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Sample records for 28-day repeat dose

  1. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Science.gov (United States)

    2010-07-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2012-04-10

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

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

    Science.gov (United States)

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

    2009-02-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民

    2012-01-01

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

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

    Science.gov (United States)

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

    2009-06-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  11. Acute and 28-day repeated oral toxicological evaluation of Kuruthi Azhal Chooranam – a Siddha preparation on rodents

    OpenAIRE

    Marimuthu Kannadasana; Ganesan Sumathy; Palanivel Thirusangu Sangeetha; Chidambaram Saravanababu; Kathirvelu Baskar

    2016-01-01

    Objective: To determine the effect of phytochemicals in acute and repeated dose of 28-day oral toxicity of Kuruthi Azhal Chooranam (KAC) in Sprague Dawley rats of both sexes. Methods: Acute oral toxicity was conducted with 2000 mg/kg body weight of KAC orally and the treated animals were observed for signs of toxicity at 30 min, 1, 2, 4 and 24 h and for up to 14 days. In repeated 28-day oral toxicity study, the KAC formulation was administered orally with 600, 900 and 1200 mg/k...

  12. Acute and 28-day repeated oral toxicological evaluation of Kuruthi Azhal Chooranam - a Siddha preparation on rodents

    Institute of Scientific and Technical Information of China (English)

    Marimuthu Kannadasana; Ganesan Sumathy; Palanivel Thirusangu Sangeetha; Chidambaram Saravanababu; Kathirvelu Baskar

    2016-01-01

    Objective:To determine the effect of phytochemicals in acute and repeated dose of 28-day oral toxicity of Kuruthi Azhal Chooranam (KAC) in Sprague Dawley rats of both sexes. Methods:Acute oral toxicity was conducted with 2 000 mg/kg body weight of KAC orally and the treated animals were observed for signs of toxicity at 30 min, 1, 2, 4 and 24 h and for up to 14 days. In repeated 28-day oral toxicity study, the KAC formulation was administered orally with 600, 900 and 1 200 mg/kg body weight/day to all the three groups of rats. The animals were observed for clinical signs of toxicity, mortality and morbidity throughout the study. Also body weight, feed consumption, haematological, plasma biochemistry and serum electrolytes, gross pathology, weights of the organ and histology were studied for no-observed-adverse-effect level. High dose of KAC formulation and control reversal groups were also included for delayed toxic effects determination. Results:In the acute toxicity study of KAC formulation, 2 000 mg/kg body weight dose exhibited no toxic signs and mortality during study. In sub-acute 28-day repeated dose toxicity study, there was no significant difference found between control and KAC treated groups (body weight, haematology, biochemistry and serum electrolytes). No abnormalities was found in gross pathology, organs weight and histological observation after KAC treatment. Conclusions:The current study suggests that LD50 of KAC was > 2 000 mg/kg and no-observed-adverse-effect level was>1 200 mg/kg/day in rats. KAC could be used as Siddha drug for various indications.

  13. 5-Day repeated inhalation and 28-day post-exposure study of graphene.

    Science.gov (United States)

    Shin, Jae Hoon; Han, Sung Gu; Kim, Jin Kwon; Kim, Boo Wook; Hwang, Joo Hwan; Lee, Jong Seong; Lee, Ji Hyun; Baek, Jin Ee; Kim, Tae Gyu; Kim, Keun Soo; Lee, Heon Sang; Song, Nam Woong; Ahn, Kangho; Yu, Il Je

    2015-01-01

    Graphene has recently been attracting increasing attention due to its unique electronic and chemical properties and many potential applications in such fields as semiconductors, energy storage, flexible electronics, biosensors and medical imaging. However, the toxicity of graphene in the case of human exposure has not yet been clarified. Thus, a 5-day repeated inhalation toxicity study of graphene was conducted using a nose-only inhalation system for male Sprague-Dawley rats. A total of three groups (20 rats per group) were compared: (1) control (ambient air), (2) low concentration (0.68 ± 0.14 mg/m(3) graphene) and (3) high concentration (3.86 ± 0.94 mg/m(3) graphene). The rats were exposed to graphene for 6 h/day for 5 days, followed by recovery for 1, 3, 7 or 28 days. The bioaccumulation and macrophage ingestion of the graphene were evaluated in the rat lungs. The exposure to graphene did not change the body weights or organ weights of the rats after the 5-day exposure and during the recovery period. No statistically significant difference was observed in the levels of lactate dehydrogenase, protein and albumin between the exposed and control groups. However, graphene ingestion by alveolar macrophages was observed in the exposed groups. Therefore, these results suggest that the 5-day repeated exposure to graphene only had a minimal toxic effect at the concentrations and time points used in this study.

  14. Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm).

    Science.gov (United States)

    Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

    2014-06-01

    The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions.

  15. 啮齿类动物28天重复剂量经口毒性改良试验简介与进展%Introduction and progress on the enhancement of repeated dose 28-day oral toxicity study in rodents

    Institute of Scientific and Technical Information of China (English)

    王恒娟; 刘兆平

    2012-01-01

    Repeated dose 28-day oral toxicity study in rodents ( OECD Test Guidelines 407) is widely used to evaluate the general toxicity of chemicals. In 1998, the Organization for Economic Co-operation and Development (OECD) enhanced existing TG 407 to develop new Test Guidelines for screening and testing potential endocrine disruptors. This procedure has been verified by an extensive international validation program. To provide reference for developing endocrine disruptor evaluation system in China, the enhanced TG 407, its progress and its advantages and disadvantages were summarized in this paper.%经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)推荐的啮齿类动物28天重复剂量经口毒性试验( OECD TG 407)是一种广泛用于评价化学物一般毒性的毒理学试验方案.OECD在1998年对其进行改良后,建立TG 407改良试验并经世界多国实验室验证,用于检测化学物的内分泌干扰作用.本文简要介绍了OECD TG 407改良试验指南,并对其进展情况以及优缺点进行综述,以期为我国的内分泌干扰物的评价体系提供参考.

