation due to BaP exposure with altitude suggests that high-altitude populations were intrinsically more resistant to BaP genotoxicity. We propose the hypothesis of a co-tolerance between UV-B and BaP in high-altitude common frog populations: local adaptation to prevent and/or repair DNA damage induced by UV-B could also protect these highland populations against DNA damage induced by BaP. The results of this study highlight the role of local adaptation along pollutant gradients leading to tolerance variation, which implies that is it necessary to take into account the history of exposure of each population and the existence of co-tolerance that can hide toxic effects of a new

Variation in genotoxic stress tolerance among frog populations exposed to UV and pollutant gradients

Energy Technology Data Exchange (ETDEWEB)

Marquis, Olivier [Laboratoire d' Ecologie Alpine, UMR CNRS 5553, Universite de Savoie, Technolac, Le Bourget du Lac (France); Miaud, Claude, E-mail: claude.miaud@univ-savoie.fr [Laboratoire d' Ecologie Alpine, UMR CNRS 5553, Universite de Savoie, Technolac, Le Bourget du Lac (France); Ficetola, Gentile Francesco [Laboratoire d' Ecologie Alpine, UMR CNRS 5553, Universite de Savoie, Technolac, Le Bourget du Lac (France); Department of Biology, Universita degli Studi di Milano, Milan (Italy); Bocher, Aurore [Laboratoire de Chimie Moleculaire et Environnement, Universite de Savoie, Le Bourget du Lac (France); Mouchet, Florence [Laboratoire d' Ecologie Fonctionnelle, UMR CNRS-UPS-INPT 5245, Institut National Polytechnique-ENSAT, Auzeville-Tolosane (France); Guittonneau, Sylvie [Laboratoire de Chimie Moleculaire et Environnement, Universite de Savoie, Le Bourget du Lac (France); Devaux, Alain [Laboratoire des Sciences de l' Environnement, Ecole Nationale des Travaux Publics de l' Etat, INRA-EFPA, Vaulx-en-Velin (France)

2009-11-08

Populations of widely distributed species can be subjected to unequal selection pressures, producing differences in rates of local adaptation. We report a laboratory experiment testing tolerance variation to UV-B and polycyclic aromatic hydrocarbons (PAHs) among common frog (Rana temporaria) populations according to their natural exposure level in the field. Studied populations were naturally distributed along two gradients, i.e. UV-B radiation with altitude and level of contamination by PAHs with the distance to emitting sources (road traffic). Tadpoles from eight populations were subjected to (1) no or high level of artificial UV-B; (2) four concentrations of benzo[a]pyrene (BaP) (0, 50, 250, 500 {mu}g L{sup -1}); (3) simultaneously to UV-B and BaP. Since both stressors are genotoxic, the number of micronucleated erythrocytes (MNE) in circulating red blood cells was used as a bioindicator of tadpole sensitivity. High-altitude populations appear to be locally adapted to better resist UV-B genotoxicity, as they showed the lowest MNE numbers. Conversely, no correlation was observed between levels of PAH contamination in the field and tadpole tolerance to BaP in the laboratory, indicating the absence of local adaptation for BaP tolerance in these populations. Nevertheless, the decrease of MNE formation due to BaP exposure with altitude suggests that high-altitude populations were intrinsically more resistant to BaP genotoxicity. We propose the hypothesis of a co-tolerance between UV-B and BaP in high-altitude common frog populations: local adaptation to prevent and/or repair DNA damage induced by UV-B could also protect these highland populations against DNA damage induced by BaP. The results of this study highlight the role of local adaptation along pollutant gradients leading to tolerance variation, which implies that is it necessary to take into account the history of exposure of each population and the existence of co-tolerance that can hide toxic effects of a

DsSWEET17, a Tonoplast-Localized Sugar Transporter from Dianthus spiculifolius, Affects Sugar Metabolism and Confers Multiple Stress Tolerance in Arabidopsis

Directory of Open Access Journals (Sweden)

Aimin Zhou

2018-05-01

Full Text Available Plant SWEETs (Sugars Will Eventually be Exported Transporters affect the growth of plants by regulating the transport of sugar from source to sink and its intracellular transport between different organelles. In this study, DsSWEET17 from Dianthus spiculifolius was identified and characterized. Real-time quantitative PCR analysis revealed that the expression of DsSWEET17 was affected by exogenous application of fructose and glucose as well as under salt, osmotic, and oxidation stress. Colocalization experiments showed that the DsSWEET17-GFP (green fluorescent protein fusion protein was localized to the FM4-64-labeled tonoplasts in Arabidopsis. Compared to the wild type, the transgenic Arabidopsis seedlings overexpressing DsSWEET17 had longer roots, greater fresh weight, and a faster root growth upon exogenous application of fructose. Furthermore, transgenic Arabidopsis seedlings had significantly higher fructose accumulation than was observed for the wild-type seedlings. The analysis of root length revealed that transgenic Arabidopsis had higher tolerance to salt, osmotic, and oxidative stresses. Taken together, our results suggest that DsSWEET17 may be a tonoplast sugar transporter, and its overexpression affects sugar metabolism and confers multiple stress tolerance in Arabidopsis.

DsSWEET17, a Tonoplast-Localized Sugar Transporter from Dianthus spiculifolius, Affects Sugar Metabolism and Confers Multiple Stress Tolerance in Arabidopsis.

Science.gov (United States)

Zhou, Aimin; Ma, Hongping; Feng, Shuang; Gong, Shufang; Wang, Jingang

2018-05-24

Plant SWEETs (Sugars Will Eventually be Exported Transporters) affect the growth of plants by regulating the transport of sugar from source to sink and its intracellular transport between different organelles. In this study, DsSWEET17 from Dianthus spiculifolius was identified and characterized. Real-time quantitative PCR analysis revealed that the expression of DsSWEET17 was affected by exogenous application of fructose and glucose as well as under salt, osmotic, and oxidation stress. Colocalization experiments showed that the DsSWEET17-GFP (green fluorescent protein) fusion protein was localized to the FM4-64-labeled tonoplasts in Arabidopsis . Compared to the wild type, the transgenic Arabidopsis seedlings overexpressing DsSWEET17 had longer roots, greater fresh weight, and a faster root growth upon exogenous application of fructose. Furthermore, transgenic Arabidopsis seedlings had significantly higher fructose accumulation than was observed for the wild-type seedlings. The analysis of root length revealed that transgenic Arabidopsis had higher tolerance to salt, osmotic, and oxidative stresses. Taken together, our results suggest that DsSWEET17 may be a tonoplast sugar transporter, and its overexpression affects sugar metabolism and confers multiple stress tolerance in Arabidopsis .

An Autonomous Distributed Fault-Tolerant Local Positioning System

Science.gov (United States)

Malekpour, Mahyar R.

2017-01-01

We describe a fault-tolerant, GPS-independent (Global Positioning System) distributed autonomous positioning system for static/mobile objects and present solutions for providing highly-accurate geo-location data for the static/mobile objects in dynamic environments. The reliability and accuracy of a positioning system fundamentally depends on two factors; its timeliness in broadcasting signals and the knowledge of its geometry, i.e., locations and distances of the beacons. Existing distributed positioning systems either synchronize to a common external source like GPS or establish their own time synchrony using a scheme similar to a master-slave by designating a particular beacon as the master and other beacons synchronize to it, resulting in a single point of failure. Another drawback of existing positioning systems is their lack of addressing various fault manifestations, in particular, communication link failures, which, as in wireless networks, are increasingly dominating the process failures and are typically transient and mobile, in the sense that they typically affect different messages to/from different processes over time.

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

Directory of Open Access Journals (Sweden)

Shalabh Dixit

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

DROUGHT TOLERANCE OF LOCAL ROTE AND CHECK VARIETIES OF GROUNDNUT (Arachis hypogaea L. UNDER DRY SEASON IN TWO LOCATIONS IN EAST NUSA TENGGARA

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Yosep S. Mau

2014-10-01

Full Text Available Groundnut is the most important pulse crop in East Nusa Tenggara (ENT; however, the crop yield in ENT is low due to erratic climatic condition, drought stress, and low yielding ability of most cultivated genotypes. Local Rote is a well-known local groundnut variety in ENT, which is a potential superior variety and parental source due its large seed size and high yielding ability. Information on its resistance to abiotic and biotic stresses is important for its future development. Five groundnut genotypes, Local Rote and check varieties were elucidated to identify drought resistant genotypes. The study was carried out in a split-plot design with three replicates in two locations during dry season 2013. Two irrigation regimes (optimum and stress conditions were assigned as main plot and 5 groundnut geno-types as sub-plot. Research results revealed significant effect of irrigation by genotype interaction on observed yield and yield compo-nent characters in both locations. Seed yields of most tested genotypes were below their yield potential. Local Rote yielded best over two locations (1.26 t.ha-1 seed yield. Yields of check varieties were below 1.0 t.ha-1. Local Rote was considered tolerant to drought based on STI, GMP, SSI and YL selection indices.

Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study.

Science.gov (United States)

Ballard, C; Sauter, M; Scheltens, P; He, Y; Barkhof, F; van Straaten, E C W; van der Flier, W M; Hsu, C; Wu, S; Lane, R

2008-09-01

The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. NCT00099216. 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.

NASA System Safety Handbook. Volume 1; System Safety Framework and Concepts for Implementation

Science.gov (United States)

Dezfuli, Homayoon; Benjamin, Allan; Everett, Christopher; Smith, Curtis; Stamatelatos, Michael; Youngblood, Robert

2011-01-01

unrtainties represents a method of probabilistic thinking wherein the analyst and decision makers recognize possible outcomes other than the outcome perceived to be "most likely." Without this type of analysis, it is not possible to determine the worth of an analysis product as a basis for making decisions related to safety and mission success. In line with these considerations the handbook does not take a hazard-analysis-centric approach to system safety. Hazard analysis remains a useful tool to facilitate brainstorming but does not substitute for a more holistic approach geared to a comprehensive identification and understanding of individual risk issues and their contributions to aggregate safety risks. The handbook strives to emphasize the importance of identifying the most critical scenarios that contribute to the risk of not meeting the agreed-upon safety objectives and requirements using all appropriate tools (including but not limited to hazard analysis). Thereafter, emphasis shifts to identifying the risk drivers that cause these scenarios to be critical and ensuring that there are controls directed toward preventing or mitigating the risk drivers. To address these and other areas, the handbook advocates a proactive, analytic-deliberative, risk-informed approach to system safety, enabling the integration of system safety activities with systems engineering and risk management processes. It emphasizes how one can systematically provide the necessary evidence to substantiate the claim that a system is safe to within an acceptable risk tolerance, and that safety has been achieved in a cost-effective manner. The methodology discussed in this handbook is part of a systems engineering process and is intended to be integral to the system safety practices being conducted by the NASA safety and mission assurance and systems engineering organizations. The handbook posits that to conclude that a system is adequately safe, it is necessary to consider a set of safety claims that

An evaluation method of fault-tolerance for digital plant protection system in nuclear power plants

International Nuclear Information System (INIS)

Lee, Jun Seok; Kim, Man Cheol; Seong, Poong Hyun; Kang, Hyun Gook; Jang, Seung Cheol

2005-01-01

In recent years, analog based nuclear power plant (NPP) safety related instrumentation and control (I and C) systems have been replaced to modern digital based I and C systems. NPP safety related I and C systems require very high design reliability compare to the conventional digital systems so that reliability assessment is very important. In the reliability assessment of the digital system, fault tolerance evaluation is one of the crucial factors. However, the evaluation is very difficult because the digital system in NPP is very complex. In this paper, the simulation based fault injection technique on simplified processor is used to evaluate the fault-tolerance of the digital plant protection system (DPPS) with high efficiency with low cost

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

Science.gov (United States)

Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby

2018-05-01

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n  = 61) or once-daily Norditropin ( n  = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P  = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.

The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

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Razavy Haide

2007-04-01

Full Text Available Abstract Background Transplant rejection has been considered to occur primarily because donor antigens are not present during the development of the recipient's immune system to induce tolerance. Thus, transplantation prior to recipient immune system development (pre-immunocompetence transplants should induce natural tolerance to the donor. Surprisingly, tolerance was often not the outcome in such 'natural tolerance models'. We explored the ability of natural tolerance to prevent immune responses to alloantigens, and the reasons for the disparate outcomes of pre-immunocompetence transplants. Results We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance. Conclusion These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited. Reviewers This article was reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott.

A Framework-Based Approach for Fault-Tolerant Service Robots

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Heejune Ahn

2012-11-01

Full Text Available Recently the component-based approach has become a major trend in intelligent service robot development due to its reusability and productivity. The framework in a component-based system should provide essential services for application components. However, to our knowledge the existing robot frameworks do not yet support fault tolerance service. Moreover, it is often believed that faults can be handled only at the application level. In this paper, by extending the robot framework with the fault tolerance function, we argue that the framework-based fault tolerance approach is feasible and even has many benefits, including that: 1 the system integrators can build fault tolerance applications from non-fault-aware components; 2 the constraints of the components and the operating environment can be considered at the time of integration, which – cannot be anticipated eaily at the time of component development; 3 consistency in system reliability can be obtained even in spite of diverse application component sources. In the proposed construction, we build XML rule files defining the rules for probing and determining the fault conditions of each component, contamination cases from a faulty component, and the possible recovery and safety methods. The rule files are established by a system integrator and the fault manager in the framework controls the fault tolerance process according to the rules. We demonstrate that the fault-tolerant framework can incorporate widely accepted fault tolerance techniques. The effectiveness and real-time performance of the framework-based approach and its techniques are examined by testing an autonomous mobile robot in typical fault scenarios.

Highway Safety Program Manual: Volume 8: Alcohol in Relation to Highway Safety.

Science.gov (United States)

National Highway Traffic Safety Administration (DOT), Washington, DC.

Volume 8 of the 19-volume Highway Safety Program Manual (which provides guidance to State and local governments on preferred highway safety practices) concentrates on alcohol in relation to highway safety. The purpose and objectives of the alcohol program are outlined. Federal authority in the area of highway safety and general policies regarding…

Pirfenidone gel in patients with localized scleroderma: a phase II study.

Science.gov (United States)

Rodríguez-Castellanos, Marco; Tlacuilo-Parra, Alberto; Sánchez-Enríquez, Sergio; Vélez-Gómez, Ezequiel; Guevara-Gutiérrez, Elizabeth

2015-01-28

Localized scleroderma is an inflammatory disease in its first stages and a fibrotic process in later stages, principally mediated by the transforming growth factor β. To date, there is no standard treatment. The objective of this study was to determine the effectiveness and safety of 8% pirfenidone gel in patients with localized scleroderma. This was an open phase II clinical trial that included 12 patients. Treatment with pirfenidone was indicated, three times daily for 6 months. Patients were evaluated clinically with the modified Localized Scleroderma Skin Severity Index (mLoSSI), as well with a durometer and histologically using hematoxylin and eosin stain and Masson's trichrome stain. The baseline mLoSSI average scores were 5.83 ± 4.80 vs. 0.83 ± 1.75 (P = 0.002) at 6 months. The initial durometer induration of the scleroderma plaques was 35.79 ± 9.10 vs. 32.47 ± 8.97 at 6 months (P = 0.05). We observed histopathological improvement with respect to epidermal atrophy, inflammation, dermal or adipose tissue fibrosis and annex atrophy from 12.25 ± 3.25 to 9.75 ± 4.35 (P = 0.032). The 8% pirfenidone gel application was well tolerated, and no side effects were detected. This is the first study on the therapeutic use of pirfenidone gel in localized scleroderma. It acts on both the inflammatory and the fibrotic phases. Considering its effectiveness, good safety profile and the advantage of topical application, pirfenidone is a treatment option in this condition.

Relationships of self-identified cold tolerance and cold-induced vasodilatation in the finger

Science.gov (United States)

Park, Joonhee; Lee, Joo-Young

2016-04-01

This study was conducted to investigate relationships of self-identified cold tolerance and cold-induced vasodilatation (CIVD) in the finger. Nine males and 34 females participated in the following 2 tests: a CIVD test and a self-reported survey. The CIVD test was conducted 30-min cold-water immersion (3.8 ± 0.3 °C) of the middle finger at an air temperature of 27.9 ± 0.1 °C. The self-reported questionnaire consisted of 28 questions about whole and local body cold and heat tolerances. By a cluster analysis on the survey results, the participants were divided into two groups: high self-identified cold tolerance (HSCT, n = 25) and low self-identified cold tolerance (LSCT, n = 18). LSCT had lower self-identified cold tolerance ( P cold or heat tolerance had relationships with cold tolerance index, T max, and amplitude ( P cold tolerance classified through a standardized survey could be a good index to predict physiological cold tolerance.

Effect of spatial variation on salinity tolerance of macroinvertebrates in Eastern Australia and implications for ecosystem protection trigger values

International Nuclear Information System (INIS)

Dunlop, Jason E.; Horrigan, Nelli; McGregor, Glenn; Kefford, Ben J.; Choy, Satish; Prasad, Rajesh

2008-01-01

Salinisation of freshwater has been identified as a serious environmental issue in Australia and around the world. Protective concentrations (trigger values) for salinity can be used to manage salinity impacts, though require locally relevant salinity tolerance information. 72-h acute salinity tolerance values were determined for 102 macroinvertebrates collected from 11 locations in four biologically distinct freshwater bio-regions in Northeast Australia and compared with sensitivities observed in Southeast Australia. The salinity tolerance of individual taxa was consistent across Northeast Australia and between Northeast and Southeast Australia. However, two distinct communities were identified in Northeast Australia using distributions of the acute tolerance values and a calculated index of salinity sensitivity. Salinity trigger values should therefore be representative of local or regionally relevant communities and may be adequately calculated using sensitivity values from throughout Eastern Australia. The results presented provide a basis for assessing salinity risk and determining trigger values for salinity in freshwater ecosystems at local and regional scales in Eastern Australia. - Salinity tolerance of macroinvertebrate communities vary in Eastern Australia hence water quality guidelines should be developed at a local or regional scale

Opportunities Suspended: The Devastating Consequences of Zero Tolerance and School Discipline Policies. Report from a National Summit on Zero Tolerance [Proceedings] (Washington, DC, June 15-16, 2000).

Science.gov (United States)

Harvard Civil rights Project, Cambridge, MA.

This report contends that public school administrators no longer rely on literal interpretations of states' and districts' zero tolerance policies and overzealously promote safety, inventing creative interpretations of the laws and using them to suspend and expel children based on relatively minor offenses. Minority students are disproportionately…

How much Baltic salmon can be consumed without exceeding the tolerable safety limit ?

Energy Technology Data Exchange (ETDEWEB)

Kristiansen, H.R. [Mobile Nutrients Ltd. (Denmark)

2004-09-15

Because Baltic salmon is a top predator preying on sprat, herring and tobis, it is very vulnerable to contamination with dioxin and PCBs. The EU safety limit (SL) for fish is 4 picogram (pg) WHOTEQ g{sup -1} fresh fish. In April 2004, Danish commercial salmon fishing was banned to in the Baltic sea around Bornholm and Gotland (mainly ICES areas 25, 26), because the Food Administration reported dioxin levels exceeding the intervention level of 3 pg g{sup -1} fresh salmon. Their report was based on data from 10 individual salmon, and 3 pooled samples, each with 10 salmon. Since dioxins are widespread in the environment, the human population face a trade off to produce sufficient food that is safe to eat and avoid eating contaminated food. The world population is increasing, and the demand for healthy food is steadily increasing. Consequently, there is a need for risk assessments, where the consequences of eating foods with different grades of contamination is evaluated. The evaluation must be based on data of high quality, and because dioxin accumulation is a slow proces, the risk assessments should consider long time periods of months and years instead of days and weeks. The purpose of the present study is to evaluate the statistical variation of dioxin data from Baltic herring and salmon. The data are used to calculate the quantity of herring and salmon, that humans of different body weight can eat without exceeding the tolerable daily intake (TDI). (In dietary recommendations exposure from dairy products etc. must also be taken into account). A PCDD/F box model is proposed that subtract losses during cooking and postprandially.

Primary (Month-6) Outcomes of the STOP-Uveitis Study: Evaluating the Safety, Tolerability, and Efficacy of Tocilizumab in Patients With Noninfectious Uveitis.

Science.gov (United States)

Sepah, Yasir Jamal; Sadiq, Mohammad Ali; Chu, David S; Dacey, Mark; Gallemore, Ron; Dayani, Pouya; Hanout, Mostafa; Hassan, Muhammad; Afridi, Rubbia; Agarwal, Aniruddha; Halim, Muhammad Sohail; Do, Diana V; Nguyen, Quan Dong

2017-11-01

To report the primary endpoint analyses of the safety and efficacy of 2 different doses of intravenous (IV) infusions of tocilizumab (TCZ), an IL-6 inhibitor, in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Randomized, controlled, multicenter clinical trial. STOP-Uveitis is a randomized, open-label safety, efficacy, and bioactivity clinical trial conducted at 5 clinical centers across the United States. The study evaluated the role of TCZ in patients with noninfectious uveitis (NIU). Thirty-seven patients with NIU were randomized into one of 2 treatment groups in a ratio of 1:1. Group 1 received IV infusions of 4 mg/kg TCZ and group 2 received IV infusions of 8 mg/kg TCZ. Infusions were given every 4 weeks in both groups until month 6 (primary endpoint). Primary outcome measure was incidence and severity of systemic and ocular adverse events through month 6. Secondary outcome measures included mean change in visual acuity (VA), vitreous haze (VH), and central macular thickness (CMT) at month 6. A total of 37 patients were randomized in the study. At month 6, 43.5% of patients who had the potential for a 2-step decrease in VH demonstrated a 2-step decrease (40% in Group 1 and 46.1% in Group 2). Mean change in CMT was -83.88 ± 136.1 μm at month 6 (-131.5 ± 41.56 μm in Group 1 and -38.92 ± 13.7 μm in Group 2). Mean change in VA was +8.22 ± 11.83 ETDRS letters at month 6 (10.9 ± 14.6 in Group 1 and 5.5 ± 7.8 in Group 2). Repeated infusions of TCZ were well tolerated. Repeated IV administrations of TCZ are well tolerated. TCZ (both 4 and 8 mg/kg) is effective in improving VA and reducing VH and CMT in eyes with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. Copyright © 2017 Elsevier Inc. All rights reserved.

Does competition influence safety?

International Nuclear Information System (INIS)

Pamme, H.

2000-01-01

Competition in the deregulated electricity market does not leave nuclear power plants unaffected. Operators seek to run their plants at maximum availability and with optimized cost structures so that specific generating costs are minimized. The 'costs of safety', with their fixed-cost character, are elements of this cost structure. Hence the question whether safety is going to suffer under the cost pressure on the market. The study shows that the process of economic optimization does not permit cost minimization for its own sake in the area of operating costs which can be influenced by management or are 'avoidable'. The basis of assessment rather must be potential risks which could entail losses of availability. Prophylactic investments made in order to avoid losses of availability to a large extent also imply unchanged or even higher levels of safety. Economic viability and safety thus are closely correlated. Competition in a deregulated marekt so far has not done any direct harm to plant safety. An even more efficient use of scarce funds and, hopefully, a tolerable political environment should allow the safety level of nuclear power plants to be upheld, and safety culture to be maintained, also in the future. (orig.) [de

Dose establishing a safety margin reduce local recurrence in subsegmental transarterial chemoembolization for small nodular hepatocellular carcinomas?

International Nuclear Information System (INIS)

Kang, Hyo Jin; Kim, Young Il; Kim, Hyo Cheol; Jae, Hwan Jun; Hur, Sae Beam; Chung, Jin Wook

2015-01-01

To test the hypothesis that a safety margin may affect local tumor recurrence (LTR) in subsegmental chemoembolization. In 101 patients with 128 hepatocellular carcinoma (HCC) nodules (1-3 cm in size and ≤ 3 in number), cone-beam CT-assisted subsegmental lipiodol chemoembolization was performed. Immediately thereafter, a non-contrast thin-section CT image was obtained to evaluate the presence or absence of intra-tumoral lipiodol uptake defect and safety margin. The effect of lipiodol uptake defect and safety margin on LTR was evaluated. Univariate and multivariate analyses were performed to indentify determinant factors of LTR. Of the 128 HCC nodules in 101 patients, 49 (38.3%) nodules in 40 patients showed LTR during follow-up period (median, 34.1 months). Cumulative 1- and 2-year LTR rates of nodules with lipiodol uptake defect (n = 27) and those without defect (n = 101) were 58.1% vs. 10.1% and 72.1% vs. 19.5%, respectively (p < 0.001). Among the 101 nodules without a defect, the 1- and 2-year cumulative LTR rates for nodules with complete safety margin (n = 52) and those with incomplete safety margin (n = 49) were 9.8% vs. 12.8% and 18.9% vs. 19.0% (p = 0.912). In multivariate analyses, ascites (p = 0.035), indistinct tumor margin on cone-beam CT (p = 0.039), heterogeneous lipiodol uptake (p = 0.023), and intra-tumoral lipiodol uptake defect (p < 0.001) were determinant factors of higher LTR. In lipiodol chemoembolization, the safety margin in completely lipiodolized nodule without defect will not affect LTR in small nodular HCCs

Safety related terms for advanced nuclear plants

International Nuclear Information System (INIS)

1995-12-01

The terms considered in this document are in widespread current use without a universal consensus as to their meaning. Other safety related terms are already defined in national or international codes and standards as well as in IAEA's Nuclear Safety Standards Series. Most of the terms in those codes and standards have been defined and used for regulatory purposes, generally for application to present reactor designs. There is no intention to duplicate the description of such regulatory terms here, but only to clarify the terms used for advanced nuclear plants. The following terms are described in this paper: Inherent safety characteristics, passive component, active component, passive systems, active system, fail-safe, grace period, foolproof, fault-/error-tolerant, simplified safety system, transparent safety

Safety related terms for advanced nuclear plants

International Nuclear Information System (INIS)

1991-09-01

The terms considered in this document are in widespread current use without a universal consensus as to their meaning. Other safety related terms are already defined in national or international codes and standards as well as in IAEA's Nuclear Safety Standards Series. Most of the terms in those codes and standards have been defined and used for regulatory purposes, generally for application to present reactor designs. There is no intention to duplicate the description of such regulatory terms here, but only to clarify the terms used for advanced nuclear plants. The following terms are described in this paper: Inherent safety characteristics, passive component, active component, passive systems, active system, fail-safe, grace period, foolproof, fault-/error-tolerant, simplified safety system, transparent safety

Comparison of diclofenac-emulgel local application with oral ibuprofen administration for the treatment of active interphalangeal hand joints osteoarthritis (Heberden and/or Bushar nodules

Directory of Open Access Journals (Sweden)

J Zacher

2007-01-01

. Tolerability of local therapy with diclofenac probably exceeds tolerability of systemic treatment with ibuprofen. This applies to gastrointestinal safety and frequency of adverse events leading to treatment withdrawal.

Nature of local benefits to communities impacted by sour gas development : Public safety and sour gas recommendation 79 : Final report

International Nuclear Information System (INIS)

2003-09-01

The Provincial Advisory Committee on Public Safety and Sour Gas of Alberta issued a report in December 2002, in which recommendations were made on how to improve the sour gas regulatory system and reduce the impacts of sour gas on public safety and health. Recommendation 79 of this report called for a study to determine the nature of local benefits such as property taxes and local business opportunities, to communities affected by sour gas development. The present document was prepared by a multi-stake holder committee consisting of representatives from municipal government, academia, industry associations, the provincial government, and the public. One of its objectives was to identify matters of importance to stake holders concerning the study. The committee examined three major areas: economic benefit, net financial benefit to municipalities, and impact of sour gas development on local residents. The results indicated that the province and municipalities in which sour gas activities take place benefit from these activities. All Albertans benefit somewhat, and those living in areas where the sour gas industry operates might benefit through employment or the net benefit accrued to municipal government. A detailed quantification of local benefits at the municipal level for individuals was provided in this document. A full accounting of costs or negative impacts that may affect some individuals was not provided. refs., 6 tabs

Iloprost infusion by a new device as a portable syringe pump: safety, tolerability and agreement

Directory of Open Access Journals (Sweden)

Paola Faggioli

2012-12-01

Full Text Available Background Iloprost, prostacyclin (PGI2 analogue, effective in treatment of peripheral arterial disease, secondary Raynaud's phenomenon (RP to connective tissue disease (CTD, vasculitis, pulmonary hypertension, is usually infused through peristaltic pump, or recently through a flow regulator.Materials and methods We tested a new portable syringe pump (Pompa Infonde®, Italfarmaco S.p.A., Cinisello Balsamo, Milano on 120 patients affected by RP to CTD and cryoglobulinaemia, in iloprost therapy with a flow regulator.Results Iloprost infused through portable syringe pump is better tolerated, better appreciated by the patients and nurses and no difference was observed on therapeutic effects, with a lower incidence of side effects statistically significant. Only 3 patients were unable to tolerate the device (2 for changes in pressure and 1 for fear and shifted to traditional method of iloprost infusion.Conclusions Iloprost infusion through the portable syringe Pompa Infonde® appears to be safe, better tolerated, more acceptable and equally effective compared to infusion through a flow regulator.

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

Science.gov (United States)

Chandra, Kumar P; Shiwalkar, Ajay; Kotecha, Jignesh; Thakkar, Purav; Srivastava, Ambrish; Chauthaiwale, Vijay; Sharma, Sanjay K; Cross, Maurice R; Dutt, Chaitanya

2009-01-01

Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double

Safety and reliability of automatization software

Energy Technology Data Exchange (ETDEWEB)

Kapp, K; Daum, R [Karlsruhe Univ. (TH) (Germany, F.R.). Lehrstuhl fuer Angewandte Informatik, Transport- und Verkehrssysteme

1979-02-01

Automated technical systems have to meet very high requirements concerning safety, security and reliability. Today, modern computers, especially microcomputers, are used as integral parts of those systems. In consequence computer programs must work in a safe and reliable mannter. Methods are discussed which allow to construct safe and reliable software for automatic systems such as reactor protection systems and to prove that the safety requirements are met. As a result it is shown that only the method of total software diversification can satisfy all safety requirements at tolerable cost. In order to achieve a high degree of reliability, structured and modular programming in context with high level programming languages are recommended.

Defining safety goals. 2. Basic Consideration on Defining Safety Goals

International Nuclear Information System (INIS)

Hakata, T.

2001-01-01

The purpose of this study is to develop basic safety goals that are rational and consistent for all nuclear facilities, including nuclear power plants and fuel cycle facilities. Basic safety goals (risk limits) by an index of radiation dose are discussed, which are based on health effects of detriment and fatality and risk levels presumably accepted by society. The contents of this paper are the personal opinions of the author. The desirable structure of safety goals is assumed to be 'basic safety goals plus specific safety goals (or supplemental safety goals) for each sort of facility, which reflects their characteristics'. The requisites of the basic safety goals must include (a) rational bases (scientific and social), (b) comprehensiveness (common to all sorts of nuclear facilities covering from normal to accidental conditions), and (c) applicability. To meet the requirements, the basic safety goals might have to be a risk profile expression by an index of radiation dose. The societal rationality is consideration of absolute risk levels (10 -6 or 10 -7 /yr) and/or relative risk factors (such as 0.1% of U.S. safety goals) that the general public accepts as tolerable. The following quantitative objectives are adopted in this study for protection of average individuals in the vicinity of a nuclear facility: 1. The additive annual radiation dose during normal operation must be -4 /yr (health detriment), 2x10 -6 /yr (latent cancer and severe hereditary effects), and 10 -7 /yr (acute fatality) from the statistics in Japan. The radiation effects on human beings are determined by recommendations of UNSCEAR (Ref. 1) and ICRP. The health effects considered are non-severe stochastic health detriment, i.e., detectable opacities of lens of eye (threshold 5 0.5 to 2 Sv), depression of hematopoiesis of bone marrow (0.5 Sv), and depression of reproductive capability (temporary sterility of testes ) (0.15 Sv). The LD 50/60 of acute fatality is ∼4 Sv, and fatalities by latent

Conservatism of lizard thermal tolerances and body temperatures across evolutionary history and geography.

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Grigg, Joseph W; Buckley, Lauren B

2013-04-23

Species may exhibit similar thermal tolerances via either common ancestry or environmental filtering and local adaptation, if the species inhabit similar environments. We ask whether upper and lower thermal limits (critical thermal maxima and minima) and body temperatures are more strongly conserved across evolutionary history or geography for lizard populations distributed globally. We find that critical thermal maxima are highly conserved with location accounting for a higher proportion of the variation than phylogeny. Notably, thermal tolerance breadth is conserved across the phylogeny despite critical thermal minima showing little niche conservatism. Body temperatures observed during activity in the field show the greatest degree of conservatism, with phylogeny accounting for most of the variation. This suggests that propensities for thermoregulatory behaviour, which can buffer body temperatures from environmental variation, are similar within lineages. Phylogeny and geography constrain thermal tolerances similarly within continents, but variably within clades. Conservatism of thermal tolerances across lineages suggests that the potential for local adaptation to alleviate the impacts of climate change on lizards may be limited.

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

Science.gov (United States)

Siproudhis, L; Jones, D; Shing, R Ng Kwet; Walker, D; Scholefield, J H

2014-03-01

Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. This is the first randomised controlled study to investigate the efficacy

Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs

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Denilson C. Albuquerque

2005-08-01

Full Text Available OBJECTIVE: To evaluate the efficacy, safety and tolerability of sildenafil among Brazilian patients with hypertension treated with combinations of anti-hypertensive drugs. MATERIALS AND METHODS: One hundred twenty hypertensive men aged 30 to 81 years old under treatment with 2 or more anti-hypertensive drugs and with erectile dysfunction (ED lasting for at least 6 months were enrolled at 7 research centers in Brazil. Patients were randomized to receive treatment with either sildenafil or placebo taken 1 hour before sexual intercourse (initial dose of 50 mg, adjusted to 25 mg or 100 mg according to efficacy and toxicity. During the following 8 weeks, patients were evaluated regarding vital signs, adverse events, therapeutic efficacy, satisfaction with treatment and use of concurrent medications. RESULTS: The primary evaluation of efficacy, which was based on responses to questions 3 and 4 of the International Index of Erectile Function, showed significant differences regarding treatment with sildenafil (p = 0.0002 and p < 0.0001, respectively. In the assessment of global efficacy, 87% of the patients treated with sildenafil reported improved erections, as compared with 37% of patients given placebos (p < 0.0001. The other secondary evaluations supported the results favoring sildenafil. The most frequent adverse events among patients treated with sildenafil were headaches (11.4%, vasodilation (11.4% and dyspepsia (6.5%. There were no significant changes in blood pressure measurements in both groups. CONCLUSION: Sildenafil is efficacious and safe for the treatment of hypertensive patients with ED who receive concurrent combinations of anti-hypertensive drugs.

SRP reactor safety evolution

International Nuclear Information System (INIS)

Rankin, D.B.

1984-01-01

The Savannah River Plant reactors have operated for over 100 reactor years without an incident of significant consequence to on or off-site personnel. The reactor safety posture incorporates a conservative, failure-tolerant design; extensive administrative controls carried out through detailed operating and emergency written procedures; and multiple engineered safety systems backed by comprehensive safety analyses, adapting through the years as operating experience, changes in reactor operational modes, equipment modernization, and experience in the nuclear power industry suggested. Independent technical reviews and audits as well as a strong organizational structure also contribute to the defense-in-depth safety posture. A complete review of safety history would discuss all of the above contributors and the interplay of roles. This report, however, is limited to evolution of the engineered safety features and some of the supporting analyses. The discussion of safety history is divided into finite periods of operating history for preservation of historical perspective and ease of understanding by the reader. Programs in progress are also included. The accident at Three Mile Island was assessed for its safety implications to SRP operation. Resulting recommendations and their current status are discussed separately at the end of the report. 16 refs., 3 figs

Reirradiation of Prostate Cancer Local Failures After Previous Curative Radiation Therapy: Long-Term Outcome and Tolerance

International Nuclear Information System (INIS)

Zilli, Thomas; Benz, Eileen; Dipasquale, Giovanna; Rouzaud, Michel; Miralbell, Raymond

2016-01-01

Purpose: To evaluate the safety, feasibility, side-effect profile, and proof of concept of external beam radiation therapy (EBRT) with or without a brachytherapy (BT) boost for salvage of exclusive local failure after primary EBRT for prostate cancer. Methods and Materials: Fourteen patients with presumed exclusive local recurrence after primary EBRT with or without BT were considered eligible for reirradiation. The median normalized total dose in 2-Gy fractions (NTD_2_G_y, α/β ratio = 1.5 Gy) was 74 Gy (range, 66-98.4 Gy) at first irradiation. Median time between the first irradiation and the reirradiation was 6.1 years (range, 4.7-10.2 years). Results: Between 2003 and 2008 salvage treatment was delivered with a median NTD_2_G_y of 85.1 Gy (range, 70-93.4) to the prostate with EBRT with (n=10) or without (n=4) BT. Androgen deprivation was given to 12 patients (median time of 12 months). No grade ≥3 toxicity was observed during and within 6 weeks after RT. After a median follow-up of 94 months (range, 48-172 months) after salvage RT, 5-year grade ≥3 genitourinary and gastrointestinal toxicity-free survival figures were 77.9% ± 11.3% and 57.1% ± 13.2%, respectively. Four patients presented with combined grade 4 genitourinary/gastrointestinal toxicity. The 5-year biochemical relapse-free, local relapse-free, distant metastasis-free, and cancer-specific survival rates were 35.7% ± 12.8%, 50.0% ± 13.4%, 85.7% ± 9.4%, and 100%, respectively. Conclusion: Salvage whole-gland reirradiation for patients with a suspicion of exclusive local recurrence after initial RT may be associated with a high rate of severe radiation-induced side effects and poor long-term biochemical and local control.

A new NEA expert group on accident-tolerant fuels

International Nuclear Information System (INIS)

Massara, Simone

2014-01-01

After the events at the Fukushima Daiichi nuclear power plant in March 2011, enhancing the accident tolerance of light water reactors (LWRs) became a topic of serious discussion. One outcome of those discussions has been to promote research into the development of advanced fuels and more robust reactor system technologies with improved performance, reliability and safety characteristics during normal operations and under accident conditions. The Fukushima Daiichi accident has highlighted in particular the importance of reducing hydrogen production rates and increasing fission product retention during extended loss of cooling accidents. In this context, the NEA organised two international workshops to share information and discuss technical and safety issues associated with the development of accident-tolerant fuels (ATFs) for LWRs. Presentations were given by experts from various organisations, industry and regulatory bodies of NEA member countries, as well as from representatives of international bodies. The presentations focused on lessons learnt from the Fukushima Daiichi accident, the desired characteristics of ATFs, potential design options and candidate materials, as well as the current state of the art in related modelling and simulation methods. During discussions following these workshop presentations, delegates agreed to establish a collaborative framework on ATFs within the NEA. Reporting to the Nuclear Science Committee, the Expert Group on Accident-tolerant Fuels for Light Water Reactors (EGATFL) will define and carry out a programme of work to help advance the scientific knowledge needed to provide the technical underpinning for the development of advanced LWR fuels with more enhanced accident tolerance compared to currently used zircaloy/UO 2 fuels. The group will foster information exchange on material properties and relevant phenomenological experiments, carry out state-of-the-art reviews, organise benchmark studies and foster international

Weapons in Schools and Zero-Tolerance Policies

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Losinski, Mickey; Katsiyannis, Antonis; Ryan, Joseph; Baughan, Cynthia

2014-01-01

Horrific events such as the fatal shooting of three high school students in Chardon, Ohio, in the winter of 2012 places tremendous pressure on state and local agencies to ensure that schools provide a safe and conducive learning environment for all students. To help curb school violence, schools have adopted zero-tolerance policies, which often…

Assessment of ecological safety of spent ionite localization in thermosetting plastics on the base of shale phenols

International Nuclear Information System (INIS)

Il'ina, O.V.; Pokonova, Yu.V.; Ivshina, O.A.

1993-01-01

The thermosetting plastic on the base of shale phenols, namely, althiein, is suggested for radioactive waste solidification. The ecological safety of spent ion exchange resins localization in althein determined according to radionuclide washing from the solidified products and the strength of these products under different storage conditions, is evaluated. The radionuclide release into environment from fixed blocks does not exceed 0.05-0.15% in respect to the initial radioactivity

Assessment of the short-term safety and tolerability of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii (PR 259 CT1) in healthy volunteers: a clinical phase I study.