  16. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate

    Science.gov (United States)

    2011-01-01

    Background The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing

  17. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate

    Directory of Open Access Journals (Sweden)

    Mortensen Alicja

    2011-06-01

    Full Text Available Abstract Background The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs and silver acetate (AgAc to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP. The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM, nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver

  18. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate.

    Science.gov (United States)

    Loeschner, Katrin; Hadrup, Niels; Qvortrup, Klaus; Larsen, Agnete; Gao, Xueyun; Vogel, Ulla; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H

    2011-06-01

    The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the

  19. Comparative 28-day repeated oral toxicity of Longdan Xieganwan, Akebia trifoliate (Thunb.) koidz., Akebia quinata (Thunb.) Decne. and Caulis aristolochiae manshuriensis in mice.

    Science.gov (United States)

    Xue, Xiang; Xiao, Ying; Gong, Likun; Guan, Shuhong; Liu, Yongzhen; Lu, Henglei; Qi, Xinming; Zhang, Yunhai; Li, Yan; Wu, Xiongfei; Ren, Jin

    2008-09-02

    Longdan Xieganwan, which contains Aristolochia species, is a traditional Chinese prescription. It has been used for thousands of years to "enhance liver". However, many cases of Longdan Xieganwan induced nephropathy were reported recently. This study was designed to compare the possible toxic effects of Longdan Xieganwan and three different Aristolochia species, i.e. Akebia trifoliate (Thunb.) koid (Akebia trifoliate), Akebia quinata (Thunb.) Decne. (Akebia quinata) and Caulis aristolochiae manshuriensis (Aristolochia manshuriensis). Mice were orally administered these drugs for 28 days. Clinical signs, body weights, serum biochemistry, organ weights and histopathology were examined. Significantly decreased body weights and obvious nephropathy were noticed in the Aristolochia manshuriensis groups at doses higher than 0.24 g/kg/d. A few endothelial cell degenerations in renal glomerulus were observed in the Akebia trifoliate group at a high-dose of 2.00 g/kg/d. No significant changes were observed in the other groups. The no-observed-adverse-effect levels (NOAELs) for Aristolochia manshuriensis, Akebia trifoliate, Akebia quinata and Longdan Xieganwan in this study for mice were 0.06 g/kg/d, 0.40 g/kg/d, higher than 3.00 g/kg/d and higher than 10.00 g/kg/d, which were equivalent to 0.25 times, 5 times, 25 times and 10 times of normal human dose in clinical prescription, respectively.

  20. Absence of tolerance in duodenal ulcer patients treated for 28 days with a bedtime dose of roxatidine or ranitidine.

    Science.gov (United States)

    Savarino, V; Mela, G S; Zentilin, P; Cutela, P; Vigneri, S; Termini, R; Di Mario, F; Ferrana, M; Malesci, A; Belicchi, M; Celle, G

    1996-01-01

    There is much experimental work on the occurrence of tolerance to the antisecretory effect of H2-receptor antagonists in healthy subjects, while data on its development in patients with duodenal ulcer are poor and conflicting. Moreover, this phenomenon has not been studied previously with 24 h gastric pH-metry in patients with active duodenal ulcer. For these reasons, we carried out a prospective pharmacodynamic investigation in 48 patients with endoscopically proven duodenal ulcer using the well-established once daily dosing schedule of H2 blockers. They were studied by means of 24 h continuous endoluminal pH-metry which was performed before, on d1 and d28 after receiving an oral bedtime dose (2200 hours) of either roxatidine 150 mg or ranitidine 300 mg, given in randomized and single-blind fashion. Eight patients did not complete the study for various reasons and 82% of ulcers healed after 4 weeks of therapy. Gastric pH was higher (P roxatidine and ranitidine. There was also no difference in pharmacodynamic data between the two active treatments. We conclude that tolerance does not develop after 1 month's treatment with a bedtime dose of H2 antagonist in patients with active duodenal ulcer and therefore data gathered on this phenomenon in healthy subjects are not applicable to ulcer patients.

  1. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  2. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study.

    Science.gov (United States)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells.

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2015-05-01

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

  6. Repeated dose 28-day oral toxicity study in Wistar rats with a mixture of five pesticides often found as residues in food: alphacypermethrin, bromopropylate, carbendazim, chlorpyrifos and mancozeb

    DEFF Research Database (Denmark)

    Jacobsen, H.; Østergaard, G.; Lam, Henrik Rye;

    2004-01-01

    , haematocrite and haemoglobin concentration was significantly reduced in both male and female rats of groups 5 and 6. Relative liver weight was significantly increased in groups 3-6 male and female rats. Absolute thyroid gland weight was significantly increased in groups 3, 5 and 6 male rats and of groups 3......-6 female rats, and relative thyroid gland weight was significantly increased in groups 2-6 male rats and of groups 3-6 female rats. Absolute thymus weight of groups 3-6 male and female rats and relative thymus weight of groups 3-6 male rats and groups 3 and 4 female rats was significantly decreased. A mild...... degree of centrilobular cell hypertrophy of the liver was seen in all male rats and of three female rats of group 6. In the thyroid gland follicular cell hypertrophy was present in one female in the control group and in six females and seven males of group 6. It was concluded that inhibition...