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Mesia, Kahunu; Cimanga, Kanyanga; Tona, Lutete; Mampunza, Ma Miezi; Ntamabyaliro, Nsengi; Muanda, Tsobo; Muyembe, Tamfum; Totté, Jozef; Mets, Tony; Pieters, Luc; Vlietinck, Arnold

2011-01-01

The aim of this study was to evaluate the short-term safety and tolerability of an antimalarial herbal medicinal product (PR 259 CT1) consisting of a quantified 80 % ethanol extract from the stem bark of Nauclea pobeguinii when given orally to healthy adult male volunteers. The amount of the major alkaloid strictosamide in the extract was determined by a validated HPLC method and was shown to be 5.6 %. The herbal preparation was formulated in a gelatine capsule form containing 500 mg of PCR 259 CT1. A sample of 15 healthy male volunteers, selected using the Lot Quality Assurance of Sampling (LQAS) method, was eligible for inclusion after fulfillment of the inclusion criteria and clinical examination by a physician. The volunteers were treated in an outpatient clinic with a drug regimen of two 500 mg capsules three times daily (each eight hours) for seven days, during meals. Safety and tolerability were monitored clinically, haematologically, biochemically and by electrocardiographic (ECG) examination at days 0, 1, 3, 7 and 14. Adverse effects were recorded by self-reporting of the participants or by detection of abnormalities in clinical examinations by a physician. The oral administration of PR 259 CT1 at high doses of 2 × 500 mg/capsule/day for 7 days was found to induce no significant changes in the concentration levels of all investigated haematological, biochemical, electrocardiogram and vital sign parameters and physical characteristics after 14 days of treatment compared to those seen in the baseline data. The concentration levels of all evaluated parameters were within the normal limits as reported in the literature. All adverse events noted were mild and self-resolving including increase of appetite (33 %), headache (20 %) and nausea (20 %). Other minor side effects were insomnia, somnolence and asthenia (7 %). Thus, PR 259 CT1 presented a significant safety and tolerability in healthy volunteers to allow its further development by starting a phase II

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

Science.gov (United States)

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

Chemotherapy and intensity modulated conformational radiotherapy for locally advanced pancreas cancers

International Nuclear Information System (INIS)

Huguet, F.; Wu, A.; Zhang, Z.; Winston, C.; Reidy, D.; Ho, A.; Allen, P.; Karyn, G.

2011-01-01

The authors report a retrospective study of the tolerance and survival of 48 patients who have been treated by a chemotherapy followed by a chemotherapy concomitant with an intensity-modulated radiotherapy for a locally advanced pancreas cancer. Results are discussed in terms of toxicity, cancer response, operability, survival rate. Tolerance is good. Local control rates, global survival rates and secondary resection rates are promising. Short communication

A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of the Rivastigmine Patch in Japanese Patients with Alzheimer’s Disease

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Yu Nakamura

2011-06-01

Full Text Available Background: As of 2010, the rivastigmine patch was licensed for the treatment of Alzheimer’s disease (AD in 64 countries. Methods: This 24-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy, safety and tolerability of the 5-cm2 (9-mg loading dose; 4.6 mg/24 h delivery rate and 10-cm2 (18-mg loading dose; 9.5 mg/24 h delivery rate rivastigmine patch in Japanese patients with AD. Results: In the primary analysis population (intent-to-treat last observation carried forward at week 24, delayed deterioration was seen with the 10-cm2 patch versus placebo on the Japanese version of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-J cog; p = 0.005 and the Japanese version of the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J; p = 0.067. Participants receiving the rivastigmine patch showed numerically less decline versus placebo at week 24 on the CIBIC plus-J, although this did not reach statistical significance. Statistical significance for the CIBIC plus-J was met following adjustment for body weight and baseline Mini-Mental State Examination score as dynamic allocation factors (p = 0.042 and on the Disability Assessment for Dementia (DAD; p = 0.024 and Mental Function Impairment (MENFIS; p = 0.016 subscales. Serious adverse events were rare and were consistent with the known safety profile of the rivastigmine patch. Conclusion: The rivastigmine patch has a favorable efficacy and tolerability profile in Japanese patients with AD.

Chemotherapy and intensity modulated conformational radiotherapy for locally advanced pancreas cancers; Chimiotherapie et radiotherapie conformationnelle avec modulation d'intensite pour les cancers du pancreas localement evolues

Energy Technology Data Exchange (ETDEWEB)

Huguet, F. [Hopital Tenon, Paris (France); Wu, A.; Zhang, Z.; Winston, C.; Reidy, D.; Ho, A.; Allen, P.; Karyn, G. [Memorial Sloan-Kettering Cancer Center, New York (United States)

2011-10-15

The authors report a retrospective study of the tolerance and survival of 48 patients who have been treated by a chemotherapy followed by a chemotherapy concomitant with an intensity-modulated radiotherapy for a locally advanced pancreas cancer. Results are discussed in terms of toxicity, cancer response, operability, survival rate. Tolerance is good. Local control rates, global survival rates and secondary resection rates are promising. Short communication

Dendritic cells in oral tolerance in the gut.

Science.gov (United States)

Rescigno, Maria

2011-09-01

Oral tolerance is a process that allows generation of systemic unresponsiveness to food antigens. Hence if the same antigen is introduced systemically even under immunogenic conditions it does not induce immune responsiveness. Dendritic cells (DCs) have been identified as essential players in this process. DCs in the gut are located in a strategic position as they can interact directly with luminal antigens or indirectly after their transcytosis across epithelial cells. DCs can then migrate to associated lymphoid tissues to induce tolerance. Antigen presenting cells in the gut are specialized in function and have divided their labour so that there are cells capable to migrate to the draining mesenteric lymph node for induction of T regulatory cells, while other subsets are resident and are required to enforce tolerance locally in the gut after food antigen exposure. In this review, I shall summarize the characteristics of antigen presenting cells in the gut and their involvement in oral tolerance induction. In addition, I will also emphasize that tolerance to food allergens may be contributed by plasmacytoid DCs in the liver that participate to the elimination or anergy of allergen-specific CD8 T cells. Hence specialized functions are associated to different subsets of antigen presenting cells and different organs. © 2011 Blackwell Publishing Ltd.

Advanced I&C for Fault-Tolerant Supervisory Control of Small Modular Reactors

Energy Technology Data Exchange (ETDEWEB)

Cole, Daniel G. [Univ. of Pittsburgh, PA (United States)

2018-01-30

In this research, we have developed a supervisory control approach to enable automated control of SMRs. By design the supervisory control system has an hierarchical, interconnected, adaptive control architecture. A considerable advantage to this architecture is that it allows subsystems to communicate at different/finer granularity, facilitates monitoring of process at the modular and plant levels, and enables supervisory control. We have investigated the deployment of automation, monitoring, and data collection technologies to enable operation of multiple SMRs. Each unit's controller collects and transfers information from local loops and optimize that unit’s parameters. Information is passed from the each SMR unit controller to the supervisory controller, which supervises the actions of SMR units and manage plant processes. The information processed at the supervisory level will provide operators the necessary information needed for reactor, unit, and plant operation. In conjunction with the supervisory effort, we have investigated techniques for fault-tolerant networks, over which information is transmitted between local loops and the supervisory controller to maintain a safe level of operational normalcy in the presence of anomalies. The fault-tolerance of the supervisory control architecture, the network that supports it, and the impact of fault-tolerance on multi-unit SMR plant control has been a second focus of this research. To this end, we have investigated the deployment of advanced automation, monitoring, and data collection and communications technologies to enable operation of multiple SMRs. We have created a fault-tolerant multi-unit SMR supervisory controller that collects and transfers information from local loops, supervise their actions, and adaptively optimize the controller parameters. The goal of this research has been to develop the methodologies and procedures for fault-tolerant supervisory control of small modular reactors. To achieve

Efficacy and safety of superficial chemical peeling in treatment of active acne vulgaris.

Science.gov (United States)

Al-Talib, Hassanain; Al-Khateeb, Alyaa; Hameed, Ayad; Murugaiah, Chandrika

2017-01-01

Acne vulgaris is an extremely common condition affecting the pilosebaceous unit of the skin and characterized by presence of comedones, papules, pustules, nodules, cysts, which might result in permanent scars. Acne vulgaris commonly involve adolescents and young age groups. Active acne vulgaris is usually associated with several complications like hyper or hypopigmentation, scar formation and skin disfigurement. Previous studies have targeted the efficiency and safety of local and systemic agents in the treatment of active acne vulgaris. Superficial chemical peeling is a skin-wounding procedure which might cause some potentially undesirable adverse events. This study was conducted to review the efficacy and safety of superficial chemical peeling in the treatment of active acne vulgaris. It is a structured review of an earlier seven articles meeting the inclusion and exclusion criteria. The clinical assessments were based on pretreatment and post-treatment comparisons and the role of superficial chemical peeling in reduction of papules, pustules and comedones in active acne vulgaris. This study showed that almost all patients tolerated well the chemical peeling procedures despite a mild discomfort, burning, irritation and erythema have been reported; also the incidence of major adverse events was very low and easily manageable. In conclusion, chemical peeling with glycolic acid is a well-tolerated and safe treatment modality in active acne vulgaris while salicylic acid peels is a more convenient for treatment of darker skin patients and it showed significant and earlier improvement than glycolic acid.

Recent Advances in Durability and Damage Tolerance Methodology at NASA Langley Research Center

Science.gov (United States)

Ransom, J. B.; Glaessgen, E. H.; Raju, I. S.; Harris, C. E.

2007-01-01

Durability and damage tolerance (D&DT) issues are critical to the development of lighter, safer and more efficient aerospace vehicles. Durability is largely an economic life-cycle design consideration whereas damage tolerance directly addresses the structural airworthiness (safety) of the vehicle. Both D&DT methodologies must address the deleterious effects of changes in material properties and the initiation and growth of damage that may occur during the vehicle s service lifetime. The result of unanticipated D&DT response is often manifested in the form of catastrophic and potentially fatal accidents. As such, durability and damage tolerance requirements must be rigorously addressed for commercial transport aircraft and NASA spacecraft systems. This paper presents an overview of the recent and planned future research in durability and damage tolerance analytical and experimental methods for both metallic and composite aerospace structures at NASA Langley Research Center (LaRC).

Aviation safety/automation program overview

Science.gov (United States)

Morello, Samuel A.

1990-01-01

The goal is to provide a technology base leading to improved safety of the national airspace system through the development and integration of human-centered automation technologies for aircraft crews and air traffic controllers. Information on the problems, specific objectives, human-automation interaction, intelligent error-tolerant systems, and air traffic control/cockpit integration is given in viewgraph form.

Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation.

Science.gov (United States)

Hu, Min; Alexander, Stephen I; Yi, Shounan

2016-12-01

Clinical transplant tolerance has been most successfully achieved combining hematopoietic chimerism with kidney transplantation. This review outlines this strategy in animal models and human transplantation, and possible clinical challenges. Kidney transplant tolerance has been achieved through chimerism in several centers beginning with Massachusetts General Hospital's success with mixed chimerism in human leukocyte antigen (HLA)-mismatched patients and the Stanford group with HLA-matched patients, and the more recent success of the Northwestern protocol achieving full chimerism. This has challenged the original view that stable mixed chimerism is necessary for organ graft tolerance. However, among the HLA-mismatched kidney transplant-tolerant patients, loss of mixed chimerism does not lead to renal-graft rejection, and the development of host Foxp3+ regulatory T cells has been observed. Recent animal models suggest that graft tolerance through bone marrow chimerism occurs through both clonal deletion and regulatory immune cells. Further, Tregs have been shown to improve chimerism in animal models. Animal studies continue to suggest ways to improve our current clinical strategies. Advances in chimerism protocols suggest that tolerance may be clinically achievable with relative safety for HLA-mismatched kidney transplants.

The enigmatic role of mast cells in dominant tolerance.

Science.gov (United States)

de Vries, Victor C; Pino-Lagos, Karina; Elgueta, Raul; Noelle, Randolph J

2009-08-01

The role of regulatory T cells (Treg) in peripheral tolerance has been studied extensively in transplantation research. Recently, mast cells have been shown to play an indispensable role in allograft tolerance. The purpose of this review is to inform the reader on the current standings of the role of mast cells in dominant tolerance with an emphasis on the interaction of mast cells with Treg. Mast cells are required to sustain peripheral tolerance via Treg. Treg can stabilize mast cells degranulation by contact-dependent mechanisms through the interaction of OX40 and its ligand OX40L, and by production of soluble factors, such as interleukin-10 and transforming growth factor-beta. Conversely, the activation and subsequent degranulation of mast cells break peripheral tolerance. Both mast cells and Treg are needed to create a local immunosuppressive environment in the transplant. Treg are not only necessary to suppress effector T-cell responses but also to stabilize mast cells. Mast cells in return could contribute to the immunosuppressive state by release of transforming growth factor-beta, interleukin-10 and specific proteases. However, the molecular basis for mast cells control of Treg suppression in organ transplantation is still unresolved.

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

Science.gov (United States)

Kwok, Charlotte S; Johnson, Emily L; Krauss, Gregory L

2017-11-01

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Internal Leakage Fault Detection and Tolerant Control of Single-Rod Hydraulic Actuators

Directory of Open Access Journals (Sweden)

Jianyong Yao

2014-01-01

Full Text Available The integration of internal leakage fault detection and tolerant control for single-rod hydraulic actuators is present in this paper. Fault detection is a potential technique to provide efficient condition monitoring and/or preventive maintenance, and fault tolerant control is a critical method to improve the safety and reliability of hydraulic servo systems. Based on quadratic Lyapunov functions, a performance-oriented fault detection method is proposed, which has a simple structure and is prone to implement in practice. The main feature is that, when a prescribed performance index is satisfied (even a slight fault has occurred, there is no fault alarmed; otherwise (i.e., a severe fault has occurred, the fault is detected and then a fault tolerant controller is activated. The proposed tolerant controller, which is based on the parameter adaptive methodology, is also prone to realize, and the learning mechanism is simple since only the internal leakage is considered in parameter adaptation and thus the persistent exciting (PE condition is easily satisfied. After the activation of the fault tolerant controller, the control performance is gradually recovered. Simulation results on a hydraulic servo system with both abrupt and incipient internal leakage fault demonstrate the effectiveness of the proposed fault detection and tolerant control method.

Tolerance through Education: How Tolerogenic Dendritic Cells Shape Immunity

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Matthias P. Domogalla

2017-12-01

Full Text Available Dendritic cells (DCs are central players in the initiation and control of responses, regulating the balance between tolerance and immunity. Tolerogenic DCs are essential in the maintenance of central and peripheral tolerance by induction of clonal T cell deletion and T cell anergy, inhibition of memory and effector T cell responses, and generation and activation of regulatory T cells. Therefore, tolerogenic DCs are promising candidates for specific cellular therapy of allergic and autoimmune diseases and for treatment of transplant rejection. Studies performed in rodents have demonstrated the efficacy and feasibility of tolerogenic DCs for tolerance induction in various inflammatory diseases. In the last years, numerous protocols for the generation of human monocyte-derived tolerogenic DCs have been established and some first phase I trials have been conducted in patients suffering from autoimmune disorders, demonstrating the safety and efficiency of this cell-based immunotherapy. This review gives an overview about methods and protocols for the generation of human tolerogenic DCs and their mechanisms of tolerance induction with the focus on interleukin-10-modulated DCs. In addition, we will discuss the prerequisites for optimal clinical grade tolerogenic DC subsets and results of clinical trials with tolerogenic DCs in autoimmune diseases.

Fault tolerant embedded computers and power electronics for nuclear robotics

International Nuclear Information System (INIS)

Giraud, A.; Robiolle, M.

1995-01-01

For requirements of nuclear industries, it is necessary to use embedded rad-tolerant electronics and high-level safety. In this paper, we first describe a computer architecture called MICADO designed for French nuclear industry. We then present outgoing projects on our industry. A special point is made on power electronics for remote-operated and legged robots. (authors). 7 refs., 2 figs

Fault tolerant embedded computers and power electronics for nuclear robotics

Energy Technology Data Exchange (ETDEWEB)

Giraud, A.; Robiolle, M.

1995-12-31

For requirements of nuclear industries, it is necessary to use embedded rad-tolerant electronics and high-level safety. In this paper, we first describe a computer architecture called MICADO designed for French nuclear industry. We then present outgoing projects on our industry. A special point is made on power electronics for remote-operated and legged robots. (authors). 7 refs., 2 figs.

SU-E-T-84: A Survey On Radiotherapy Table Tolerances and Couch Overrides of Over 350 Institutions

International Nuclear Information System (INIS)

Chinsky, B; Patel, R; Panfil, J; Surucu, M; Roeske, J

2015-01-01

Purpose: Table overrides are relatively common in radiotherapy, yet are a potential safety concern. The goal of this study was to survey current departmental policies on treatment couch overrides and table tolerance values used clinically. Methods: A 25 question electronic survey on couch overrides and tolerances was sent to full members of the AAPM. In the first part of the survey, participants were asked: if table overrides were allowed at their institution, who was allowed to perform these overrides, and if imaging was required with overrides. In the second part of the survey, individuals were asked to provide table tolerance data for the following sites: brain/head & neck, lung, breast, abdomen/pelvis and prostate. Each site was further divided into IMRT/VMAT and 3D conformal techniques. Free-text spaces were provided, allowing respondents to enter any table tolerance data they were unable to specify under the treatment sites listed. Results: A total of 361 individuals responded, of which approximately half participated in the couch tolerances portion of the survey. Overall, 86% of respondents’ institutions allow couch tolerance overrides at treatment. Therapists were the most common staff members permitted to perform overrides, followed by physicists, dosimetrists, and physicians, respectively. Of the institutions allowing overrides, 34% reported overriding daily. More than half of the centers require documentation of the override and/or a setup image (acquired after override) to radiographically verify the treatment site. With respect to table tolerances, groups resulting from the free-text responses were at the two extremes; SRS/SBRT were the tightest, while clinical setup/mets/extremities were the most generous. There was no qualitative difference between IMRT/VMAT and 3D conformal table tolerances. Conclusion: This work is intended to stimulate a discussion within the radiotherapy community. This discussion, supplemented by the survey results provides an

SU-E-T-84: A Survey On Radiotherapy Table Tolerances and Couch Overrides of Over 350 Institutions

Energy Technology Data Exchange (ETDEWEB)

Chinsky, B; Patel, R; Panfil, J; Surucu, M; Roeske, J [Loyola University Medical Center, Maywood, IL (United States)

2015-06-15

Purpose: Table overrides are relatively common in radiotherapy, yet are a potential safety concern. The goal of this study was to survey current departmental policies on treatment couch overrides and table tolerance values used clinically. Methods: A 25 question electronic survey on couch overrides and tolerances was sent to full members of the AAPM. In the first part of the survey, participants were asked: if table overrides were allowed at their institution, who was allowed to perform these overrides, and if imaging was required with overrides. In the second part of the survey, individuals were asked to provide table tolerance data for the following sites: brain/head & neck, lung, breast, abdomen/pelvis and prostate. Each site was further divided into IMRT/VMAT and 3D conformal techniques. Free-text spaces were provided, allowing respondents to enter any table tolerance data they were unable to specify under the treatment sites listed. Results: A total of 361 individuals responded, of which approximately half participated in the couch tolerances portion of the survey. Overall, 86% of respondents’ institutions allow couch tolerance overrides at treatment. Therapists were the most common staff members permitted to perform overrides, followed by physicists, dosimetrists, and physicians, respectively. Of the institutions allowing overrides, 34% reported overriding daily. More than half of the centers require documentation of the override and/or a setup image (acquired after override) to radiographically verify the treatment site. With respect to table tolerances, groups resulting from the free-text responses were at the two extremes; SRS/SBRT were the tightest, while clinical setup/mets/extremities were the most generous. There was no qualitative difference between IMRT/VMAT and 3D conformal table tolerances. Conclusion: This work is intended to stimulate a discussion within the radiotherapy community. This discussion, supplemented by the survey results provides an

76 FR 38077 - Special Local Regulations and Safety Zones; Recurring Events in Captain of the Port New York Zone

Science.gov (United States)

2011-06-29

...: All Zone. waters of Long Island Sound in an area bound by the following points: 40[deg]51'43.5'' N 073... Zone. located in approximate position 40[deg]51'52'' N 073[deg]56'24'' W (NAD 1983), approximately 1750...] RIN 1625-AA00; 1625-AA08 Special Local Regulations and Safety Zones; Recurring Events in Captain of...

An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.