  7. Acute, 28days sub acute and genotoxic profiling of Quercetin-Magnesium complex in Swiss albino mice.

    Science.gov (United States)

    Ghosh, Nilanjan; Sandur, Rajendra; Ghosh, Deepanwita; Roy, Souvik; Janadri, Suresh

    2017-02-01

    Quercetin-Magnesium complex is one of the youngest alkaline rare earth metal (Magnesium) complexes with flavonoids (Quercetin) in organo-metalic family. Earlier studies describe the details of the complex formation, characterization and antioxidant study of the complex but toxicity profile is still under darkness. The present study was taken up to investigate the oral acute toxicity, 28days repeated oral sub-acute toxicity study and genotoxicity study of Quercetin-Magnesium complex in Swiss albino mice. Quercetin-Magnesium complex showed mortality at a dose of 185mg/kg in the Swiss albino mice. In 28days repeated oral toxicity study, Quercetin-Magnesium complex was administered to both sex of Swiss albino mice at dose levels of 150, 130 and 100mg/kg body weight respectively. Where 150mg/kg dose shows increased levels of white blood cells and changes in total protein, serum creatinine and blood urea nitrogen. Histopathological study of Quercetin-Magnesium complex shows minor structural alteration in kidney at 150mg/kg dose. No observed toxic level found in 130mg/kg or below doses. No genotoxic effect found in any doses of the complex. Therefore 130mg/kg or below dose level could be better for further study.

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

    Science.gov (United States)

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

    1995-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2001-01-15

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

  10. Repeated dose pharmacokinetics of pancopride in human volunteers.

    Science.gov (United States)

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

    1994-11-01

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

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

    Science.gov (United States)

    Mahboob, Mohammed; Kaleem, Mohammed; Siddiqui, Javed

    2004-10-01

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

  12. Pharmacology of ayahuasca administered in two repeated doses.

    Science.gov (United States)

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

    2012-02-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mehtap Okyay Karaca

    2015-01-01

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

  15. Efficacy and safety of a popular thermogenic drink after 28 days of ingestion

    Directory of Open Access Journals (Sweden)

    Stout Jeffrey R

    2008-10-01

    Full Text Available Abstract Background We have recently demonstrated that consuming a thermogenic drink (TD acutely increases energy expenditure and serum markers of lipolysis in healthy, college-aged individuals. The purpose of this study was to determine if consuming TD over 28 days affects its acute thermogenic and lipolytic effects as well as body composition and clinical chemistry safety markers. Methods Sixty healthy, males (mean ± SE; 23 ± 1 years, 177 ± 2 cm, 81.7 ± 2.1 kg, 22.8 ± 1.4% body fat; n = 30 and females (23 ± 1 years, 166 ± 2 cm, 62.1 ± 1.8 kg, 28.3 ± 1.4% body fat; n = 30 reported to the laboratory on day 0 (T1 for determination of body composition, resting energy expenditure (REE as well as glycerol and free fatty acid (FFA levels before and after ingesting either 336 ml of TD or a non-caloric, non-caffeinated placebo (PLA drink. Following day 0, participants supplemented daily with 336 ml·day-1 of either TD or PLA and repeated identical testing procedures on day 28 (T2. Day 28 area under the curve (AUC values were calculated for REE, FFA, and glycerol. Day 28 acute data and prolonged AUC comparisons between groups were analyzed using ANOVAs with repeated measures. Results Percent body fat (p = 0.02 and fat mass (p = 0.01 decreased in the TD group compared to the PLA group after 28 days. Day 28 FFA AUC values (p = 0.048 were greater in the TD group compared to the PLA group. There was no significant difference in day 28 REE AUC values (p = 0.30 or glycerol AUC values (p = 0.21, although a significant increase in REE values in the PLA group may have confounded these findings. There were no differences between groups concerning blood and clinical safety markers. Conclusion Within-group elevations in FFA and REE values in the TD group were still evident following a 28-day supplementation period which may contribute to the observed decrements in %BF. Further, prolonged TD supplementation did not alter the assessed clinical safety markers

  16. Physiological effects following administration of Citrus aurantium for 28 days in rats

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Deborah K., E-mail: deborah.hansen@fda.hhs.gov [Division of Personalized Nutrition and Medicine, U.S. FDA/NCTR, 3900 NCTR Rd., Jefferson, AR 72079 (United States); George, Nysia I. [Division of Personalized Nutrition and Medicine, U.S. FDA/NCTR, 3900 NCTR Rd., Jefferson, AR 72079 (United States); White, Gene E. [Toxicological Pathology Associates, 3900 NCTR Rd., Jefferson, AR 72079 (United States); Pellicore, Linda S. [Office of New Drugs, U.S. FDA/Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD 20903 (United States); Abdel-Rahman, Ali; Fabricant, Daniel [Office of Nutrition, Labeling and Dietary Supplements, U.S. FDA/Center for Food Safety and Nutrition, HFS-810, College Park, MD 20740 (United States)

    2012-06-15

    Background: Since ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats. Method: Female Sprague–Dawley rats were dosed daily by gavage for 28 days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50 mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats. Results and conclusion: Synephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine.

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  18. 28-Day inhalation toxicity of graphene nanoplatelets in Sprague-Dawley rats.

    Science.gov (United States)

    Kim, Jin Kwon; Shin, Jae Hoon; Lee, Jong Seong; Hwang, Joo Hwan; Lee, Ji Hyun; Baek, Jin Ee; Kim, Tae Gyu; Kim, Boo Wook; Kim, Jin Sik; Lee, Gun Ho; Ahn, Kangho; Han, Sung Gu; Bello, Dhimiter; Yu, Il Je

    2016-09-01

    Graphene, a two-dimensional engineered nanomaterial, is now being used in many applications, such as electronics, biological engineering, filtration, lightweight and strong nanocomposite materials, and energy storage. However, there is a lack of information on the potential health effects of graphene in humans based on inhalation, the primary engineered nanomaterial exposure pathway in workplaces. Thus, an inhalation toxicology study of graphene was conducted using a nose-only inhalation system for 28 days (6 h/day and 5 days/week) with male Sprague-Dawley rats that were then allowed to recover for 1-, 28-, and 90-day post-exposure period. Animals were separated into 4 groups (control, low, moderate, and high) with 15 male rats (5 rats per time point) in each group. The measured mass concentrations for the low, moderate, and high exposure groups were 0.12, 0.47, and 1.88 mg/m(3), respectively, very close to target concentrations of 0.125, 0.5, and 2 mg/m(3). Airborne graphene exposure was monitored using several real-time instrumentation over 10 nm to 20 μm for size distribution and number concentration. The total and respirable elemental carbon concentrations were also measured using filter sampling. Graphene in the air and biological media was traced using transmission electron microscopy. In addition to mortality and clinical observations, the body weights and food consumption were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for blood biochemical tests, and the organ weights were measured. No dose-dependent effects were recorded for the body weights, organ weights, bronchoalveolar lavage fluid inflammatory markers, and blood biochemical parameters at 1-day post-exposure and 28-day post-exposure. The inhaled graphenes were mostly ingested by macrophages. No distinct lung pathology was observed at the 1-, 28- and 90-day post-exposure. The inhaled graphene was translocated to lung

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Science.gov (United States)

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

    2017-05-01

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

  1. Dietary tryptophan and threonine supply to 28 days old weaned piglets

    DEFF Research Database (Denmark)

    Fernández, José Adalberto; Strathe, Anders Bjerring

    2009-01-01

    The effects of dietary levels of tryptophan (TRP) and threonine (THR) on appetite, growth performance and faecal score were assessed in an experiment with 360 weaned piglets. Littermate male castrates and females (1:1), weaned at 28 days of age, were given free access to feed during 28 days. Six...

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

    NARCIS (Netherlands)

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

    2010-01-01

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

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

    CERN Document Server

    Yepes, Pablo P; Taddei, Phillip J

    2010-01-01

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

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

    Science.gov (United States)

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

    1999-03-01

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

  5. Prediction of 28-day Compressive Strength of Concrete from Early Strength and Accelerated Curing Parameters

    OpenAIRE

    T.R. Neelakantan; S. Ramasundaram; Shanmugavel, R.; R. Vinoth

    2013-01-01

    Predicting 28-day compressive strength of concrete is an important research task for many years. In this study, concrete specimens were cured in two phases, initially at room temperature for a maximum of 30 h and later at a higher temperature for accelerated curing for a maximum of 3 h. Using the early strength obtained after the two-phase curing and the curing parameters, regression equations were developed to predict the 28-day compressive strength. For the accelerated curing (higher temper...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-12-31

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

  7. Acute and 28-day subchronic toxicity studies of mangiferin, a glucosylxanthone isolated from Mangifera indica L. stem bark.

    Directory of Open Access Journals (Sweden)

    Yalena Prado

    2015-02-01

    Full Text Available Context: Pharmacological properties of mangiferin have been reported, but few studies have investigated mangiferin toxicity. Aims: To study the acute and 28-day toxicity effects of mangiferin in rodents. Methods: Single doses of mangiferin were administered by oral or i.p. route or were applied dermally to Sprague-Dawley rats and Balb/C mice. Clinical symptoms of animals were observed during 14 days after treatment. Animals also received single oral doses daily for 28 consecutive days. Blood biochemistry, hematology and pathology findings were reported. Results: In the acute study, no toxic effects were observed after dermal exposure to mangiferin 2000 mg/kg but transient dyspnea, flank position and piloerection were observed after oral administration to this xanthone. I.p. administration induced similar toxicity signs, but at the highest dose (2000 mg/kg all mice, one female rat and one male rat died. Rats orally treated with mangiferin (250-1000 mg/kg for 28 days did not show any abnormal clinical signs or hematology alterations, when compared to control group animals. Histopathological alterations like vacuolar degeneration, necrosis and increment of apoptosis of the acinar cells were observed in the exocrine pancreas of rats at 1000 mg/kg. This suggesting that exocrine pancreas was the target organ for mangiferin’s toxicity. Conclusions: These studies indicated that acute and subchronic toxicities of mangiferin for oral exposure are low.

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

    Science.gov (United States)

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

    2012-12-01

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

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

    Science.gov (United States)

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

    2015-10-01

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

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

    Science.gov (United States)

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

    2016-07-01

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

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

    Science.gov (United States)

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

    2012-07-01

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

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

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

    2005-08-01

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

  15. Reductions in 28-day mortality following hospital admission for upper gastrointestinal hemorrhage.

    Science.gov (United States)

    Crooks, Colin; Card, Tim; West, Joe

    2011-07-01

    It is unclear whether mortality from upper gastrointestinal hemorrhage is changing: any differences observed might result from changes in age or comorbidity of patient populations. We estimated trends in 28-day mortality in England following hospital admission for gastrointestinal hemorrhage. We used a case-control study design to analyze data from all adults administered to a National Health Service hospital, for upper gastrointestinal hemorrhage, from 1999 to 2007 (n=516,153). Cases were deaths within 28 days of admission (n=74,992), and controls were survivors to 28 days. The 28-day mortality was derived from the linked national death register. A logistic regression model was used to adjust trends in nonvariceal and variceal hemorrhage mortality for age, sex, and comorbidities and to investigate potential interactions. During the study period, the unadjusted, overall, 28-day mortality following nonvariceal hemorrhage was reduced from 14.7% to 13.1% (unadjusted odds ratio, 0.87; 95% confidence interval: 0.84-0.90). The mortality following variceal hemorrhage was reduced from 24.6% to 20.9% (unadjusted odds ratio, 0.8; 95% confidence interval: 0.69-0.95). Adjustments for age and comorbidity partly accounted for the observed trends in mortality. Different mortality trends were identified for different age groups following nonvariceal hemorrhage. The 28-day mortality in England following both nonvariceal and variceal upper gastrointestinal hemorrhage decreased from 1999 to 2007, and the reduction had been partly obscured by changes in patient age and comorbidities. Our findings indicate that the overall management of bleeding has improved within the first 4 weeks of admission. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Reductions in 28-Day Mortality Following Hospital Admission for Upper Gastrointestinal Hemorrhage

    Science.gov (United States)