Science.gov (United States)

Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T

2013-08-01

Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc

Safety and tolerability of iobitridol in general and in patients with risk factors: Results in more than 160 000 patients

Energy Technology Data Exchange (ETDEWEB)

Maurer, Martin, E-mail: martin.maurer@charite.de [Charite - University Medicine Berlin, Department of Radiology, Augustenburger Platz 1, 13353 Berlin (Germany); Heine, Oliver [Guerbet GmbH, Otto-Vogler-Str. 11, 65843 Sulzbach (Germany); Wolf, Michael [Michael Wolf Information Systems, Viktoriastr. 26, 66346 Puettlingen (Germany); Freyhardt, Patrick; Schnapauff, Dirk; Hamm, Bernd [Charite - University Medicine Berlin, Department of Radiology, Augustenburger Platz 1, 13353 Berlin (Germany)

2011-11-15

Objective: To review the safety, the tolerability and the diagnostic effectiveness of iobitridol under daily practice conditions in the general population and at-risk patients in a post-marketing surveillance study. Materials and methods: A total of 160 639 patients (55.1% male, 43.6% female, mean age 58.6 years) were analysed in 555 centers. Patients underwent X-ray examinations using iobitridol (Xenetix, Guerbet, Sulzbach, Germany) as IV contrast medium (mean volume 85.6 ml). 21.8% of all patients had at least one risk factor (e.g., renal impairment), 7.3% were at-risk patients with allergies or who had previously reacted to contrast medium. Antiallergic pretreatment before contrast medium administration was given in 1144 patients (0.7%). Adverse events were documented and the image quality was assessed. Results: A diagnosis was possible in 99.5% of all cases. The image quality was rated good or excellent in 92.2%. The adverse event rate (e.g., nausea, urticaria) observed was 0.6% in all patients, 1.6% in patients with allergies and 6.0% in patients with a previous reaction to contrast medium. Adverse events occurred more often in women than in men (p < 0.001). Pretreatment did not decrease the rate of adverse events. The rate of adverse events was not increased in higher doses of iobitridol, even if administered to high-risk patients. Conclusions: Iobitridol was shown to be a safe and well-tolerated contrast medium with a low incidence of adverse events in patients with and without risk factors resulting in a good or excellent image quality in most patients.

Data-driven design of fault diagnosis and fault-tolerant control systems

CERN Document Server

Ding, Steven X

2014-01-01

Data-driven Design of Fault Diagnosis and Fault-tolerant Control Systems presents basic statistical process monitoring, fault diagnosis, and control methods, and introduces advanced data-driven schemes for the design of fault diagnosis and fault-tolerant control systems catering to the needs of dynamic industrial processes. With ever increasing demands for reliability, availability and safety in technical processes and assets, process monitoring and fault-tolerance have become important issues surrounding the design of automatic control systems. This text shows the reader how, thanks to the rapid development of information technology, key techniques of data-driven and statistical process monitoring and control can now become widely used in industrial practice to address these issues. To allow for self-contained study and facilitate implementation in real applications, important mathematical and control theoretical knowledge and tools are included in this book. Major schemes are presented in algorithm form and...

A fault-tolerant one-way quantum computer

International Nuclear Information System (INIS)

Raussendorf, R.; Harrington, J.; Goyal, K.

2006-01-01

We describe a fault-tolerant one-way quantum computer on cluster states in three dimensions. The presented scheme uses methods of topological error correction resulting from a link between cluster states and surface codes. The error threshold is 1.4% for local depolarizing error and 0.11% for each source in an error model with preparation-, gate-, storage-, and measurement errors

Fault-tolerant distributed measurement systems

Energy Technology Data Exchange (ETDEWEB)

Gater, C.

1987-01-01

A 100 kbit/s battery-powered fault-tolerant communications network was developed for use in industrial distributed measurement systems, where a loop controller supervises up to 64 addressable field devices with a network polling period of 250ms. Safety and reliability were optimized using fibre-optic data links and low-power circuitry throughout. Based on a highly redundant loop topology of two receiver/two transmitter communications nodes, the network can tolerate any double node or any quadruple linked failure. Each node circuit is designed to operate continuously for five years using a standard D-type lithium cell, and consists essentially of a CMOS single-chip microcomputer, a specially designed CMOS communications interface chip, some analogue circuity for the optical receivers and transmitters, and interfaces for a sensor/actuator and roving hand-held terminal. The communications interface was implement on a 2436-cell CMOS gate array and feature a self-test facility which provides over 86% fault coverage using only three test vectors. The chip can also be used in the loop controller. Control procedures developed to detect, locate, and reconfigure around faults that occur in the communications network.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): a randomized simulated post-exposure study in healthy volunteers.

Science.gov (United States)

Mahendra, Bangalore Jayakrishnappa; Madhusudana, Shampur Narayan; Ashwathnarayana, Doddabele Hanumanthaiah; Sampath, Gadey; datta, Soma Subhra; Sudarshan, Mysore Kalappa; Venkatesh, Gonibeedu Manjunatah; Muhamuda, Kader; Bilagumba, Gangaboraiah; Shamanna, Manjula

2007-12-05

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered to older infants and children naïve to pneumococcal vaccination.

Science.gov (United States)

Wysocki, Jacek; Brzostek, Jerzy; Szymański, Henryk; Tetiurka, Bogusław; Toporowska-Kowalska, Ewa; Wasowska-Królikowska, Krystyna; Sarkozy, Denise A; Giardina, Peter C; Gruber, William C; Emini, Emilio A; Scott, Daniel A

2015-03-30

Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children vaccine (PCV13) has been developed and approved in many countries worldwide. Assess the safety and immunogenicity of PCV13 in healthy older infants and children naïve to previous pneumococcal vaccination. This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age-appropriate catch-up schedules: Group 1 (aged 7 to vaccine doses only; and Group 3 (aged 24 to vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events. The proportion of immunological responders was ≥88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration. Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naïve to pneumococcal vaccination. Copyright © 2015. Published by Elsevier Ltd.

Basking behavior predicts the evolution of heat tolerance in Australian rainforest lizards.

Science.gov (United States)

Muñoz, Martha M; Langham, Gary M; Brandley, Matthew C; Rosauer, Dan F; Williams, Stephen E; Moritz, Craig

2016-11-01

There is pressing urgency to understand how tropical ectotherms can behaviorally and physiologically respond to climate warming. We examine how basking behavior and thermal environment interact to influence evolutionary variation in thermal physiology of multiple species of lygosomine rainforest skinks from the Wet Tropics of northeastern Queensland, Australia (AWT). These tropical lizards are behaviorally specialized to exploit canopy or sun, and are distributed across marked thermal clines in the AWT. Using phylogenetic analyses, we demonstrate that physiological parameters are either associated with changes in local thermal habitat or to basking behavior, but not both. Cold tolerance, the optimal sprint speed, and performance breadth are primarily influenced by local thermal environment. Specifically, montane lizards are more cool tolerant, have broader performance breadths, and higher optimum sprinting temperatures than their lowland counterparts. Heat tolerance, in contrast, is strongly affected by basking behavior: there are two evolutionary optima, with basking species having considerably higher heat tolerance than shade skinks, with no effect of elevation. These distinct responses among traits indicate the multiple selective pressures and constraints that shape the evolution of thermal performance. We discuss how behavior and physiology interact to shape organisms' vulnerability and potential resilience to climate change. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

Safety, Tolerability, and Antihypertensive Effect of SER100, an Opiate Receptor-Like 1 (ORL-1) Partial Agonist, in Patients With Isolated Systolic Hypertension.

Science.gov (United States)

Kantola, Ilkka; Scheinin, Mika; Gulbrandsen, Trygve; Meland, Nils; Smerud, Knut T

2017-11-01

The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours. Seventeen patients completed treatment. There were no serious or severe adverse events. Relative to placebo SER100 induced an average reduction of SBP during the 2 treatment days of 7.0 mm Hg (P = 0.0032), whereas the average reduction of diastolic blood pressure (DBP) over the same period was 3.8 mm Hg (P = 0.0011). For patients with ISH, this short-term cross-over study of SC SER100 demonstrated an acceptable safety profile and consistent, significant lowering of SBP and DBP. As initial clinical proof of concept for a new class of drugs, a nociceptin agonist peptide, the results were encouraging and warrant further research. © 2016, The American College of Clinical Pharmacology.

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

Science.gov (United States)

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

2012-09-01

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

Tolerance

DEFF Research Database (Denmark)

Tønder, Lars

Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech....

A novel zinc-finger-like gene from Tamarix hispida is involved in salt and osmotic tolerance.

Science.gov (United States)

An, Yan; Wang, Yucheng; Lou, Lingling; Zheng, Tangchun; Qu, Guan-Zheng

2011-11-01

In the present study, a zinc-finger-like cDNA (ThZFL) was cloned from the Tamarix hispida. Northern blot analysis showed that the expression of ThZFL can be induced by salt, osmotic stress and ABA treatment. Overexpression of the ThZFL confers salt and osmotic stress tolerance in both yeast Saccharomyces cerevisiae and tobacco. Furthermore, MDA levels in ThZFL transformed tobacco were significantly decreased compared with control plants under salt and osmotic stress, suggesting ThZFL may confer stress tolerance by decreasing membrane lipid peroxidation. Subcellular localization analysis showed the ThZFL protein is localized in the cell wall. Our results indicated the ThZFL gene is an excellent candidate for genetic engineering to improve salt and osmotic tolerance in agricultural plants.

Safety and efficacy of targeted hyperthermia treatment utilizing gold nanorod therapy in spontaneous canine neoplasia.

Science.gov (United States)

Schuh, Elizabeth M; Portela, Roberta; Gardner, Heather L; Schoen, Christian; London, Cheryl A

2017-10-02

Hyperthermia is an established anti-cancer treatment but is limited by tolerance of adjacent normal tissues. Parenteral administration of gold nanorods (NRs) as a photosensitizer amplifies the effects of hyperthermia treatment while sparing normal tissues. This therapy is well tolerated and has demonstrated anti-tumor effects in mouse models. The purpose of this phase 1 study was to establish the safety and observe the anti-tumor impact of gold NR enhanced (plasmonic) photothermal therapy (PPTT) in client owned canine patients diagnosed with spontaneous neoplasia. Seven dogs underwent gold NR administration and subsequent NIR PPTT. Side effects were mild and limited to local reactions to NIR laser. All of the dogs enrolled in the study experienced stable disease, partial remission or complete remission. The overall response rate (ORR) was 28.6% with partial or complete remission of tumors at study end. PPTT utilizing gold nanorod therapy can be safely administered to canine patients. Further studies are needed to determine the true efficacy in a larger population of canine cancer patients and to and identify those patients most likely to benefit from this therapy.

Safety of MR liver specific contrast media

Energy Technology Data Exchange (ETDEWEB)

Bellin, Marie-France [Hopital Paul Brousse, Universite Paris 11, Villejuif Cedex (France); Webb, Judith A.W. [St. Bartholomew' s Hospital, Department of Diagnostic Imaging, London (United Kingdom); Molen, Aart J. van der [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands); Thomsen, Henrik S. [Copenhagen University Hospital at Herlev, Department of Diagnostic Radiology 54E2, Herlev (Denmark); Morcos, Sameh K. [Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Department of Diagnostic Imaging, Sheffield (United Kingdom)

2005-08-01

Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

Safety of MR liver specific contrast media

International Nuclear Information System (INIS)

Bellin, Marie-France; Webb, Judith A.W.; Molen, Aart J. van der; Thomsen, Henrik S.; Morcos, Sameh K.

2005-01-01

Over the past few years a number of magnetic resonance (MR) liver specific contrast agents have been introduced. In this report the safety issues of these agents are addressed. A literature search was carried out. Based on the available information, simple guidelines on the safety issue of liver specific contrast agents have been produced by the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The report and guidelines were discussed at the 11th European Symposium on Urogenital Radiology in Santiago de Compostela. Liver specific contrast agents appear in general to be safe and well tolerated. However, the incidence of adverse reactions with iron oxides and the intravenous manganese based agent seems to be slightly higher than with gadolinium based agents. However, no safety information from comparative clinical trials has been published. Guidelines on the safety aspects are presented. (orig.)

Fault-tolerant and Diagnostic Methods for Navigation

DEFF Research Database (Denmark)

Blanke, Mogens

2003-01-01

to diagnose faults and autonomously provide valid navigation data, disregarding any faulty sensor data and use sensor fusion to obtain a best estimate for users. This paper discusses how diagnostic and fault-tolerant methods are applicable in marine systems. An example chosen is sensor fusion for navigation......Precise and reliable navigation is crucial, and for reasons of safety, essential navigation instruments are often duplicated. Hardware redundancy is mostly used to manually switch between instruments should faults occur. In contrast, diagnostic methods are available that can use analytic redundancy...

Evaluation of Vaginal Drug Levels and Safety of a Locally Administered Glycerol Monolaurate Cream in Rhesus Macaques.

Science.gov (United States)

Kirtane, Ameya R; Rothenberger, Meghan K; Frieberg, Abby; Nephew, Karla; Schultz-Darken, Nancy; Schmidt, Thomas; Reimann, Thomas; Haase, Ashley T; Panyam, Jayanth

2017-07-01

The human immunodeficiency virus epidemic affects millions of people worldwide. As women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. Glycerol monolaurate (GML), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. However, on account of its low aqueous solubility, fabrication of high-dose formulations of GML has proven difficult. We describe the development of a vaginal cream that could be loaded with up to 35% GML. Vaginal drug levels and safety of 3 formulations containing increasing concentrations of GML (5%w/w, 15%w/w, and 35%w/w) were tested in rhesus macaques after vaginal administration. GML concentration in the vaginal tissue increased as the drug concentration in the cream increased, with 35% GML cream resulting in tissue concentration of ∼0.5 mg/g, albeit with high interindividual variability. Compared with the vehicle control, none of the GML creams had any significant effect on the vaginal flora and cytokine (macrophage inflammatory protein 3α and interleukin 8) levels, suggesting that high-dose GML formulations do not induce local adverse effects. In summary, we describe the development of a highly loaded vaginal cream of GML, and vaginal drug levels and safety after local administration in macaques. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Safety and tolerability of tigecycline for the treatment of complicated skin and soft-tissue and intra-abdominal infections: an analysis based on five European observational studies.

Science.gov (United States)

Guirao, Xavier; Sánchez García, Miguel; Bassetti, Matteo; Bodmann, Klaus Friedrich; Dupont, Hervé; Montravers, Philippe; Heizmann, Wolfgang R; Capparella, Maria Rita; Simoneau, Damien; Eckmann, Christian

2013-07-01

Tigecycline is approved for the treatment of complicated skin and soft-tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs) in adults. In this analysis the safety and tolerability profile of tigecycline (used alone or in combination) for the treatment of patients with approved indications of cSSTI and cIAI were examined under real-life clinical conditions. Individual patient-level data were pooled from five European observational studies (July 2006 to October 2011). A total of 254 cSSTI and 785 cIAI patients were included. The mean age was 63 years; 34.4% and 56.6% were in intensive care units, 90.9% and 88.1% had at least one comorbidity and mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores at the beginning of treatment were 15.0 ± 7.9 and 16.9 ± 7.6, respectively. Data on adverse events (AEs) were available for 198 cSSTI and 590 cIAI patients in three studies. Nausea and vomiting were reported in ≤ 2% of patients. The most common serious AEs were multi-organ failure (4.0% and 10.0% in cSSTI and cIAI patients, respectively) and sepsis (4.0% and 6.1%, respectively). Death was recorded for 24/254 (9.4%) cSSTI and 147/785 (18.7%) cIAI patients. Mortality rates were higher in the group with a baseline APACHE II score of >15 compared with those with a score of ≤ 15 (18.7% versus 3.5% for cSSTI patients and 23.8% versus 16.0% for cIAI patients). A similar trend was seen when cIAI patients were stratified by Sequential Organ Failure Assessment (SOFA) score. The safety and tolerability of tigecycline, alone and in combination, are consistent with the level of critical illness among patients in these real-life studies.

Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease

DEFF Research Database (Denmark)

Pitt, Bertram; Kober, Lars; Ponikowski, Piotr

2013-01-01

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroida......Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non......-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD)....

Safety of subcutaneous microinjections (mesotherapy) in musicians.

Science.gov (United States)

Navarte, Danik Arana; Rosset-Llobet, Jaume

2011-06-01

Determine the safety and tolerance of mesotherapy as a technique for the treatment of musculoskeletal complaints in musicians. 67 patients (55.2% women) were subjected to a total of 267 mesotherapy sessions. A mesotherapy needle or normal needle was used randomly. The drugs employed were thiocolchicoside and diazepam as muscular relaxants, pentoxifylline or buflomedil as vasodilators, and piroxicam as an anti-inflammatory, as directed. A visual analogue scale was used to quantify the pain produced by the microinjections as well as the degree of immediate and midterm side effects as reported on a standard questionnaire. A mean of 155.5 microinjections were performed per session, of which 45.6% were perceived as painful by the patient with a mean severity of 4.3 out of 10. The pain reduced to 0.5 out of 10 after 24 hours. The most sensitive areas were the levator scapulae and splenius muscles. Systemic symptoms were reported by 5.99% of the musicians after the mesotherapy sessions (muscular weakness 1.5%, rash 1.5%, drowsiness 1.1% and itching 1.1%, being the most frequent). The mean severity of these symptoms was 2.77 out of 10. In all cases the symptoms had completely disappeared after 24 hours. No patient referred to signs of local or systemic infection. The application of drugs by means of subcutaneous injections (mesotherapy) in musicians is a technique that is safe, well tolerated, and without any severe complications.

Glovebox and Experiment Safety

Science.gov (United States)

Maas, Gerard

2005-12-01

Human spaceflight hardware and operations must comply with NSTS 1700.7. This paper discusses how a glovebox can help.A short layout is given on the process according NSTS/ISS 13830, explaining the responsibility of the payload organization, the approval authority of the PSRP and the defined review phases (0 till III).Amongst others, the following requirement has to be met:"200.1 Design to Tolerate Failures. Failure tolerance is the basic safety requirement that shall be used to control most payload hazards. The payload must tolerate a minimum number of credible failures and/or operator errors determined by the hazard level. This criterion applies when the loss of a function or the inadvertent occurrence of a function results in a hazardous event.200.1a Critical Hazards. Critical hazards shall be controlled such that no single failure or operator error can result in damage to STS/ISS equipment, a nondisabling personnel injury, or the use of unscheduled safing procedures that affect operations of the Orbiter/ISS or another payload.200.1b Catastrophic Hazards. Catastrophic hazards shall be controlled such that no combination of two failures or operator errors can result in the potential for a disabling or fatal personnel injury or loss of the Orbiter/ISS, ground facilities or STS/ISS equipment."For experiments in material science, biological science and life science that require real time operator manipulation, the above requirement may be hard or impossible to meet. Especially if the experiment contains substances that are considered hazardous when released into the habitable environment. In this case operation of the experiment in a glovebox can help to comply.A glovebox provides containment of the experiment and at the same time allows manipulation and visibility to the experiment.The containment inside the glovebox provides failure tolerance because the glovebox uses a negative pressure inside the working volume (WV). The level of failure tolerance is dependent of

Enhanced Maritime Safety through Diagnosis and Fault Tolerant Control

DEFF Research Database (Denmark)

Blanke, Mogens

2001-01-01

Faults in steering, navigation instruments or propulsion machinery are serious on a marine vessel since the consequence could be loss of maneuvering ability, and imply risk of damage to vessel personnel or environment. Early diagnosis and accomodation of faults could enhance safety. Fault...... of properties of a falty system; means to determine remedial actions. The paper illustrates the techniques by two marine examples, sensor fusion for automatic steering and control of the main engine....

TED: A Tolerant Edit Distance for segmentation evaluation.

Science.gov (United States)

Funke, Jan; Klein, Jonas; Moreno-Noguer, Francesc; Cardona, Albert; Cook, Matthew

2017-02-15

In this paper, we present a novel error measure to compare a computer-generated segmentation of images or volumes against ground truth. This measure, which we call Tolerant Edit Distance (TED), is motivated by two observations that we usually encounter in biomedical image processing: (1) Some errors, like small boundary shifts, are tolerable in practice. Which errors are tolerable is application dependent and should be explicitly expressible in the measure. (2) Non-tolerable errors have to be corrected manually. The effort needed to do so should be reflected by the error measure. Our measure is the minimal weighted sum of split and merge operations to apply to one segmentation such that it resembles another segmentation within specified tolerance bounds. This is in contrast to other commonly used measures like Rand index or variation of information, which integrate small, but tolerable, differences. Additionally, the TED provides intuitive numbers and allows the localization and classification of errors in images or volumes. We demonstrate the applicability of the TED on 3D segmentations of neurons in electron microscopy images where topological correctness is arguable more important than exact boundary locations. Furthermore, we show that the TED is not just limited to evaluation tasks. We use it as the loss function in a max-margin learning framework to find parameters of an automatic neuron segmentation algorithm. We show that training to minimize the TED, i.e., to minimize crucial errors, leads to higher segmentation accuracy compared to other learning methods. Copyright © 2016. Published by Elsevier Inc.