    Crooks, Colin; Card, Tim; West, Joe

    2011-01-01

    Background & Aims It is unclear whether mortality from upper gastrointestinal hemorrhage is changing: any differences observed might result from changes in age or comorbidity of patient populations. We estimated trends in 28-day mortality in England following hospital admission for gastrointestinal hemorrhage. Methods We used a case-control study design to analyze data from all adults administered to a National Health Service hospital, for upper gastrointestinal hemorrhage, from 1999 to 2007 (n = 516,153). Cases were deaths within 28 days of admission (n = 74,992), and controls were survivors to 28 days. The 28-day mortality was derived from the linked national death register. A logistic regression model was used to adjust trends in nonvariceal and variceal hemorrhage mortality for age, sex, and comorbidities and to investigate potential interactions. Results During the study period, the unadjusted, overall, 28-day mortality following nonvariceal hemorrhage was reduced from 14.7% to 13.1% (unadjusted odds ratio, 0.87; 95% confidence interval: 0.84–0.90). The mortality following variceal hemorrhage was reduced from 24.6% to 20.9% (unadjusted odds ratio, 0.8; 95% confidence interval: 0.69–0.95). Adjustments for age and comorbidity partly accounted for the observed trends in mortality. Different mortality trends were identified for different age groups following nonvariceal hemorrhage. Conclusions The 28-day mortality in England following both nonvariceal and variceal upper gastrointestinal hemorrhage decreased from 1999 to 2007, and the reduction had been partly obscured by changes in patient age and comorbidities. Our findings indicate that the overall management of bleeding has improved within the first 4 weeks of admission. PMID:21447331

  17. Prediction of compressive strength up to 28 days from microstructure of Portland cement

    DEFF Research Database (Denmark)

    Svinning, K.; Høskuldsson, Agnar; Justnes, H.

    2008-01-01

    The influence of the characteristics or the microstructure of Portland cement on compressive strength up to 28 days has been statistically investigated by application of partial least square (PLS) analysis. The main groups of characteristics were mineralogy and superficial microstructure represen...

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

    Science.gov (United States)

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

    2013-11-01

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

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

    OpenAIRE

    Pei, Z; Pang, SF; Cheung, RTF

    2000-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2007-01-01

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

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

    Science.gov (United States)

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

    2008-02-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-02-01

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

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

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

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

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

    Science.gov (United States)

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

    2012-04-01

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

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

    Science.gov (United States)

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

    1997-04-01

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

  7. Efficacy of a 28-day oral cyanocobalamin supplementation on vitamin B status in Spanish institutionalized elderly.

    Science.gov (United States)

    Albers, Ulrike; Pedrero-Chamizo, Raquel; Meléndez, Agustin; Pietrzik, Klaus; Castillo, Manuel J; González-Gross, Marcela

    2012-04-01

    Cobalamin deficiency is a common problem in the elderly. There is no consensus about adequate doses for supplementation. We performed an intervention study in order to establish the efficacy of a supplement providing 500 µg cyanocobalamin for four weeks in sixty-four institutionalized elderly residents, over 60 years of age, in Madrid (Spain). Before and after treatment, concentrations of serum cobalamin, serum holotranscobalamin, serum total homocysteine, and serum and red blood cell folate were analyzed. Clusters were built according to the initial cobalamin status and differences in the effect of supplementation were checked using a general linear model for repeated measures. Cobalamin and holotranscobalamin increased highly significantly from 308 to 558 pmol/L and from 54 to 96 pmol/L (p cyanocobalamin daily for only four weeks, a shorter period than that found in former studies, may be considered suitable in institutionalized elderly.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1992-08-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

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

  12. Coenzyme q10 abrogated the 28 days aluminium chloride induced oxidative changes in rat cerebral cortex.

    Science.gov (United States)

    Majumdar, Anuradha S; Nirwane, Abhijit; Kamble, Rahul

    2014-05-01

    The present study was designed to elucidate the impact of oral administration of aluminium chloride for 28 days with respect to oxidative stress in the cerebral cortex of female rats. Further, to investigate the potentials of Coenzyme (Co) Q10 (4, 8, and 12 mg/kg, i.p.) in mitigating the detrimental changes. Biochemical estimations of cerebral lipid peroxidation (LPO), reduced glutathione (GSH), vitamin E and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were carried out after 28 days of aluminium chloride (AlCl3) and Co Q10 exposures along with histopathological examination of cerebral cortex of the rats. Subacute exposure to AlCl3(5 mg/kg) led to significant decrease in levels of GSH, vitamin E and activities of SOD, CAT, GPx, and an increase in LPO of cerebral cortex. These aberrations were restored by Co Q10 (12 mg/kg, i.p.). This protection offered was comparable to that of L-deprenyl (1 mg/kg, i.p.) which served as a reference standard. Histopathological evaluations confirmed that the normal cerebral morphology was maintained by Co Q10. Thus, AlCl3 exposure hampers the activities of various antioxidant enzymes and induces oxidative stress in cerebral cortex of female Wistar rats. Supplementation with intraperitoneal Co Q10 abrogated these deleterious effects of AlCl3.

  13. The 28-day exposure to fenpropathrin decreases locomotor activity and reduces activity of antioxidant enzymes in mice brains.

    Science.gov (United States)

    Nieradko-Iwanicka, Barbara; Borzęcki, Andrzej

    2016-04-01

    Fenpropathrin (Fen) is a pyrethroid (Pyr) insecticide. Pyrs are used in veterinary medicine, in agriculture and for domestic purposes. As their use increases, new questions about their side effects and mode of action in non-target organisms arise. The objective of this work was to characterize dose-response relationship for in vivo motor function and memory in mice exposed to Fen for 28 days and to assess its influence on activity of antioxidant enzymes in mice brains. The experiment was performed using 64 female mice. Fen at the dose of 11.9mg/kg of body mass, 5.95mg/kg or 2.38mg/kg was administered ip to the mice for 28 consecutive days. Motor function and spatial working memory were tested on days 7, 14 and 28. On day 29, the animals were sacrificed and brains were used to determine activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Fen significantly decreased locomotor activity in mice receiving the highest dose at every stage of the experiment. Lower doses reduced locomotion on days 7 and 14. Fen did not produce memory impairment. A decrease in activities of SOD and GPx was recorded in mice brains. The decrease of SOD activity in mice brains results from direct inhibition of the enzyme by Fen and/or increased utilization due to excessive free radical formation in conditions of Fen-induced oxidative stress. The reduction in GPx activity is probably due to limited glutathione availability. The reduced locomotor activity is a behavioral demonstration of Fen-induced damage in the dopaminergic system. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  14. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate

    DEFF Research Database (Denmark)

    Löschner, Katrin; Hadrup, Niels; Qvortrup, Klaus

    2011-01-01

    NPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or Ag......Ac. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy...