A randomized double-masked study to compare the ocular safety, tolerability, and efficacy of bromfenac 0.075% compared with vehicle in cataract surgery subjects

Science.gov (United States)

Hosseini, Kamran; Walters, Thomas; DaVanzo, Robert; Lindstrom, Richard L

2016-01-01

Purpose The aim of this study was to evaluate the safety, tolerability, and efficacy of a low-dose version of bromfenac 0.075% in DuraSite® (bromfenac 0.075%) compared with DuraSite® vehicle (vehicle) alone for the treatment of postoperative inflammation and ocular pain after cataract surgery. Methods A multicenter, double-masked, vehicle-controlled, parallel-group clinical trial of 240 subjects randomized in a 2:1 ratio to bromfenac 0.075% or vehicle was conducted. Subjects were dosed BID beginning 1 day before the cataract surgery, the day of surgery, and 14 days after surgery. A slit lamp biomicroscopy examination was performed to evaluate the signs of inflammation, including anterior chamber cells (ACC) and anterior chamber flare (ACF). The primary efficacy variable was the proportion of subjects with an ACC grade of 0 at Day 15. Secondary efficacy endpoints included the proportion of subjects who achieved a pain score of 0 at each postsurgical visual analog scale (VAS) assessment and the proportion of subjects with an ACF grade of 0 at Day 15. Results At Day 15, proportionally more subjects in the bromfenac 0.075% group than in the vehicle group had an ACC grade of 0 (57.1% vs 18.8%, respectively; P<0.001). At each of the postsurgical time points (Days 1, 8, 15, and 29), proportionally more bromfenac 0.075%-treated subjects (76.8%, 90.5%, 92.9%, and 85.1%, respectively) had no pain (a VAS score of 0) compared with the vehicle-treated subjects (48.2%, 38.8%, 42.4%, and 47.1%, respectively), and at each time point, these differences in proportions were statistically significant (P<0.001). More subjects in the bromfenac 0.075% group had complete ACF resolution (151/167; 90.4%) compared to those in the vehicle group (54/85; 63.5%). There were no new safety signals reported. Conclusion Bromfenac 0.075% in DuraSite is safe, well tolerated, and effective at reducing inflammation and preventing pain associated with cataract surgery. PMID:27920490

Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

Science.gov (United States)

Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

2014-09-01

We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

Fault-tolerant Control of a Cyber-physical System

Science.gov (United States)

Roxana, Rusu-Both; Eva-Henrietta, Dulf

2017-10-01

Cyber-physical systems represent a new emerging field in automatic control. The fault system is a key component, because modern, large scale processes must meet high standards of performance, reliability and safety. Fault propagation in large scale chemical processes can lead to loss of production, energy, raw materials and even environmental hazard. The present paper develops a multi-agent fault-tolerant control architecture using robust fractional order controllers for a (13C) cryogenic separation column cascade. The JADE (Java Agent DEvelopment Framework) platform was used to implement the multi-agent fault tolerant control system while the operational model of the process was implemented in Matlab/SIMULINK environment. MACSimJX (Multiagent Control Using Simulink with Jade Extension) toolbox was used to link the control system and the process model. In order to verify the performance and to prove the feasibility of the proposed control architecture several fault simulation scenarios were performed.

Ferrocyanide Safety Program: Data requirements for the ferrocyanide safety issue developed through the data quality objectives (DQO) process

International Nuclear Information System (INIS)

Buck, J.W.; Anderson, C.M.; Pulsipher, B.A.; Toth, J.J.; Turner, P.J.; Cash, R.J.; Dukelow, G.T.; Meacham, J.E.

1993-12-01

This document records the data quality objectives (DQO) process applied to the Ferrocyanide Waste Tank Safety Issue at the Hanford Site by the Pacific Northwest Laboratory and Westinghouse Hanford Company. Specifically, the major recommendations and findings from this Ferrocyanide DQO process are presented so that decision makers can determine the type, quantity, and quality of data required for addressing tank safety issues. The decision logic diagrams and error tolerance equations also are provided. Finally, the document includes the DQO sample-size formulas for determining specific tank sampling requirements

Involvement of a hypersensitive-like reaction in tolerance to fire ...

African Journals Online (AJOL)

Gene expression time course showed that expression of chloroplast, mitochondrial and nuclear genes, whose transcription is redox-dependent, was down regulated or suppressed in tolerant cultivar, Harrow Sweet, in comparison with susceptible cultivar, Williams. Monitoring of oxidative burst by localization of hydrogen ...

Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters.

Science.gov (United States)

Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

2017-12-01

The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled "Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers" (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73.

Meat Processing Plant Microbiome and Contamination Patterns of Cold-Tolerant Bacteria Causing Food Safety and Spoilage Risks in the Manufacture of Vacuum-Packaged Cooked Sausages.

Science.gov (United States)

Hultman, Jenni; Rahkila, Riitta; Ali, Javeria; Rousu, Juho; Björkroth, K Johanna

2015-10-01

Refrigerated food processing facilities are specific man-made niches likely to harbor cold-tolerant bacteria. To characterize this type of microbiota and study the link between processing plant and product microbiomes, we followed and compared microbiota associated with the raw materials and processing stages of a vacuum-packaged, cooked sausage product affected by a prolonged quality fluctuation with occasional spoilage manifestations during shelf life. A total of 195 samples were subjected to culturing and amplicon sequence analyses. Abundant mesophilic psychrotrophs were detected within the microbiomes throughout the different compartments of the production plant environment. However, each of the main genera of food safety and quality interest, e.g., Leuconostoc, Brochothrix, and Yersinia, had their own characteristic patterns of contamination. Bacteria from the genus Leuconostoc, commonly causing spoilage of cold-stored, modified-atmosphere-packaged foods, were detected in high abundance (up to >98%) in the sausages studied. The same operational taxonomic units (OTUs) were, however, detected in lower abundances in raw meat and emulsion (average relative abundance of 2%±5%), as well as on the processing plant surfaces (food safety concerns related to their resilient existence on surfaces. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Efficacy and Safety of Low-Dose-Rate Endorectal Brachytherapy as a Boost to Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Distal Rectal Cancer: A Phase-II Clinical Trial.

Science.gov (United States)

Omidvari, Shapour; Zohourinia, Shadi; Ansari, Mansour; Ghahramani, Leila; Zare-Bandamiri, Mohammad; Mosalaei, Ahmad; Ahmadloo, Niloofar; Pourahmad, Saeedeh; Nasrolahi, Hamid; Hamedi, Sayed Hasan; Mohammadianpanah, Mohammad

2015-08-01

Despite advances in rectal cancer treatment over the last decade, local control and risk of late side effects due to external beam radiation therapy (EBRT) remain as concerns. The present study aimed to investigate the efficacy and the safety of low-dose-rate endorectal brachytherapy (LDRBT) as a boost to neoadjuvant chemoradiation for use in treating locally advanced distal rectal adenocarcinomas. This phase-II clinical trial included 34 patients (as the study arm) with newly diagnosed, locally advanced (clinical T3-T4 and/or N1/N2, M0) lower rectal cancer. For comparative analysis, 102 matched patients (as the historical control arm) with rectal cancer were also selected. All the patients were treated with LDRBT (15 Gy in 3 fractions) and concurrent chemoradiation (45-50.4 Gy). Concurrent chemotherapy consisted of oxaliplatin 130 mg/m(2) intravenously on day 1 plus oral capecitabine 825 mg/m(2) twice daily during LDRBT and EBRT. The study results revealed a significant differences between the study arm and the control arm in terms in the pathologic tumor size (2.1 cm vs. 3.6 cm, P = 0.001), the pathologic tumor stage (35% T3-4 vs. 65% T3-4, P = 0.003), and the pathologic complete response (29.4% vs. 11.7%, P < 0.028). Moreover, a significantly higher dose of EBRT (P = 0.041) was found in the control arm, and a longer time to surgery was observed in the study arm (P < 0.001). The higher rate of treatment-related toxicities, such as mild proctitis and anemia, in the study arm was tolerable and easily manageable. A boost of LDRBT can optimize the pathologic complete response, with acceptable toxicities, in patients with distal rectal cancer.

Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis.

NARCIS (Netherlands)

Kerkhof, P.C.M. van de; Berth-Jones, J.; Griffiths, C.E.; Harrison, P.V.; Honigsmann, H.; Marks, R.; Roelandts, R.; Schopf, E.; Trompke, C.

2002-01-01

BACKGROUND: As psoriasis patients often require continuous treatment optimal therapy has to provide efficacy and a good safety profile over the long term. OBJECTIVES: The aim of this multicentre study was to assess the efficacy, safety and tolerability of tacalcitol (4 microg g(-1)) ointment

Colonising Safety : creating risk through the enforcement of biomedical constructions of safety.

NARCIS (Netherlands)

Kadetz, P.

2013-01-01

In the normative health care discourse, safety is represented as a concept that is at once universal, irrefutable, and inherently beneficent. Yet, research at local levels in the Philippines challenges these assumptions embedded in the biomedical construction of safety. This article examines how the

Oral Glucose Tolerance Test Revisted | Mshelia | Nigerian Journal of ...

African Journals Online (AJOL)

Objective: The present review was undertaken to create the required utilization of oral glucose tolerance test in a developing country with a high prevalence of diabetes mellitus and its complications. Sources of data: This review is primarily based on available literature on local and international studies on oral glucose ...

Idaho Safety Manual.

Science.gov (United States)

Idaho State Dept. of Education, Boise. Div. of Vocational Education.

This manual is intended to help teachers, administrators, and local school boards develop and institute effective safety education as a part of all vocational instruction in the public schools of Idaho. This guide is organized in 13 sections that cover the following topics: introduction to safety education, legislation, levels of responsibility,…

Tolerance and safety evaluation of N,N-dimethylglycine, a naturally occurring organic compound, as a feed additive in broiler diets.

Science.gov (United States)

Kalmar, Isabelle D; Verstegen, Martin W A; Maenner, Klaus; Zentek, Jurgen; Meulemans, Godelieve; Janssens, Geert P J

2012-06-01

N,N-Dimethylglycine (DMG) is a tertiary amino acid that naturally occurs as an intermediate metabolite in choline-to-glycine metabolism. The objective of the present trial was to evaluate tolerance, safety and bioaccumulation of dietary DMG in broilers when supplemented at 1 g and 10 g Na-DMG/kg. A feeding trial was conducted using 480 1-d-old broiler chicks that were randomly allocated to twenty-four pens and fed one of three test diets added with 0, 1 or 10 g Na-DMG/kg during a 39 d growth period. Production performance was recorded to assess tolerance and efficacy of the supplement. At the end of the trial, toxicity was evaluated by means of haematology, plasma biochemistry and histopathology of liver, kidney and heart (n 12), whereas bioaccumulation was assessed on breast meat, liver, blood, kidney and adipose tissue (n 8). Carcass traits were similar between the control and 1 g Na-DMG/kg feed groups (P>0·05), but the feed:gain ratio was significantly improved at 1 g Na-DMG/kg feed compared with the control or the 10-fold dose (P=0·008). Histological examinations showed no pathological effects and results of haematology and plasma biochemistry revealed similar values between the test groups (P>0·05). Bioaccumulation occurred at the 10-fold dose, but the resulting DMG content in breast meat was comparable with, for instance, wheat bran and much lower than uncooked spinach. In conclusion, DMG at 1 g Na-DMG/kg improved the feed:gain ratio in broilers without DMG being accumulated in consumer parts. Furthermore, dietary supplementation with DMG up to 10 g Na-DMG/kg did not induce toxicity or impaired performance in broilers.

Concomitant chemo-radiotherapy for the locally advanced rectum cancer; Chimioradiotherapie concomitante dans le cancer du rectum localement evolue

Energy Technology Data Exchange (ETDEWEB)

Haoui, M.; Aksil, N.; Boualga, K.; Moussaoui, D.; Ladj, O. [Service de radiotherapie-oncologie, centre anti-cancer, Blida (Algeria)

2010-10-15

The authors report a retrospective study which aimed at assessing the use of a concomitant chemo-radiotherapy, its tolerance and its feasibility in the case of a locally advanced rectum cancer. Based on data obtained among 62 patients presenting a rectum cancer, they analyse the results in terms of tolerance (cases of leukopenia, anemia, diarrhea, radiodermatitis), of relapses, and survival. Toxicity is acceptable and the concomitant treatment renders the tumour operable in many cases. Short communication

Defect-Tolerant Monolayer Transition Metal Dichalcogenides

DEFF Research Database (Denmark)

Pandey, Mohnish; Rasmussen, Filip Anselm; Kuhar, Korina

2016-01-01

Localized electronic states formed inside the band gap of a semiconductor due to crystal defects can be detrimental to the material's optoelectronic properties. Semiconductors with a lower tendency to form defect induced deep gap states are termed defect-tolerant. Here we provide a systematic first...... the gap. These ideas are made quantitative by introducing a descriptor that measures the degree of similarity of the conduction and valence band manifolds. Finally, the study is generalized to nonpolar nanoribbons of the TMDs where we find that only the defect sensitive materials form edge states within......-principles investigation of defect tolerance in 29 monolayer transition metal dichalcogenides (TMDs) of interest for nanoscale optoelectronics. We find that the TMDs based on group VI and X metals form deep gap states upon creation of a chalcogen (S, Se, Te) vacancy, while the TMDs based on group IV metals form only...

Crafting tolerance

DEFF Research Database (Denmark)

Kirchner, Antje; Freitag, Markus; Rapp, Carolin

2011-01-01

Ongoing changes in social structures, orientation, and value systems confront us with the growing necessity to address and understand transforming patterns of tolerance as well as specific aspects, such as social tolerance. Based on hierarchical analyses of the latest World Values Survey (2005......–08) and national statistics for 28 countries, we assess both individual and contextual aspects that influence an individual's perception of different social groupings. Using a social tolerance index that captures personal attitudes toward these groupings, we present an institutional theory of social tolerance. Our...

An approach to the verification of a fault-tolerant, computer-based reactor safety system: A case study using automated reasoning: Volume 1: Interim report

International Nuclear Information System (INIS)

Chisholm, G.H.; Kljaich, J.; Smith, B.T.; Wojcik, A.S.

1987-01-01

The purpose of this project is to explore the feasibility of automating the verification process for computer systems. The intent is to demonstrate that both the software and hardware that comprise the system meet specified availability and reliability criteria, that is, total design analysis. The approach to automation is based upon the use of Automated Reasoning Software developed at Argonne National Laboratory. This approach is herein referred to as formal analysis and is based on previous work on the formal verification of digital hardware designs. Formal analysis represents a rigorous evaluation which is appropriate for system acceptance in critical applications, such as a Reactor Safety System (RSS). This report describes a formal analysis technique in the context of a case study, that is, demonstrates the feasibility of applying formal analysis via application. The case study described is based on the Reactor Safety System (RSS) for the Experimental Breeder Reactor-II (EBR-II). This is a system where high reliability and availability are tantamount to safety. The conceptual design for this case study incorporates a Fault-Tolerant Processor (FTP) for the computer environment. An FTP is a computer which has the ability to produce correct results even in the presence of any single fault. This technology was selected as it provides a computer-based equivalent to the traditional analog based RSSs. This provides a more conservative design constraint than that imposed by the IEEE Standard, Criteria For Protection Systems For Nuclear Power Generating Stations (ANSI N42.7-1972)

Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial.

Science.gov (United States)

Granel, Brigitte; Daumas, Aurélie; Jouve, Elisabeth; Harlé, Jean-Robert; Nguyen, Pierre-Sébastien; Chabannon, Christian; Colavolpe, Nathalie; Reynier, Jean-Charles; Truillet, Romain; Mallet, Stéphanie; Baiada, Antoine; Casanova, Dominique; Giraudo, Laurent; Arnaud, Laurent; Veran, Julie; Sabatier, Florence; Magalon, Guy

2015-12-01

In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed. This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. GFRS (Groupe Francophone de Recherche sur la Sclérodermie). NCT01813279. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Noise tolerant spatiotemporal chaos computing.

Science.gov (United States)

Kia, Behnam; Kia, Sarvenaz; Lindner, John F; Sinha, Sudeshna; Ditto, William L

2014-12-01

We introduce and design a noise tolerant chaos computing system based on a coupled map lattice (CML) and the noise reduction capabilities inherent in coupled dynamical systems. The resulting spatiotemporal chaos computing system is more robust to noise than a single map chaos computing system. In this CML based approach to computing, under the coupled dynamics, the local noise from different nodes of the lattice diffuses across the lattice, and it attenuates each other's effects, resulting in a system with less noise content and a more robust chaos computing architecture.

Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

Science.gov (United States)

Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

2014-03-01

The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

Desonide: a review of formulations, efficacy and safety.

Science.gov (United States)

Kahanek, Nr; Gelbard, Cg; Hebert, Aa

2008-07-01

Desonide is a low-potency topical corticosteroid that has been used for decades in the treatment of steroid-responsive dermatoses. The favorable safety profile of this topical agent makes it ideal for patients of all ages. This article provides a review of desonide's history, pharmacodynamic properties, vehicle technology, efficacy and safety. Randomized controlled trials, as well as open-label and non-comparative studies, case series and reports, experimental models, and data from the Galderma pharmacovigiliance program were reviewed in order to address the clinical efficacy and safety of desonide. Clinical efficacy and safety have been proven in multiple clinical trials. In addition to cream, lotion and ointment formulations, the recently developed hydrogel and foam preparations have increased desonide's versatility and patient tolerability.

Chloroplast RNA-Binding Protein RBD1 Promotes Chilling Tolerance through 23S rRNA Processing in Arabidopsis.

Directory of Open Access Journals (Sweden)

Shuai Wang

2016-05-01

Full Text Available Plants have varying abilities to tolerate chilling (low but not freezing temperatures, and it is largely unknown how plants such as Arabidopsis thaliana achieve chilling tolerance. Here, we describe a genome-wide screen for genes important for chilling tolerance by their putative knockout mutants in Arabidopsis thaliana. Out of 11,000 T-DNA insertion mutant lines representing half of the genome, 54 lines associated with disruption of 49 genes had a drastic chilling sensitive phenotype. Sixteen of these genes encode proteins with chloroplast localization, suggesting a critical role of chloroplast function in chilling tolerance. Study of one of these proteins RBD1 with an RNA binding domain further reveals the importance of chloroplast translation in chilling tolerance. RBD1 is expressed in the green tissues and is localized in the chloroplast nucleoid. It binds directly to 23S rRNA and the binding is stronger under chilling than at normal growth temperatures. The rbd1 mutants are defective in generating mature 23S rRNAs and deficient in chloroplast protein synthesis especially under chilling conditions. Together, our study identifies RBD1 as a regulator of 23S rRNA processing and reveals the importance of chloroplast function especially protein translation in chilling tolerance.

Design of passive fault-tolerant flight controller against actuator failures

Directory of Open Access Journals (Sweden)

Xiang Yu

2015-02-01

Full Text Available The problem of designing passive fault-tolerant flight controller is addressed when the normal and faulty cases are prescribed. First of all, the considered fault and fault-free cases are formed by polytopes. As considering that the safety of a post-fault system is directly related to the maximum values of physical variables in the system, peak-to-peak gain is selected to represent the relationships among the amplitudes of actuator outputs, system outputs, and reference commands. Based on the parameter dependent Lyapunov and slack methods, the passive fault-tolerant flight controllers in the absence/presence of system uncertainty for actuator failure cases are designed, respectively. Case studies of an airplane under actuator failures are carried out to validate the effectiveness of the proposed approach.

Bioinformatics approach of salt tolerance gene in mangrove plant Rhizophora stylosa

Science.gov (United States)

Basyuni, M.; Sumardi

2017-01-01

This study descibes bioinformatics approach on the analyze of the salt tolerance genes in mangrove plant, Rhizophora stylosa on DDBJ/EMBL/GenBank as well as similarity, phylogenetic, potential peptide, and subcellular localization. The DNA sequence between salt tolerance gene from R. stylosa exhibited 42-11% between themselves The target peptide value of mitochondria varied from 0.163 to 0.430, indicated it was possible to exist. These results suggested the importance of understanding the diversity and functional of properties of the different amino acids in mangrove OSC genes. To clarify the relationship among the salt-tolerant genes in R. stylosa, a phylogenetic tree was constructed. The phylogenetic tree shows that there are three clusters, first branch of Cu/Zn SOD and reverse transcriptase genes, the second branch consists of the majority genes and the last group was MAP3K alpha protein kinase only. The present study, therefore, suggested that salt tolerance genes form distinct clusters in the tree.

Non-clinical safety evaluation of intranasal iota-carrageenan.