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

    Directory of Open Access Journals (Sweden)

    Jae-Seuk Park

    2010-12-01

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

  16. Consuming a multi-ingredient thermogenic supplement for 28 days is apparently safe in healthy adults

    Directory of Open Access Journals (Sweden)

    Roxanne M. Vogel

    2015-07-01

    Full Text Available Background: Thermogenic (TRM supplements are often used by people seeking to decrease body weight. Many TRM supplements are formulated with multiple ingredients purported to increase energy expenditure and maximize fat loss. However, in the past some TRM ingredients have been deemed unsafe and removed from the market. Therefore, it is important to verify the safety of multi-ingredient TRM supplements with chronic consumption. Objective: To assess the safety of daily consumption of a multi-ingredient TRM supplement over a 28-day period in healthy adults. Design: Twenty-three recreationally active adults (11M, 12F; 27.1±5.4 years, 171.6±9.6 cm, 76.8±16.1 kg, 26±5 BMI were randomly assigned either to consume a multi-ingredient TRM supplement (SUP; n=9 or remain unsupplemented (CRL; n=14 for 28 days. Participants maintained their habitual dietary and exercise routines for the duration of the study. Fasting blood samples, resting blood pressure, and heart rate were taken before and after the supplementation period. Samples were analyzed for complete blood counts, comprehensive metabolic, and lipid panels. Results: Significant (p<0.05 group by time interactions were present for diastolic BP, creatinine, estimated glomerular filtration rate (eGFR, chloride, CO2, globulin, albumin:globulin (A/G, and high-density lipoprotein (HDL. Dependent t-tests conducted on significant variables revealed significant (p<0.05 within-group differences in SUP for diastolic BP (+6.2±5.3 mmHG, creatinine (+0.09±0.05 mg/dL, eGFR (−11.2±5.8 mL/min/1.73, globulin (−0.29±0.24 g/dL, A/G (+0.27±0.23, and HDL (−5.0±5.5 mg/dL, and in CRL for CO2 (−1.9±1.5 mmol/L between time points. Each variable remained within the accepted physiological range. Conclusion: Results of the present study support the clinical safety of a multi-ingredient TRM containing caffeine, green tea extract, and cayenne powder. Although there were statistically significant (p<0.05 intragroup

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

    Science.gov (United States)

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

    1987-06-01

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

  18. Glycidol induces axonopathy and aberrations of hippocampal neurogenesis affecting late-stage differentiation by exposure to rats in a framework of 28-day toxicity study.

    Science.gov (United States)

    Akane, Hirotoshi; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Abe, Hajime; Shibutani, Makoto

    2014-01-30

    Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop axonopathy. To investigate the possibility whether similar effects on adult neurogenesis could be induced by exposure in a framework of 28-day toxicity study, glycidol was orally administered to 5-week-old male Sprague-Dawley rats by gavage at 0, 30 or 200 mg/kg for 28 days. At 200 mg/kg, animals revealed progressively worsening gait abnormalities as well as histopathological and immunohistochemical changes suggestive of axonal injury as evidenced by generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells and axonal degeneration in the sciatic nerves. At the same dose, animals revealed aberrations in neurogenesis at late-stage differentiation as evidenced by decreases of both doublecortin(+) and dihydropyrimidinase-like 3(+) cells in the subgranular zone (SGZ) and increased reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein(+) mature neurons in the dentate hilus. These effects were essentially similar to that observed in offspring after maternal exposure to glycidol. These results suggest that glycidol causes aberrations in adult neurogenesis in the SGZ at the late stage involving the process of neurite extension similar to the developmental exposure study in a standard 28-day toxicity study.

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

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-10-01

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

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

    Science.gov (United States)

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

    2012-12-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2015-04-01

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

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

    Science.gov (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

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

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

    Science.gov (United States)

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

    2017-09-01

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

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

    Science.gov (United States)

    Dent, M P

    2007-08-01

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

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

    Science.gov (United States)

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

    2014-09-01

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

  7. Shock Index and Prediction of Traumatic Hemorrhagic Shock 28-Day Mortality: Data from the DCLHb Resuscitation Clinical Trials

    Directory of Open Access Journals (Sweden)

    Edward P. Sloan

    2014-11-01

    Full Text Available Introduction: To assess the ability of the shock index (SI to predict 28-day mortality in traumatic hemorrhagic shock patients treated in the diaspirin cross-linked hemoglobin (DCLHb resuscitation clinical trials. Methods: We used data from two parallel DCLHb traumatic hemorrhagic shock efficacy trials, one in U.S. emergency departments, and one in the European Union prehospital setting to assess the relationship between SI values and 28-day mortality. Results: In the 219 patients, the mean age was 37 years, 64% sustained a blunt injury, 48% received DCLHb, 36% died, and 88% had an SI>1.0 at study entry. The percentage of patients with an SI>1.0 dropped by 57% (88 to 38% from the time of study entry to 120 minutes after study resuscitation (p1.0, 1.4, and 1.8 at any time point were 2.3, 2.7, and 3.1 times, respectively, more likely to die by 28 days than were patients with SI values below these cutoffs (p1.0 were 3.9x times more likely to die by 28 days (40 vs. 15%, p<0.001. Although the distribution of SI values differed based on treatment group, the receiver operator characeristics data showed no difference in SI predictive ability for 28-day mortality in patients treated with DCLHb. Conclusion: In these traumatic hemorrhagic shock patients, the shock index correlates with 28-day mortality, with higher SI values indicating greater mortality risk. Although DCLHb treatment did alter the distribution of SI values, it did not influence the ability of the SI to predict 28-day mortality. [West J Emerg Med. 2014;15(7:–0.