Science.gov (United States)

Hebar, Alexandra; Koller, Christiane; Seifert, Jan-Marcus; Chabicovsky, Monika; Bodenteich, Angelika; Bernkop-Schnürch, Andreas; Grassauer, Andreas; Prieschl-Grassauer, Eva

2015-01-01

Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded) iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug's action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application.

Non-clinical safety evaluation of intranasal iota-carrageenan.

Directory of Open Access Journals (Sweden)

Alexandra Hebar

Full Text Available Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug's action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application.

Safety regulations: Implications of the new risk perspectives

International Nuclear Information System (INIS)

Aven, T.; Ylönen, M.

2016-01-01

The current safety regulations for industrial activities are to a large extent functionally oriented and risk-based (informed), expressing what to achieve rather than the means and solutions needed. They are founded on a probability-based perspective on risk, with the use of risk assessment, risk acceptance criteria and tolerability limits. In recent years several risk researchers have argued for the adoption of some new types of risk perspectives which highlight uncertainties rather than probabilities in the way risk is defined, the point being to better reflect the knowledge, and lack of knowledge, dimension of risk. The Norwegian Petroleum Safety Authority has recently implemented such a perspective. The new ISO standard 31000 is based on a similar thinking. In this paper we discuss the implications of these perspectives on safety regulation, using the oil & gas and nuclear industries as illustrations. Several suggestions for how to develop the current safety regulations in line with the ideas of the new risk perspectives are outlined, including some related to the use of risk acceptance criteria (tolerability limits). We also point to potential obstacles and incentives that the larger societal and institutional setting may impose on industry as regards the adoption of the new risk perspectives. - Highlights: • Some new types of risk perspectives have been promoted. • They have been implemented for example by the Norwegian Petroleum Safety Authority. • The paper studies the implication of these perspectives on the risk regulation. • Suggestions for how to develop the regulations are provided • Obstacles and incentives for the implementation of the perspectives are pointed to.

Mast cell protease 6 is required for allograft tolerance.

Science.gov (United States)

de Vries, V C; Elgueta, R; Lee, D M; Noelle, R J

2010-09-01

It has been shown that mast cells (MC) are absolutely required for transplant acceptance. However, only a few of the numerous mediators produced by MC have been proposed as potential mechanisms for the observed immunosuppression. The role of proteases in acquired immune tolerance as such has not yet been addressed. In this study, we have shown the requirement for MC protease 6 (MCP6), an MC-specific tryptase, to establish tolerance toward an allogeneic skin graft. The substrate for MCP6 is interleukin (IL)-6, cytokine generally considered to indicate transplant rejection. Herein we have shown an inverse correlation between MCP6 and IL-6. High expression of MCP6 is accompanied by low levels of IL-6 when the allograft is accepted, whereas low expression of MCP6 in combination with high levels of IL-6 are observed in rejecting grafts. Moreover, tolerance toward an allogeneic graft cannot be induced in MCP6(-/-) mice. Rejection observed in these mice was comparable to that of MC-deficient hosts; it is T-cell mediated. These findings suggest that MCP6 actively depletes the local environment of IL-6 to maintain tolerance. 2010. Published by Elsevier Inc.

Air Pollution tolerance indices (apti) of some plants around Otorogun ...

African Journals Online (AJOL)

MICHAEL

ABSTRACT: The study examined the air pollution tolerance indices (APTI) of six plant species around. Otorogun gas plant in Ughelli-South Local Government Area of Delta State. Four physiological and biochemical parameters, which are leaf relative water content (RWC), Ascorbic acid content (AA), total leaf chlorophyll ...

Tachyphylaxis to local anaesthetics. What is the clinical evidence?

DEFF Research Database (Denmark)

Kongsgaard, U E; Werner, M U

2016-01-01

: We performed a systematic review of the literature utilising the databases PubMed and Embase employing the search terms [Tachyphylaxis AND Local Anaesthetics AND Human] AND [Tolerance AND Local Anaesthetics AND Human]. RESULTS: A total of 66 records were identified. Thirty-four articles were assessed...

Compromise and Toleration

DEFF Research Database (Denmark)

Rostbøll, Christian F.

Political compromise is akin to toleration, since both consist of an "agreement to disagree." Compromise and toleration also share a predicament of being regarded as ambiguous virtues that require of us to accept something we actually regard as wrong. However, we misunderstand the nature, justifi...... in compromise are more stringent than those for being tolerated. Still, the limits of compromise cannot be drawn to narrowly if it is to remain its value as a form of agreement that respects and embodies the differences of opinion in society.......Political compromise is akin to toleration, since both consist of an "agreement to disagree." Compromise and toleration also share a predicament of being regarded as ambiguous virtues that require of us to accept something we actually regard as wrong. However, we misunderstand the nature......, justification, and limits of compromise if we see it merely as a matter of toleration. While toleration is mainly a matter of accepting citizens' equal right to co-existence as subjects to law, political compromise includes the parties in making law – it makes them co-authors of law. Toleration entails...

Differential tolerance to nickel between Dreissena polymorpha and Dreissena rostriformis bugensis populations.

Science.gov (United States)

Potet, Marine; Giambérini, Laure; Pain-Devin, Sandrine; Louis, Fanny; Bertrand, Carole; Devin, Simon

2018-01-15

Differential tolerance to stress is partly responsible for the heterogeneity of biomarker responses between populations of a sentinel species. Although currently used for freshwater biomonitoring, studies concerning inter-populational variability in tolerance to contaminants for the zebra mussel (Dreissena polymorpha) are scarce. Moreover, this well-known invader is currently replaced by another, the quagga mussel (Dreissena rostriformis bugensis). To evaluate the differential tolerance between dreissenids, several populations of both species were exposed to a high concentration of nickel. A LT 50 (time when 50% of individuals were dead) was established for each population. Biomarker responses and internal nickel concentration were also measured, to link tolerance with physiological status. Results evidenced that D. polymorpha populations are more heterogeneous and more tolerant than D. r. bugensis ones. For D. polymorpha populations only, LT 50 values were positively correlated with the nickel contamination in situ, with higher anti-oxidative defences and a higher Integrated Biomarker Response value in the field. Such findings may be explained by local adaptation and invasion dynamic within each species. The significance of this differential tolerance when using biomarker responses for biomonitoring purposes is thus discussed.

Sulfasalazine efficacy and tolerability in rheumatic diseases

Directory of Open Access Journals (Sweden)

V. V. Badokin

2005-01-01

Full Text Available Sulfasalazine is one of the main disease modifying drugs for the treatment of chronic inflammatory joint and spine diseases. The article describes mechanism of action of sulfasalazine and its main metabolites. Detailed information about anti-inflammatory and immunosuppressive action of the drug is presented. Results of many studies of sulfasalazine efficacy in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and reactive arthritis are discussed from the evidence based medicine point of view. Data on sulfasalazine tolerability and safety are presented with separate discussion of hypersensitivity and dose-dependent adverse reactions so as their treatment and prophylaxis.

Recognition and Toleration

DEFF Research Database (Denmark)

Lægaard, Sune

2010-01-01

Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms...... or interpretations of recognition and toleration are considered, confusing and problematic uses of the terms are noted, and the compatibility of toleration and recognition is discussed. The article argues that there is a range of legitimate and importantly different conceptions of both toleration and recognition...

Teaching Tolerance? Associational Diversity and Tolerance Formation

DEFF Research Database (Denmark)

Rapp, Carolin; Freitag, Markus

2015-01-01

, a closer look is taken at how associational diversity relates to the formation of tolerance and the importance of associations as schools of tolerance are evaluated. The main theoretical argument follows contact theory, wherein regular and enduring contact in diverse settings reduces prejudice and thereby...

Environmental restoration and decontamination and decommissioning safety documentation

International Nuclear Information System (INIS)

Hansen, J.L.; Frauenholz, L.H.; Kerr, N.R.

1993-01-01

This document presents recommendations of a working group designated by the Environmental Restoration and Remediation (ER) and Decontamination and Decommissioning (D ampersand D) subcommittees of the Westinghouse M ampersand O (Management and Operation) Nuclear Facility Safety Committee. A commonalty of approach to safety documentation specific to ER and D ampersand D activities was developed and is summarized below. Allowance for interpretative tolerance and documentation flexibility appropriate to the activity, graded for hazard category, duration, and complexity, was a primary consideration in development of this guidance

Functional genomics of physiological plasticity and local adaptation in killifish.

Science.gov (United States)

Whitehead, Andrew; Galvez, Fernando; Zhang, Shujun; Williams, Larissa M; Oleksiak, Marjorie F

2011-01-01

Evolutionary solutions to the physiological challenges of life in highly variable habitats can span the continuum from evolution of a cosmopolitan plastic phenotype to the evolution of locally adapted phenotypes. Killifish (Fundulus sp.) have evolved both highly plastic and locally adapted phenotypes within different selective contexts, providing a comparative system in which to explore the genomic underpinnings of physiological plasticity and adaptive variation. Importantly, extensive variation exists among populations and species for tolerance to a variety of stressors, and we exploit this variation in comparative studies to yield insights into the genomic basis of evolved phenotypic variation. Notably, species of Fundulus occupy the continuum of osmotic habitats from freshwater to marine and populations within Fundulus heteroclitus span far greater variation in pollution tolerance than across all species of fish. Here, we explore how transcriptome regulation underpins extreme physiological plasticity on osmotic shock and how genomic and transcriptomic variation is associated with locally evolved pollution tolerance. We show that F. heteroclitus quickly acclimate to extreme osmotic shock by mounting a dramatic rapid transcriptomic response including an early crisis control phase followed by a tissue remodeling phase involving many regulatory pathways. We also show that convergent evolution of locally adapted pollution tolerance involves complex patterns of gene expression and genome sequence variation, which is confounded with body-weight dependence for some genes. Similarly, exploiting the natural phenotypic variation associated with other established and emerging model organisms is likely to greatly accelerate the pace of discovery of the genomic basis of phenotypic variation.

Data requirements for the Ferrocyanide Safety Issue developed through the data quality objectives process

International Nuclear Information System (INIS)

Meacham, J.E.; Cash, R.J.; Dukelow, G.T.; Babad, H.; Buck, J.W.; Anderson, C.M.; Pulsipher, B.A.; Toth, J.J.; Turner, P.J.

1994-08-01

This document records the data quality objectives (DQO) process applied to the Ferrocyanide Safety Issue at the Hanford Site. Specifically, the major recommendations and findings from this Ferrocyanide DQO process are presented. The decision logic diagrams and decision error tolerances also are provided. The document includes the DQO sample-size formulas for determining specific tank sampling requirements, and many of the justifications for decision thresholds and decision error tolerances are briefly described. More detailed descriptions are presented in other Ferrocyanide Safety Program companion documents referenced in this report. This is a living document, and the assumptions contained within will be refined as more data from sampling and characterization become available

Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.

Directory of Open Access Journals (Sweden)

Vincent Meininger

Full Text Available The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS; it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1 to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg or placebo. In Part 2, 36 subjects were randomized (3∶1 to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG, and clinical laboratory tests. Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological, and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated

Mechanical tolerance stackup and analysis

CERN Document Server

Fischer, Bryan R

2004-01-01

BackgroundDimensioning and TolerancingTolerance Format and Decimal PlacesConverting Plus/Minus Dimensions and Tolerances into Equal Bilaterally Toleranced DimensionsVariation and Sources of VariationTolerance AnalysisWorst-case Tolerance StackupsStatistical Tolerance StackupsGeometric Dimensioning and Tolerancing (GD&T)Converting Plus/Minus Tolerancing to Positional Tolerancing and Projected Tolerance ZonesDiametral and Radial Tolerance StackupsSpecifying Material Condition Modifiers and Their Effect on Tolerance Stackups The Tolerance Stackup SketchThe Tolerance Stackup Report FormTolerance S

Improving patient safety in radiology: a work in progress

International Nuclear Information System (INIS)

Sze, Raymond W.

2008-01-01

The purpose of this paper is to share the experiences, including successes and failures, as well as the ongoing process of developing and implementing a safety program in a large pediatric radiology department. Building a multidisciplinary pediatric radiology safety team requires successful recruitment of team members, selection of a team leader, and proper and ongoing training and tools, and protected time. Challenges, including thorough examples, are presented on improving pediatric radiology safety intradepartmentally, interdepartmentally, and institutionally. Finally, some major challenges to improving safety in pediatric radiology, and healthcare in general, are presented along with strategies to overcome these challenges. Our safety program is a work in progress; this article is a personal account and the reader is asked for tolerance of its occasional subjective tone and contents. (orig.)

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)

Drug safety evaluation of defibrotide.

Science.gov (United States)

Richardson, Paul G; Corbacioglu, Selim; Ho, Vincent Trien-Vinh; Kernan, Nancy A; Lehmann, Leslie; Maguire, Craig; Maglio, Michelle; Hoyle, Margaret; Sardella, Marco; Giralt, Sergio; Holler, Ernst; Carreras, Enric; Niederwieser, Dietger; Soiffer, Robert

2013-01-01

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). Defibrotide (DF) has been shown in Phase II and III trials to improve complete response in patients with severe VOD (sVOD). None of the articles, to date, provide a comprehensive review of the safety of DF in VOD and/or a range of other conditions. This article reviews current clinical findings on DF, primarily in terms of safety for use in treatment and prophylaxis of VOD, and relevant safety data for its use in other diseases. The literature review was conducted using a PubMed search with the fixed term 'defibrotide' in combination with ≥ 1 of 'safety', 'veno-occlusive disease' (with and without 'treatment', 'prevention'), 'oncology', 'myeloma', 'microangiopathy', 'anti-thrombotic' and 'peripheral vascular disorder'. Related articles from the EBMT and ASH conference websites were also included. DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD.

Safety and tolerability of high doses of glucocorticoides

Directory of Open Access Journals (Sweden)

Rakić Branislava D.

2016-01-01

Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

Tolerance to and cross tolerance between ethanol and nicotine.

Science.gov (United States)

Collins, A C; Burch, J B; de Fiebre, C M; Marks, M J

1988-02-01

Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.

LOFT pressurizer safety: relief valve reliability

Energy Technology Data Exchange (ETDEWEB)

Brown, E.S.

1978-01-18

The LOFT pressurizer self-actuating safety-relief valves are constructed to the present state-of-the-art and should have reliability equivalent to the valves in use on PWR plants in the U.S. There have been no NRC incident reports on valve failures to lift that would challenge the Technical Specification Safety Limit. Fourteen valves have been reported as lifting a few percentage points outside the +-1% Tech. Spec. surveillance tolerance (9 valves tested over and 5 valves tested under specification). There have been no incident reports on failures to reseat. The LOFT surveillance program for assuring reliability is equivalent to nuclear industry practice.

LOFT pressurizer safety: relief valve reliability

International Nuclear Information System (INIS)

Brown, E.S.

1978-01-01

The LOFT pressurizer self-actuating safety-relief valves are constructed to the present state-of-the-art and should have reliability equivalent to the valves in use on PWR plants in the U.S. There have been no NRC incident reports on valve failures to lift that would challenge the Technical Specification Safety Limit. Fourteen valves have been reported as lifting a few percentage points outside the +-1% Tech. Spec. surveillance tolerance (9 valves tested over and 5 valves tested under specification). There have been no incident reports on failures to reseat. The LOFT surveillance program for assuring reliability is equivalent to nuclear industry practice

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study.

Science.gov (United States)

Hunt, Hazel; Donaldson, Kirsteen; Strem, Mark; Zann, Vanessa; Leung, Pui; Sweet, Suzanne; Connor, Alyson; Combs, Dan; Belanoff, Joseph

2018-05-01

CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone. © 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

Science.gov (United States)

Malow, Beth; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2012-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures…

Open hemorrhoidectomy under local anesthesia for symptomatic ...

African Journals Online (AJOL)

standard treatment for prolapsed hemorrhoids. The procedure is commonly done under general or regional anesthesia. This study is aimed to assess the feasibility and tolerability of open – hemorrhoidectomy under local anaesthesia in our setting.

Understanding the safety and tolerability of facial filling therapeutics.

Science.gov (United States)

Kulichova, Daniela; Borovaya, Alyona; Ruzicka, Thomas; Thomas, Peter; Gauglitz, Gerd G

2014-09-01

Aesthetic medicine represents an emerging field for many specialties. Nowadays, a plethora of approaches are available to rejuvenate the human body and face, the latter being a frequent target for the placement of filling substances to correct wrinkles and volume loss. Nevertheless, based on the many products on the market, treating clinicians must pay specific attention to the properties of the respective materials, their associated side effects and any specific handling requirements to prevent potential short- and long-term adverse events. Types of filling materials, including biodegradable and non-biodegradable products, related complications, their conservative and invasive treatment options, as well as prevention strategies are described in this review. A profound knowledge of the facial anatomy as well as extensive experience with the various filling techniques and suitable materials for the respective areas remains crucial to prevent adverse events associated with filling procedures to the human face. Since side effects such as malar edema and foreign body granuloma do affect patients physically and psychologically to a significant extent and their successful treatment still remains challenging, further in depth studies on the tolerability of many filling materials utilized are required.

Transparent reliability model for fault-tolerant safety systems

International Nuclear Information System (INIS)

Bodsberg, Lars; Hokstad, Per

1997-01-01

A reliability model is presented which may serve as a tool for identification of cost-effective configurations and operating philosophies of computer-based process safety systems. The main merit of the model is the explicit relationship in the mathematical formulas between failure cause and the means used to improve system reliability such as self-test, redundancy, preventive maintenance and corrective maintenance. A component failure taxonomy has been developed which allows the analyst to treat hardware failures, human failures, and software failures of automatic systems in an integrated manner. Furthermore, the taxonomy distinguishes between failures due to excessive environmental stresses and failures initiated by humans during engineering and operation. Attention has been given to develop a transparent model which provides predictions which are in good agreement with observed system performance, and which is applicable for non-experts in the field of reliability

Relative safety profiles of high dose statin regimens

Directory of Open Access Journals (Sweden)

Carlos Escobar

2008-06-01

Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

Discussion on safety culture general contract model of consultation enterprises

International Nuclear Information System (INIS)

Dong Huimin; Zhang Hao

2012-01-01

With a high safety requirement, long construction period, a large amount of investment and many influencing factors of the preparation and implementation of project schedule, local nuclear power always is built through EPC. Safety level depends on EPC. Some measures should be taken for local consultation enterprises to improve situation of safety. Some suggestion as follows: safety culture should be received enough attention; management system should be established in according with requirement of safety culture; try to encourage employee involvement; to assess it in time; safety system should be entirely compatible with enterprises system. (authors)

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

Science.gov (United States)

Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

2015-07-01

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Local tolerance testing under REACH: Accepted non-animal methods are not on equal footing with animal tests.

Science.gov (United States)

Sauer, Ursula G; Hill, Erin H; Curren, Rodger D; Raabe, Hans A; Kolle, Susanne N; Teubner, Wera; Mehling, Annette; Landsiedel, Robert

2016-07-01

In general, no single non-animal method can cover the complexity of any given animal test. Therefore, fixed sets of in vitro (and in chemico) methods have been combined into testing strategies for skin and eye irritation and skin sensitisation testing, with pre-defined prediction models for substance classification. Many of these methods have been adopted as OECD test guidelines. Various testing strategies have been successfully validated in extensive in-house and inter-laboratory studies, but they have not yet received formal acceptance for substance classification. Therefore, under the European REACH Regulation, data from testing strategies can, in general, only be used in so-called weight-of-evidence approaches. While animal testing data generated under the specific REACH information requirements are per se sufficient, the sufficiency of weight-of-evidence approaches can be questioned under the REACH system, and further animal testing can be required. This constitutes an imbalance between the regulatory acceptance of data from approved non-animal methods and animal tests that is not justified on scientific grounds. To ensure that testing strategies for local tolerance testing truly serve to replace animal testing for the REACH registration 2018 deadline (when the majority of existing chemicals have to be registered), clarity on their regulatory acceptance as complete replacements is urgently required. 2016 FRAME.

Safety culture giving impetus to the development of nuclear power enterprise

International Nuclear Information System (INIS)

Zhang Ying

2011-01-01

Jiangsu Nuclear Power Corporation (JNPC) have been continuously assimilating excellent nuclear safety culture at home and abroad and improving the plant safety operation and internal management level of corporation since the successful construction of Phase I project and the gradual success of the expansion project. Implemented the 'top management 8 expectations', executed the '3 into 1' (quality, environment and occupational health safety) management system. The culture of 'zero tolerance' has been deeply rooted. The safety culture brings people's heart closer, which is not only accepted by the employees, but also climbs up to a higher level and adds momentum to the scientific development of Tianwan Nuclear Power Station Base. (author)

Advax™, a novel microcrystalline polysaccharide particle engineered from delta inulin, provides robust adjuvant potency together with tolerability and safety.