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

    Science.gov (United States)

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

    2017-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Charles H King

    2011-09-01

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

  10. Tamarind seed polysaccharide: a 28-day dietary study in Sprague-Dawley rats.

    Science.gov (United States)

    Heimbach, James T; Egawa, Hiroshi; Marone, Palma Ann; Bauter, Mark R; Kennepohl, Elke

    2013-01-01

    Forty male and 40 female Crl:SD® CD® IGS rats were fed diets containing 0, 40,000, 80,000, or 120,000 ppm tamarind seed polysaccharide (equivalent to 3450.8, 6738.9, or 10 597.1 mg/kg bw/day and 3602.1, 7190.1, or 10,690.7 mg/kg bw/day for males and females, respectively) for 28 days. Animals were observed for adverse clinical signs, body weight, feed consumption, hematology and clinical chemistry parameters, urinalysis values were recorded, and at the end of the study the rats underwent a full necropsy. Functional Observational Battery (FOB) and Motor Activity (MA) tests were performed on all animals. There were no mortalities, no clinical or ophthalmologic signs, body weight, body weight gain, food consumption and food efficiency, FOB or MA findings associated with the administration of tamarind seed polysaccharide. Initial statistically significant decreases in body weight gain and food consumption resolved after the first week and were considered the result of reduced palatability. There were no adverse changes in hematology, coagulation, clinical chemistry or urinalysis parameters in male or female rats considered the result of test substance administration. At necropsy, there were no macroscopic, histopathological findings, estrus cycle, or organ weight changes deemed related to administration of the test substance. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for tamarind seed polysaccharide in the diet was the highest concentration tested of 120,000 ppm (equivalent to 10,597 mg/kg bw/day and 10,691 mg/kg bw/day for male and female rats, respectively).

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

    DEFF Research Database (Denmark)

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

    1993-01-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Science.gov (United States)

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

    2016-02-01

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

  14. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

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

    National Research Council Canada - National Science Library

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

    2015-01-01

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

  16. Incremental effects of 28 days of beta-alanine supplementation on high-intensity cycling performance and blood lactate in masters female cyclists.

    Science.gov (United States)

    Glenn, J M; Gray, M; Stewart, R; Moyen, N E; Kavouras, S A; DiBrezzo, R; Turner, R; Baum, J

    2015-12-01

    Within the aging population, there exists a subset of individuals termed masters athletes (MA). As masters-level competition increases in popularity, MA must find methods to enhance individual athletic performance. Longitudinal beta-alanine (BA) supplementation is suggested to enhance physical capability during exercise; however, these effects have not been evaluated in MA. To examine the longitudinal effects of BA on time to exhaustion (TTE), total work completed (TWC), and lactate clearance in female MA cyclists. Twenty-two female MA (age = 53.3 ± 1.0) participated in this double-blind design. Subjects were randomly assigned to BA (n = 11; 800 mg BA + 8 g dextrose) or placebo (PLA; n = 11; 8 g dextrose) groups and supplemented 4 doses/day over 28 days. Every 7 days, subjects completed a cycling TTE at 120% VO2max, and TWC was calculated. Blood lactate was measured at baseline, immediate post, and 20-min post each TTE. No significant differences existed between groups for any variable at baseline (p > 0.05). After 28 days supplementation, BA had greater TTE (23 vs 1% change) and TWC (21 vs 2% change) than PLA (p < 0.05). Following the 20-min TTE recovery, lactate was 24% lower in BA compared to PLA (4.35 vs. 5.76 mmol/L, respectively). No differences existed for variables during intermittent weeks. 28 days of BA supplementation increased cycling performance via an enhanced time to exhaustion and total work completed with associated lactate clearance during passive rest in female MA.

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

    Science.gov (United States)

    Dubrova, Yuri E

    2005-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran

    2016-01-01

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

  19. Toxicogenomic analysis of gene expression changes in rat liver after a 28-day oral benzene exposure

    NARCIS (Netherlands)

    Heijne, W.H.M.; Jonker, D.; Stierum, R.H.; Ommen, B. van; Groten, J.P.

    2005-01-01

    Benzene is an industrial chemical, component of automobile exhaust and cigarette smoke. After hepatic bioactivation benzene induces bone marrow, blood and hepatic toxicity. Using a toxicogenomics approach this study analysed the effects of benzene at three dose levels on gene expression in the liver

  20. Toxicogenomic analysis of gene expression changes in rat liver after a 28-day oral benzene exposure

    NARCIS (Netherlands)

    Heijne, W.H.M.; Jonker, D.; Stierum, R.H.; Ommen, B. van; Groten, J.P.

    2005-01-01

    Benzene is an industrial chemical, component of automobile exhaust and cigarette smoke. After hepatic bioactivation benzene induces bone marrow, blood and hepatic toxicity. Using a toxicogenomics approach this study analysed the effects of benzene at three dose levels on gene expression in the liver

  1. Lack of histological cerebellar changes in Wistar rats given pulegone for 28 days. Comparison of immersion and perfusion tissue fixation

    DEFF Research Database (Denmark)

    Mølck, Anne-Marie; Poulsen, Morten; Lauridsen, Søren Tindgard

    1998-01-01

    Pulegone was given orally by gavage to groups of 28 SPF Wistar rats at dosage levels of 0 or 160 mg/kg body weight per day for 28 days. Clinically treated animals showed slackness, depression, decreased food consumption, and body weight. The loss of body weight was accompanied by a marked decrease...