Science.gov (United States)

Petrovsky, Nikolai; Cooper, Peter D

2015-11-04

There is an ongoing need for new adjuvants to facilitate development of vaccines against HIV, tuberculosis, malaria and cancer, amongst many others. Unfortunately, the most potent adjuvants are often associated with toxicity and safety issues. Inulin, a plant-derived polysaccharide, has no immunological activity in its native soluble form but when crystallized into a stable microcrystalline particulate from (delta inulin) acquires potent adjuvant activity. Delta inulin has been shown to enhance humoral and cellular immune responses against a broad range of co-administered viral, bacterial, parasitic and toxin antigens. Inulin normally crystallizes as large heterogeneous particles with a broad size distribution and variable solubility temperatures. To ensure reproducible delta inulin particles with a consistent size distribution and temperature of solubility, a current Good Manufacturing Practice (cGMP) process was designed to produce Advax™ adjuvant. In its cCMP form, Advax™ adjuvant has proved successful in human trials of vaccines against seasonal and pandemic influenza, hepatitis B and insect sting anaphylaxis, enhancing antibody and T-cell responses while being safe and well tolerated. Advax™ adjuvant represents a novel human adjuvant that enhances both humoral and cellular immunity. This review describes the discovery and development of Advax™ adjuvant and research into its unique mechanism of action. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2017-12-01

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

Neck injury tolerance under inertial loads in side impacts.

Science.gov (United States)

McIntosh, Andrew S; Kallieris, Dimitrios; Frechede, Bertrand

2007-03-01

Neck injury remains a major issue in road safety. Current side impact dummies and side impact crashworthiness assessments do not assess the risk of neck injury. These assessments are limited by biofidelity and knowledge regarding neck injury criteria and tolerance levels in side impacts. Side impact tests with PMHS were performed at the Heidelberg University in the 1980s and 1990s to improve primarily the understanding of trunk dynamics, injury mechanisms and criteria. In order to contribute to the definition of human tolerances at neck level, this study presents an analysis of the head/neck biomechanical parameters that were measured in these tests and their relationship to neck injury severity. Data from 15 impact tests were analysed. Head accelerations, and neck forces and moments were calculated from 9-accelerometer array head data, X-rays and anthropometric data. Statistically significant relationships were observed between resultant head acceleration and neck force and neck injury severity. The average resultant head acceleration for AIS 2 neck injuries was 112 g, while resultant neck force was 4925 N and moment 241 Nm. The data compared well to other test data on cadavers and volunteers. It is hoped that the paper will assist in the understanding of neck injuries and the development of tolerance criteria.

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...

Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

Directory of Open Access Journals (Sweden)

Xu HR

2016-05-01

Full Text Available Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK, and pharmacodynamics (PD of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg, ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t and maximum plasma concentration (Cmax. Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively. Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (% and mean glucose area under effect curve 0–4 hours change from baseline (% (P<0.001. Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo. All adverse events were mild in intensity and resolved without any treatment

Electrochemotherapy increases local control after incomplete ...

African Journals Online (AJOL)

Ibrahim Eldaghayes

2016-11-24

Nov 24, 2016 ... The treatment was well tolerated, and the patient is still disease free after 12 months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in equines carrying soft tissue tumors. Keywords: Cisplatin, Electrochemotherapy, Equine, Fibrosarcoma.

A study on the feasibility and a possible form of local residents participation in nuclear safety regulation

International Nuclear Information System (INIS)

Lee, Sang Hoon; Son, Moon Kyu; Kim, Seong Sook

2003-02-01

It is expected that the results of this study will help policy makers in the government and nuclear industry enhance the confidence of local residents and citizens in the safety of nuclear energy. It is also believed that the citizen confidence on the nuclear energy will help them implement nuclear policies more efficiently and more safely. Considering that the newly sworn-in government is to involve citizens in wide variety of policy areas, this study fits with the policy directions of the new government. Most importantly, desirable citizen participation in public decision-making is to contribute to the enhancement of the working democracy

A study on the feasibility and a possible form of local residents participation in nuclear safety regulation

Energy Technology Data Exchange (ETDEWEB)

Lee, Sang Hoon; Son, Moon Kyu [Korea Association for Nuclear Technology, Taejon (Korea, Republic of); Kim, Seong Sook [Shila Univ., Busan (Korea, Republic of)

2003-02-15

It is expected that the results of this study will help policy makers in the government and nuclear industry enhance the confidence of local residents and citizens in the safety of nuclear energy. It is also believed that the citizen confidence on the nuclear energy will help them implement nuclear policies more efficiently and more safely. Considering that the newly sworn-in government is to involve citizens in wide variety of policy areas, this study fits with the policy directions of the new government. Most importantly, desirable citizen participation in public decision-making is to contribute to the enhancement of the working democracy.

Application of organ tolerance dose-constraints in clinical studies in radiation oncology

International Nuclear Information System (INIS)

Doerr, Wolfgang; Herrmann, Thomas; Baumann, Michael

2014-01-01

In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of ''tolerance doses'' in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one's own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology. (orig.) [de

Remember Tolerance Differently

DEFF Research Database (Denmark)

Tønder, Lars

2012-01-01

This essay questions the linear conception of history which often accompanies the way contemporary democratic theory tends to disavow tolerance's discontinuities and remainders. In the spirit of Foucault's genealogy of descent, the idea is to develop a new sense of tolerance's history, not by inv......This essay questions the linear conception of history which often accompanies the way contemporary democratic theory tends to disavow tolerance's discontinuities and remainders. In the spirit of Foucault's genealogy of descent, the idea is to develop a new sense of tolerance's history......, not by invoking a critique external to contemporary democratic theory, but by witnessing the history of tolerance paraliptically, with an eye to what it obscures and yet presupposes....

A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer

DEFF Research Database (Denmark)

Tyrrell, C J; Kaisary, A V; Iversen, P

1998-01-01

To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer.......To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer....

Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

Energy Technology Data Exchange (ETDEWEB)

Gillmann, Clarissa, E-mail: clarissa.gillmann@med.uni-heidelberg.de [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Jäkel, Oliver [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Heidelberg Ion Beam Therapy Center (HIT), Heidelberg (Germany); Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Schlampp, Ingmar [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Karger, Christian P. [Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany)

2014-04-01

Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a

The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.

Science.gov (United States)

Grossberg, George T; Manes, Facundo; Allegri, Ricardo F; Gutiérrez-Robledo, Luis Miguel; Gloger, Sergio; Xie, Lei; Jia, X Daniel; Pejović, Vojislav; Miller, Michael L; Perhach, James L; Graham, Stephen M

2013-06-01

Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9�

Induced tolerance from a sublethal insecticide leads to cross-tolerance to other insecticides.

Science.gov (United States)

Hua, Jessica; Jones, Devin K; Relyea, Rick A

2014-04-01

As global pesticide use increases, the ability to rapidly respond to pesticides by increasing tolerance has important implications for the persistence of nontarget organisms. A recent study of larval amphibians discovered that increased tolerance can be induced by an early exposure to low concentrations of a pesticide. Since natural systems are often exposed to a variety of pesticides that vary in mode of action, we need to know whether the induction of increased tolerance to one pesticide confers increased tolerance to other pesticides. Using larval wood frogs (Lithobates sylvaticus), we investigated whether induction of increased tolerance to the insecticide carbaryl (AChE-inhibitor) can induce increased tolerance to other insecticides that have the same mode of action (chlorpyrifos, malathion) or a different mode of action (Na(+)channel-interfering insecticides; permethrin, cypermethrin). We found that embryonic exposure to sublethal concentrations of carbaryl induced higher tolerance to carbaryl and increased cross-tolerance to malathion and cypermethrin but not to chlorpyrifos or permethrin. In one case, the embryonic exposure to carbaryl induced tolerance in a nonlinear pattern (hormesis). These results demonstrate that that the newly discovered phenomenon of induced tolerance also provides induced cross-tolerance that is not restricted to pesticides with the same mode of action.

Aluminium localization and toxicity symptoms related to root growth ...

Indian Academy of Sciences (India)

We correlated root growth inhibition with aluminium (Al3+) localization and toxicity symptoms in rice roots using seedlings of two genotypes (tolerant and sensitive) that were exposed to different AlCl3 concentrations. Al3+ localization was evaluated by hematoxylin in primary roots and by morin in cross-sections of the root ...

Safety and interlock system for Tristan

International Nuclear Information System (INIS)

Takeda, S.; Kudo, K.; Katoh, T.; Akiyama, A.

1987-01-01

This report describes alarm and interlock system of TRISTAN, concentrating on personnel safety. The basis of TRISTAN machine-control system (TMS) is an N-to-N computer network and KEK NODAL which offers high software productivity. TMC achieves high flexibility of operation both for normal operation and for the fast commissioning. However, to assure the safety of personnel and the TRISTAN machine operation, the safety system has to continue functioning during TMC failure as well. A distributed safety and interlock system (DSIS) is used for diversification of risks in TRISTAN system. DSIS is functionally subdivided along local system lines and has a hierarchical structure of 12 programmable sequence controllers (PSCs). Optical fiber links connect the PSCs at subsystem level and a PSC at the supervisory level of TRISTAN central control room (TCCR). The subsystem PSCs provide the interlock functions between their local devices. The local PSCs interact with the central system through a limited number of summarized signals. The central PSC provides the interlock functions between the subsystems and interacts with an operator's panel. Personnel safety is based on a system of electrical interlock keys, emergency push-buttons around the tunnel, at the entrance gates or in the control room

Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.

Science.gov (United States)

Moreno, Francisco A; Wiegand, Christopher B; Taitano, E Keolani; Delgado, Pedro L

2006-11-01

Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p

Electrochemotherapy increases local control after incomplete ...

African Journals Online (AJOL)

... horse with electrochemotherapy (ECT) using cisplatin as chemotherapy agent. Two sessions of ECT were performed at two-week intervals using local cisplatin followed by trains of biphasic electric pulses applied using different electrodes until complete coverage of the area was achieved. The treatment was well tolerated ...

[Safety and tolerability of GLP-1 receptor agonists].

Science.gov (United States)

Soldevila, Berta; Puig-Domingo, Manel

2014-09-01

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

An open-label, long-term study examining the safety and tolerability of pregabalin in Japanese patients with central neuropathic pain

Directory of Open Access Journals (Sweden)

Onouchi K

2014-07-01

Full Text Available Kenji Onouchi,1 Hiroaki Koga,2 Kazumasa Yokoyama,3 Tamotsu Yoshiyama4 1Aida Memorial Rehabilitation Hospital, Moriya, Japan; 2Kumamoto Rehabilitation Hospital, Kikuchi-Gun, Japan; 3Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; 4Pfizer Japan Inc., Tokyo, Japan Purpose: Studies of pregabalin for the treatment of central neuropathic pain have been limited to double-blind trials of 4–17 weeks in duration. The purpose of this study was to assess the long-term safety and tolerability of pregabalin in Japanese patients with central neuropathic pain. The efficacy of pregabalin was also assessed as a secondary measure. Patients and methods: This was a 53-week, multicenter, open-label trial of pregabalin (150–600 mg/day in Japanese patients with central neuropathic pain due to spinal cord injury, multiple sclerosis, or cerebral stroke. Results: A total of 103 patients received pregabalin (post-stroke =60; spinal cord injury =38; and multiple sclerosis =5. A majority of patients (87.4% experienced one or more treatment-related adverse events, most commonly somnolence, weight gain, dizziness, or peripheral edema. The adverse event profile was similar to that seen in other indications of pregabalin. Most treatment-related adverse events were mild (89.1% or moderate (9.2% in intensity. Pregabalin treatment improved total score, sensory pain, affective pain, visual analog scale (VAS, and present pain intensity scores on the Short-Form McGill Pain Questionnaire (SF-MPQ and ten-item modified Brief Pain Inventory (mBPI-10 total score at endpoint compared with baseline. Improvements in SF-MPQ VAS and mBPI-10 total scores were evident in all patient subpopulations. Mean changes from baseline in SF-MPQ VAS and mBPI-10 scores at endpoint were –20.1 and –1.4, respectively. Conclusion: These findings demonstrate that pregabalin is generally well tolerated and provides sustained efficacy over a 53-week treatment period in

Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain

Directory of Open Access Journals (Sweden)

Webster LR

2012-01-01

Full Text Available Lynn R Webster1, John F Peppin2, Frederick T Murphy3,4, Jeffrey K Tobias5, Geertrui F Vanhove51Lifetree Clinical Research and Pain Clinic, Lifetree Medical Inc, Salt Lake City, UT, USA; 2Clinical Research Division, The Pain Treatment Center of the Bluegrass, Lexington, KY, USA; 3Altoona Center for Clinical Research, Duncansville, PA, USA; 4University of Pennsylvania, School of Medicine, Philadelphia, PA, USA; 5NeurogesX Inc, San Mateo, CA, USABackground: The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain.Methods: This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4® [Ferndale Laboratories Inc, Ferndale, MI], Topicaine® Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL] for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included “pain now” Numeric Pain Rating Scale (NPRS scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs, clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for “average pain for the past 24 hours” from baseline to weeks 2 through 12.Results: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate

A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers.

Science.gov (United States)

Haass-Koffler, Carolina L; Goodyear, Kimberly; Long, Victoria M; Tran, Harrison H; Loche, Antonella; Cacciaglia, Roberto; Swift, Robert M; Leggio, Lorenzo

2017-11-15

Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N=48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses (N=32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

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

2013-02-01

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

Safety vs. reputation: risk controversies in emerging policy networks regarding school safety in the Netherlands

NARCIS (Netherlands)

Binkhorst, J.; Kingma, S.F.

2012-01-01

This article deals with risk controversies in emerging policy networks regarding school safety in the Netherlands. It offers a grounded account of the interpretations of school risks and safety measures by the various stakeholders of the policy network, in particular, schools, local government and

Technological progress, safety, and the guardian role of inspection

Energy Technology Data Exchange (ETDEWEB)

Critchley, O H

1981-08-01

Technological innovation is accompanied by unforeseen human consequences as well as benefits, and progress has produced a public awareness of the potential for hazards that has led to efficient safety-inspection procedures. Because no safety procedure is foolproof, the public learns to tolerate certain levels of risk from technology if it concludes that the benefits are worthwhile. The perception of values often transcends simple cost/benefit analysis. Safety technology and regulation developed during the past 50 years has benefited from earlier disastrous accidents enough to give the nuclear power industry an unprecedented safety record. Efforts to understand and anticipate human error have refined the role of inspection without achieving absolute reliability. Well-directed inspections that accept human fallibility will achieve more than design and organizational improvements. 42 references. (DCK)

Improving operating room safety

Directory of Open Access Journals (Sweden)

Garrett Jill

2009-11-01

Full Text Available Abstract Despite the introduction of the Universal Protocol, patient safety in surgery remains a daily challenge in the operating room. This present study describes one community health system's efforts to improve operating room safety through human factors training and ultimately the development of a surgical checklist. Using a combination of formal training, local studies documenting operating room safety issues and peer to peer mentoring we were able to substantially change the culture of our operating room. Our efforts have prepared us for successfully implementing a standardized checklist to improve operating room safety throughout our entire system. Based on these findings we recommend a multimodal approach to improving operating room safety.

Sustainable tourism as a method of forming a tolerant society

Directory of Open Access Journals (Sweden)

Dryga Svetlana

2016-01-01

Full Text Available The article concentrates on potential capabilities for the development of sustainable tourism, as well as its role in the formation of tolerant social relations. The authors revealed the profound impact of sustainable and hike tourism on emergence of the phenomenon ‘new tourist’. They also offered the description of levels of tolerance and their influence on the sustainable tendencies in modern tourism. There is a growing trend for tourism in modern international community to act as a high-powered regulator of socio-cultural relations and, simultaneously, as the crucial factor of counteraction to that xenophobia. A head-on clash of local and foreign cultures, which is an integral part of the very notion of tourism, is not supposed to assume itself in highly extreme forms, with the air of predominance of any of them, moreover, to be based on national, racial, religious, linguistic or educational differences. To put the idea across more efficiently, the authors resorted to exploiting such useful tools as the analysis and synthesis methodology, as well as that of comparison and prognostics. What is produced in the outcome of this study is revealing and emphasizing the levels of tolerance, characterizing the uneasy interrelationships between the so-called ‘new’ tourists and local community. The research findings could find practical applications for designing of new tourist products and elaborating of new networks of footpaths for walking tours.

The safety of istradefylline for the treatment of Parkinson's disease.

Science.gov (United States)

Müller, Thomas

2015-05-01

Antagonism of the A2A receptor improves motor behavior in patients with Parkinson's disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline , has the longest half-life out of the available A2A receptor antagonists. Istradefylline easily crosses the blood-brain barrier and shows a high affinity to the human A2A receptor. This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients. Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.

Use of the ketogenic diet in the neonatal intensive care unit-Safety and tolerability.

Science.gov (United States)

Thompson, Lindsey; Fecske, Erin; Salim, Mohammad; Hall, Ara

2017-02-01

Drug-resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug-resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1-2 weeks was utilized, with gradual increases in the ketogenic ratio every 2-3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common side effects observed were constipation, hypoglycemia, and weight loss. Serum β-hydroxybutyrate levels demonstrated improved reliability as a marker of ketosis when compared to urine ketones in this population. Perceived benefits to the infants included improved seizure control, increased alertness, and decreased need for invasive respiratory support. These cases demonstrate that the use of the ketogenic diet for treatment of neonatal encephalopathy and refractory epilepsy can be undertaken safely in the NICU and is well tolerated by carefully screened neonates and infants. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Pilot, Multicenter, Open-Label Evaluation of Safety, Tolerability and Efficacy of a Novel, Topical Multipotent Growth Factor Formulation for the Periorbital Region.

Science.gov (United States)

Sundaram, Hema; Gold, Michael; Waldorf, Heidi; Lupo, Mary; Nguyen, Vivien L; Karnik, Jwala

2015-12-01

This multicenter, open-label pilot study evaluated safety, efficacy and tolerability of a topical formulation containing a multipotent growth factor resignaling complex (MRCx), when applied to infraorbital and lateral canthal skin. Thirty-nine female subjects with mean age of 56.8 years who had periorbital lines and wrinkles, uneven skin texture, puffiness, and lack of skin firmness were enrolled, and 38 completed the study. All subjects applied the multipotent growth factor formulation bilaterally to the periorbital area, twice daily for 60 days. Efficacy and treatment-related adverse events were evaluated at Baseline and days 14, 30, and 60. Investigators rated the periorbital areas based on 10-point scales. Subjects' self-reported compliance with treatment was greater than 99% throughout the study. At day 60, all subjects had improvement in infraorbital brightness (≥ 2 points), moistness (≥ 2 points), wrinkles (≥ 1 point), sallowness (≥ 1 point), crepiness (≥ 1 point), smooth texture (≥ 1 point), skin tightness (≥ 1 point), and skin tone (≥ 1 point). Investigator-rated assessments showed ≥ 1-point improvement for lateral canthal wrinkles, dyschromia/mottled pigmentation, skin tone, overall brightness, and moistness. Investigator-rated scoring on the Global Aesthetic Improvement Scale (GAIS) demonstrated that 67.6% of subjects were much improved/improved at day 14, and 63.1% remained improved at day 60. Overall, 76.2% and 79.0% of subjects were very pleased/pleased/mostly pleased with the appearance of their infraorbital and lateral canthal areas at day 60. Adverse events comprised one case of mild canthal erythema, and one case of mild eye irritation, both of which were respectively resolved. This pilot study demonstrated that the topical multipotent growth factor formulation was safe, effective and well tolerated for periorbital skin rejuvenation.

Relationships among Safety Climate, Safety Behavior, and Safety Outcomes for Ethnic Minority Construction Workers

Directory of Open Access Journals (Sweden)

Sainan Lyu

2018-03-01

Full Text Available In many countries, it is common practice to attract and employ ethnic minority (EM or migrant workers in the construction industry. This primarily occurs in order to alleviate the labor shortage caused by an aging workforce with a lack of new entrants. Statistics show that EM construction workers are more likely to have occupational fatal and nonfatal injuries than their local counterparts; however, the mechanism underlying accidents and injuries in this vulnerable population has been rarely examined. This study aims to investigate relationships among safety climate, safety behavior, and safety outcomes for EM construction workers. To this end, a theoretical research model was developed based on a comprehensive review of the current literature. In total, 289 valid questionnaires were collected face-to-face from 223 Nepalese construction workers and 56 Pakistani construction workers working on 15 construction sites in Hong Kong. Structural equation modelling was employed to validate the constructs and test the hypothesized model. Results show that there were significant positive relationships between safety climate and safety behaviors, and significant negative relationships between safety behaviors and safety outcomes for EM construction workers. This research contributes to the literature regarding EM workers by providing empirical evidence of the mechanisms by which safety climate affects safety behaviors and outcomes. It also provides insights in order to help the key stakeholders formulate safety strategies for EM workers in many areas where numerous EM workers are employed, such as in the U.S., the UK, Australia, Singapore, Malaysia, and the Middle East.

Relationships among Safety Climate, Safety Behavior, and Safety Outcomes for Ethnic Minority Construction Workers.

Science.gov (United States)

Lyu, Sainan; Hon, Carol K H; Chan, Albert P C; Wong, Francis K W; Javed, Arshad Ali

2018-03-09

In many countries, it is common practice to attract and employ ethnic minority (EM) or migrant workers in the construction industry. This primarily occurs in order to alleviate the labor shortage caused by an aging workforce with a lack of new entrants. Statistics show that EM construction workers are more likely to have occupational fatal and nonfatal injuries than their local counterparts; however, the mechanism underlying accidents and injuries in this vulnerable population has been rarely examined. This study aims to investigate relationships among safety climate, safety behavior, and safety outcomes for EM construction workers. To this end, a theoretical research model was developed based on a comprehensive review of the current literature. In total, 289 valid questionnaires were collected face-to-face from 223 Nepalese construction workers and 56 Pakistani construction workers working on 15 construction sites in Hong Kong. Structural equation modelling was employed to validate the constructs and test the hypothesized model. Results show that there were significant positive relationships between safety climate and safety behaviors, and significant negative relationships between safety behaviors and safety outcomes for EM construction workers. This research contributes to the literature regarding EM workers by providing empirical evidence of the mechanisms by which safety climate affects safety behaviors and outcomes. It also provides insights in order to help the key stakeholders formulate safety strategies for EM workers in many areas where numerous EM workers are employed, such as in the U.S., the UK, Australia, Singapore, Malaysia, and the Middle East.

Safety and efficacy of radioactive seed localization with I-125 prior to lumpectomy and/or excisional biopsy

International Nuclear Information System (INIS)

Sung, Janice S.; King, Valencia; Thornton, Cynthia M.; Brooks, Jennifer D.; Fry, Charles W.; El-Tamer, Mahmoud; Dauer, Lawrence T.; Brogi, Edi; St Germain, Jean M.; Morris, Elizabeth A.

2013-01-01

Purpose: To evaluate the safety and efficacy of pre-operative I-125 radioactive seed localization (RSL) as an alternative to wire localization (WL). Methods: A waiver was granted by the institutional review board for this HIPAA compliant study. Review of 356 consecutive single site nonpalpable mammographic and ultrasound guided I-125 RSLs done between November 2011 and April 2012 was conducted. Preoperative mammograms and specimen radiographs were reviewed for seed-target distance, lesion location, and target/seed removal. During a brief surgical training period, 35 of 356 women had both RSL and wire localization (WL) of the same lesion. Chi-square and single sample t-tests were used to compare margin status and duration of procedures. Results: Of the 356 RSLs, 303 (85.1%) were performed ≥1 day before surgery. Mammographic guidance was used in 330 (93%) and ultrasound in 26 (7%). Mean seed to target distance was 1 mm (range 0–20 mm); all targeted lesions were retrieved. In 31 women in whom mammographic guidance was used for both RSL and WL, median procedure time was not significantly different (RSL 9.0 min; WL 7.0 min; p = 0.91), and median seed migration distance was <1 mm (range 0–15 mm). No difference was detected between margin status with RSL alone versus WL (p = 0.40 and p = 0.65 for positive and <1 mm margins, respectively). Two adverse events occurred requiring an additional wire/surgery. Conclusion: RSL ≥ 1 day before surgery is a safe effective procedure for pre-operative localization, with few adverse events and surgical outcomes comparable to those achieved with wire localization

Retrospective Evaluation of Safety, Efficacy and Risk Factors for Pneumothorax in Simultaneous Localizations of Multiple Pulmonary Nodules Using Hook Wire System.

Science.gov (United States)

Zhong, Yan; Xu, Xiao-Quan; Pan, Xiang-Long; Zhang, Wei; Xu, Hai; Yuan, Mei; Kong, Ling-Yan; Pu, Xue-Hui; Chen, Liang; Yu, Tong-Fu

2017-09-01

To evaluate the safety and efficacy of the hook wire system in the simultaneous localizations for multiple pulmonary nodules (PNs) before video-assisted thoracoscopic surgery (VATS), and to clarify the risk factors for pneumothorax associated with the localization procedure. Between January 2010 and February 2016, 67 patients (147 nodules, Group A) underwent simultaneous localizations for multiple PNs using a hook wire system. The demographic, localization procedure-related information and the occurrence rate of pneumothorax were assessed and compared with a control group (349 patients, 349 nodules, Group B). Multivariate logistic regression analyses were used to determine the risk factors for pneumothorax during the localization procedure. All the 147 nodules were successfully localized. Four (2.7%) hook wires dislodged before VATS procedure, but all these four lesions were successfully resected according to the insertion route of hook wire. Pathological diagnoses were acquired for all 147 nodules. Compared with Group B, Group A demonstrated significantly longer procedure time (p pneumothorax (p = 0.019). Multivariate logistic regression analysis indicated that position change during localization procedure (OR 2.675, p = 0.021) and the nodules located in the ipsilateral lung (OR 9.404, p pneumothorax. Simultaneous localizations for multiple PNs using a hook wire system before VATS procedure were safe and effective. Compared with localization for single PN, simultaneous localizations for multiple PNs were prone to the occurrence of pneumothorax. Position change during localization procedure and the nodules located in the ipsilateral lung were independent risk factors for pneumothorax.

A Nucleus-localized Long Non-Coding RNA Enhances Drought and Salt Stress Tolerance

KAUST Repository

Qin, Tao

2017-09-09

Long non-coding RNAs (lncRNAs) affect gene expression through a wide range of mechanisms and are considered as important regulators in many essential biological processes. A large number of lncRNA transcripts have been predicted or identified in plants in recent years. However, the biological functions for most of them are still unknown. In this study, we identified an Arabidopsis thaliana lncRNA, Drought induced RNA (DRIR), as a novel positive regulator of plant response to drought and salt stress. DRIR was expressed at a low level under non-stress conditions but can be significantly activated by drought and salt stress as well as by abscisic acid (ABA) treatment. We identified a T-DNA insertion mutant, drirD, which had higher expression of the DRIR gene than the wild type plants. The drirD mutant exhibits increased tolerance to drought and salt stress. Overexpressing DRIR in Arabidopsis also increased tolerance to drought and salt stress of the transgenic plants. The drirD mutant and the overexpressing seedlings are more sensitive to ABA than the wild type in stomata closure and seedling growth. Genome-wide transcriptome analysis demonstrated that the expression of a large number of genes was altered in drirD and the overexpressing plants. These include genes involved in ABA signaling, water transport and other stress-relief processes. Our study reveals a mechanism whereby DRIR regulates plant response to abiotic stress by modulating the expression of a series of genes involved in stress response.

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

Science.gov (United States)

Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

2018-03-16

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990�

Liposomal topical capsaicin in post-herpetic neuralgia: a safety pilot study

Directory of Open Access Journals (Sweden)

Manoel Jacobsen Teixeira

2015-03-01

Full Text Available Topical treatments have gained popularity for general use as an adjunct to systemic drugs in neuropathic pain, but their use produces variable clinical results and local adverse events. Objective To evaluate the safety and analgesic effect of a formulation of liposomal capsaicin (LC (0.025% in patients with post herpetic neuralgia (PHN. Method Patients who remained symptomatic after first-and second-line treatment were randomized to receive LC for six weeks in a placebo-controlled, crossover design study. Clinical assessment was performed at baseline, in the second, fourth and sixth week of treatment. Results Thirteen patients completed both treatment periods. Visual Analog Scale (VAS was significantly decreased after the end of the study (p = 0.008, however the effect of treatment was not significant (p = 0.076. There was no difference on global impression of change and other pain characteristics. LC was safe and well tolerated. However, at the concentration used, its analgesic effects were marginal and not significant.

Over-expression of a novel JAZ family gene from Glycine soja, increases salt and alkali stress tolerance

International Nuclear Information System (INIS)

Zhu, Dan; Cai, Hua; Luo, Xiao; Bai, Xi; Deyholos, Michael K.; Chen, Qin; Chen, Chao; Ji, Wei; Zhu, Yanming

2012-01-01

Highlights: ► We isolated and characterized a novel JAZ family gene, GsJAZ2, from Glycine soja. ► Overexpression of GsJAZ2 enhanced plant tolerance to salt and alkali stress. ► The transcriptions of stress marker genes were higher in GsJAZ2 overexpression lines. ► GsJAZ2 was localized to nucleus. -- Abstract: Salt and alkali stress are two of the main environmental factors limiting crop production. Recent discoveries show that the JAZ family encodes plant-specific genes involved in jasmonate signaling. However, there is only limited information about this gene family in abiotic stress response, and in wild soybean (Glycine soja), which is a species noted for its tolerance to alkali and salinity. Here, we isolated and characterized a novel JAZ family gene, GsJAZ2, from G. soja. Transcript abundance of GsJAZ2 increased following exposure to salt, alkali, cold and drought. Over-expression of GsJAZ2 in Arabidopsis resulted in enhanced plant tolerance to salt and alkali stress. The expression levels of some alkali stress response and stress-inducible marker genes were significantly higher in the GsJAZ2 overexpression lines as compared to wild-type plants. Subcellular localization studies using a GFP fusion protein showed that GsJAZ2 was localized to the nucleus. These results suggest that the newly isolated wild soybean GsJAZ2 is a positive regulator of plant salt and alkali stress tolerance.

Substitute safety rods: Physics design and NTG calibration

International Nuclear Information System (INIS)

Baumann, N.P.

1991-07-01

Under certain assumed accident conditions, an SRS reactor may loose most of its bulk moderator while maintaining flow to fuel assemblies. If this occurs immediately after operation at power, components normally dependent on convective heat transfer to the moderator will heat up with the possibility of melting that component. One component at risk is the safety rod. Tests have shown that the current cadmium safety rod, which contains aluminum as well as cadmium, can fail at temperatures only slightly in excess of 500 deg C. Computations indicate that such temperatures can be reached with operating powers well below the 50% power limit now imposed by other accident scenarios. Safety rod melting would thus establish a new lower operating limit. A substitute safety rod that could tolerate much higher temperatures would eliminate this limit. This memorandum details the physics characteristics of a suitable replacement rod. 7 refs

Differential tolerance to cyanobacterial exposure between geographically distinct populations of Perca fluviatilis.

Science.gov (United States)

Persson, Karl-Johan; Bergström, Kristofer; Mazur-Marzec, Hannah; Legrand, Catherine

2013-12-15

Toxic cyanobacterial blooms are an important problem worldwide. Cyanobacteria may negatively impact young-of-the-year (YOY) fish directly (toxin production, turbidity, decrease in water quality) or indirectly (trophic toxin transfer, changes in prey species composition). Here we test whether there are any differences in cyanobacterial tolerance between four geographically distinct populations of European perch (Perca fluviatilis). We show that P. fluviatilis may develop tolerance against cyanobacteria demonstrated by the ability of individuals from a marine site (exposed to annual cyanobacterial blooms) to increase their detoxification more than individuals from an oligotrophic site (rarely exposed to cyanobacteria). Our results also revealed significant interaction effects between genotypes within a population and response to cyanobacterial exposure in terms of absolute growth and detoxification activity. This genotype by treatment interaction may result in local adaptations to cyanobacterial exposure in P. fluviatilis. Hence, the sensitivity against cyanobacterial exposure may differ between within species populations increasing the importance of local management of fish populations. Copyright © 2013 Elsevier Ltd. All rights reserved.

Induction of Oral Tolerance with Transgenic Plants Expressing Antigens for Prevention/Treatment of Autoimmune, Allergic and Inflammatory Diseases.

Science.gov (United States)

Ma, Shengwu; Liao, Yu-Cai; Jevnikar, Anthony M

2015-01-01

The prevalence and incidence of autoimmune and allergic diseases have increased dramatically over the last several decades, especially in the developed world. The treatment of autoimmune and allergic diseases is typically with the use of non-specific immunosuppressive agents that compromise the integrity of the host immune system and therefore, increase the risk of infections. Antigenspecific immunotherapy by reinstating immunological tolerance towards self antigens without compromising immune functions is a much desired goal for the treatment of autoimmune and allergic diseases. Mucosal administration of antigen is a long-recognized method of inducing antigen-specific immune tolerance known as oral tolerance, which is viewed as having promising potential in the treatment of autoimmune and allergic diseases. Plant-based expression and delivery of recombinant antigens provide a promising new platform to induce oral tolerance, having considerable advantages including reduced cost and increased safety. Indeed, in recent years the use of tolerogenic plants for oral tolerance induction has attracted increasing attention, and considerable progress has been made. This review summarizes recent advances in using plants to deliver tolerogens for induction of oral tolerance in the treatment of autoimmune, allergic and inflammatory diseases.

Combined transperineal radiofrequency (RF) interstitial hyperthermia and brachytherapy for localized prostate cancer (PC)

International Nuclear Information System (INIS)

Urakami, Shinji; Gonda, Nobuko; Kikuno, Nobuyuki

2001-01-01

Hyperthermia has been used effectively as a radiation sensitizer. Interstitial hyperthermoradiotherapy has been therefore utilized as a minimal invasive therapy in attempts to improve local tumor control for various cancers, but not for urological cancer. The purpose of this study was to investigate the safety and feasibility of transperineal hyperthermoradiotherapy for localized PC. Based on our basic study of hyperthermoradiotherapy, we devised the procedure of combined transperineal RF interstitial hyperthermia and brachytherapy for localized prostate cancer. Two patients with localized PC underwent transperineal RF interstitial hyperthermia combined with brachytherapy operation the 192-Ir remote after-loading system (RALS). Under transrectal ultrasound guidance, a total number of 12-18 stainless steel needles for 192-Ir RALS were implanted into the prostatic gland and seminal vesicles (SV) in an optimized pattern. Eight of the needles were used as electrodes for hyperthermia, and were electrically insultated using the vinyl catheter along the length of the subdermal fatty tissue to protect from overheating. Three other needles were utilized for continuous temperature mapping in the prostate. Rectal temperature was also monitored. Total radiation doses of 70 Gy to the prostate and SV were planned as a combination of brachytherapy (24 Gy/4 fraction) and external irradiation using a four-field box technique (46 Gy/23 fraction). Hyperthermic treatment (goal of 42 to 43 deg C for 60 minutes) was performed twice following the 1st and 4th brachytherapy at an interval of more than 48 hours for the recovery of cancer cells from thermotolerance. Both patients reached the treatment goal of all intraprostatic temperatures >43.0 deg C, which was considered favorable for hyperthermia, and the rectal temperatures of both patients remained <38 deg C during hyperthermia. In serial PSA measurements of both patients, serum PSA was less than 1.0 ng/ml within 3 months and has since

45 CFR 1321.75 - Licenses and safety.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false Licenses and safety. 1321.75 Section 1321.75... AND COMMUNITY PROGRAMS ON AGING Service Requirements § 1321.75 Licenses and safety. The State shall... that the facility complies with all applicable State and local health, fire, safety, building, zoning...

Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults.

Science.gov (United States)

Gasparini, Roberto; Conversano, Michele; Bona, Gianni; Gabutti, Giovanni; Anemona, Alessandra; Dull, Peter M; Ceddia, Francesca

2010-04-01

This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.

Genetic Architecture of Aluminum Tolerance in Rice (Oryza sativa) Determined through Genome-Wide Association Analysis and QTL Mapping

Science.gov (United States)

Famoso, Adam N.; Zhao, Keyan; Clark, Randy T.; Tung, Chih-Wei; Wright, Mark H.; Bustamante, Carlos; Kochian, Leon V.; McCouch, Susan R.

2011-01-01

Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype–genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and

Optimization of safety equipment outages improves safety

International Nuclear Information System (INIS)

Cepin, Marko

2002-01-01

Testing and maintenance activities of safety equipment in nuclear power plants are an important potential for risk and cost reduction. An optimization method is presented based on the simulated annealing algorithm. The method determines the optimal schedule of safety equipment outages due to testing and maintenance based on minimization of selected risk measure. The mean value of the selected time dependent risk measure represents the objective function of the optimization. The time dependent function of the selected risk measure is obtained from probabilistic safety assessment, i.e. the fault tree analysis at the system level and the fault tree/event tree analysis at the plant level, both extended with inclusion of time requirements. Results of several examples showed that it is possible to reduce risk by application of the proposed method. Because of large uncertainties in the probabilistic safety assessment, the most important result of the method may not be a selection of the most suitable schedule of safety equipment outages among those, which results in similarly low risk. But, it may be a prevention of such schedules of safety equipment outages, which result in high risk. Such finding increases the importance of evaluation speed versus the requirement of getting always the global optimum no matter if it is only slightly better that certain local one

Food safety assurance systems: Microbiological testing, sampling plans, and microbiological criteria

NARCIS (Netherlands)

Zwietering, M.H.; Ross, T.; Gorris, L.G.M.

2014-01-01

Microbiological criteria give information about the quality or safety of foods. A key component of a microbiological criterion is the sampling plan. Considering: (1) the generally low level of pathogens that are deemed tolerable in foods, (2) large batch sizes, and (3) potentially substantial

Towards confidence in transport safety

International Nuclear Information System (INIS)

Robison, R.W.

1992-01-01

The U.S. Department of Energy (US DOE) plans to demonstrate to the public that high-level waste can be transported safely to the proposed repository. The author argues US DOE should begin now to demonstrate its commitment to safety by developing an extraordinary safety program for nuclear cargo it is now shipping. The program for current shipments should be developed with State, Tribal, and local officials. Social scientists should be involved in evaluating the effect of the safety program on public confidence. The safety program developed in cooperation with western states for shipments to the Waste Isolation Pilot plant is a good basis for designing that extraordinary safety program

Bending-Tolerant Anodes for Lithium-Metal Batteries.

Science.gov (United States)

Wang, Aoxuan; Tang, Shan; Kong, Debin; Liu, Shan; Chiou, Kevin; Zhi, Linjie; Huang, Jiaxing; Xia, Yong-Yao; Luo, Jiayan

2018-01-01

Bendable energy-storage systems with high energy density are demanded for conformal electronics. Lithium-metal batteries including lithium-sulfur and lithium-oxygen cells have much higher theoretical energy density than lithium-ion batteries. Reckoned as the ideal anode, however, Li has many challenges when directly used, especially its tendency to form dendrite. Under bending conditions, the Li-dendrite growth can be further aggravated due to bending-induced local plastic deformation and Li-filaments pulverization. Here, the Li-metal anodes are made bending tolerant by integrating Li into bendable scaffolds such as reduced graphene oxide (r-GO) films. In the composites, the bending stress is largely dissipated by the scaffolds. The scaffolds have increased available surface for homogeneous Li plating and minimize volume fluctuation of Li electrodes during cycling. Significantly improved cycling performance under bending conditions is achieved. With the bending-tolerant r-GO/Li-metal anode, bendable lithium-sulfur and lithium-oxygen batteries with long cycling stability are realized. A bendable integrated solar cell-battery system charged by light with stable output and a series connected bendable battery pack with higher voltage is also demonstrated. It is anticipated that this bending-tolerant anode can be combined with further electrolytes and cathodes to develop new bendable energy systems. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

INTERCULTURAL ASPECTS AND TOLERANCE IN THE BANAT COUNTY

Directory of Open Access Journals (Sweden)

Iulia PARA

2014-04-01

Full Text Available The aim of this paper is to present the outcome of our researches regarding the spirit of tolerance in the Banat County. It is a personal overview (based on official documents and other bibliographical sources of those aspects of the history of multicultural environment in Banat, which may be an explanation for the spirit of tolerance, cooperation, good relations. This attitude could be considered an inspiration for the rest of the country. The article describes the situation before 1989, when, according to the census, besides the local Romanians, there were also lots of Germans (Schwaben, Hungarians, Serbians, Italians, and Jews. After the events of 1989, the ethnic structure of the Banat County has changed – most of the Germans, Italians, and Jews have left the country and so did a lot of highly-skilled Romanians, who emigrated to Germany, Austria, the U.S.A., Australia and mainly Canada.

Fault Tolerant Feedback Control