  2. Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats

    NARCIS (Netherlands)

    Gosens, Ilse; Mathijssen, Liesbeth E A M; Bokkers, Bas G H|info:eu-repo/dai/nl/304847062; Muijser, Hans; Cassee, Flemming R.|info:eu-repo/dai/nl/143038990

    2014-01-01

    There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies

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

    Science.gov (United States)

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

    1990-01-01

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

  4. Kinetics of radioiodine in the rats treated repeatedly with mercuric chloride

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-12-31

    Repeated administration of HgCl{sub 2} at doses of 0.5 and 1.0 mg/kg b.w. for 28 days decreased I-125 concentrations in the thyroid gland in a dose-related manner. In contrast, the carcass retention of I-125 increased, especially in the group treated with a smaller dose of mercury. Both doses of mercury markedly changed the distribution pattern of I-125 in the organs. However, the changes were transitory. (author). 15 refs, 2 figs, 1 tab.

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

    Science.gov (United States)

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

    2007-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Roskos Lorin

    2010-01-01

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

  7. Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Windeløv, Nis A; Ibsen, Michael

    2013-01-01

    sepsis admitted to the intensive care unit (ICU). Clinical scores/variables, infection, TEG, biochemistry, therapy, and overall mortality were recorded. RESULTS: Fifty patients (60% men, median age 62 years, 28-day mortality 24%) were included. At admission, 22%, 48%, and 30% had a hypocoagulable......PURPOSE: The aim of this study was to assess associations between consecutive thrombelastography (TEG) profiles and standard coagulation tests and disease severity and mortality in patients with severe sepsis. MATERIALS AND METHODS: This was a prospective observational study of adults with severe......, normocoagulable, and hypercoagulable TEG clot strength (maximum amplitude [MA]), respectively. Hypocoagulable patients had higher Sequential Organ Failure Assessment and disseminated intravascular coagulation scores compared with hypercoagulable patients and higher 28-day mortality compared with normocoagulable...

  8. Downregulation of immediate-early genes linking to suppression of neuronal plasticity in rats after 28-day exposure to glycidol

    Energy Technology Data Exchange (ETDEWEB)

    Akane, Hirotoshi [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Saito, Fumiyo [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Shiraki, Ayako [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Takeyoshi, Masahiro; Imatanaka, Nobuya [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Itahashi, Megu [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Murakami, Tomoaki [Laboratory of Veterinary Toxicology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2014-09-01

    We previously found that the 28-day oral toxicity study of glycidol at 200 mg/kg/day in rats resulted in axonopathy in both the central and peripheral nervous systems and aberrations in the late-stage of hippocampal neurogenesis targeting the process of neurite extension. To capture the neuronal parameters in response to glycidol toxicity, these animals were subjected to region-specific global gene expression profiling in four regions of cerebral and cerebellar architectures, followed by immunohistochemical analysis of selected gene products. Expression changes of genes related to axonogenesis and synaptic transmission were observed in the hippocampal dentate gyrus, cingulate cortex and cerebellar vermis at 200 mg/kg showing downregulation in most genes. In the corpus callosum, genes related to growth, survival and functions of glial cells fluctuated their expression. Immunohistochemically, neurons expressing gene products of immediate-early genes, i.e., Arc, Fos and Jun, decreased in their number in the dentate granule cell layer, cingulate cortex and cerebellar vermis. We also applied immunohistochemical analysis in rat offspring after developmental exposure to glycidol through maternal drinking water. The results revealed increases of Arc{sup +} neurons at 1000 ppm and Fos{sup +} neurons at ≥ 300 ppm in the dentate granule cell layer of offspring only at the adult stage. These results suggest that glycidol suppressed neuronal plasticity in the brain after 28-day exposure to young adult animals, in contrast to the operation of restoration mechanism to increase neuronal plasticity at the adult stage in response to aberrations in neurogenesis after developmental exposure. - Highlights: • Neuronal toxicity parameters after 28-day glycidol treatment were examined in rats. • Region-specific global gene expression profiling was conducted in brain regions. • Cortical tissues downregulated genes on axonogenesis and synaptic transmission. • Cortical tissues

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

    Science.gov (United States)

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

    2014-06-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Schulze Johannes

    2012-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Germana Freire Rocha Caldas

    2013-01-01

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

  14. Relative toxicity of bifenthrin to Hyalella azteca in 10 day versus 28 day exposures.

    Science.gov (United States)

    Anderson, Brian S; Phillips, Bryn M; Voorhees, Jennifer P; Petersen, Megan A; Jennings, Lydia L; Fojut, Tessa L; Vasquez, Martice E; Siegler, Catherine; Tjeerdema, Ronald S

    2015-04-01

    Many watersheds in the Central Valley region of California are listed as impaired due to pyrethroid-associated sediment toxicity. The Central Valley Regional Water Quality Control Board is developing numeric sediment quality criteria for pyrethroids, beginning with bifenthrin. Criteria are being developed using existing data, along with data from 10 d and 28 d toxicity tests with Hyalella azteca conducted as part of the current study. A single range-finder and 2 definitive tests were conducted for each test duration. Median lethal concentrations (LC50s), as well as LC20s and inhibition concentrations (IC20s) were calculated based on measured whole sediment bifenthrin concentrations and interstitial water concentrations. Sediment LC50s were also corrected for organic C content. Average LC50s were not significantly different in 10 d versus 28 d tests with H. azteca: 9.1 and 9.6 ng/g bifenthrin for 10 d and 28 d tests, respectively. Average LC20 values were also similar with concentrations at 7.1 and 7.0 for 10 d and 28 d tests, respectively. Bifenthrin inhibition concentrations (IC20s) based on amphipod growth were variable, particularly in the 28 d tests, where a clear dose-response relationship was observed in only 1 of the definitive experiments. Average amphipod growth IC20s were 3.9 and 9.0 ng/g for 10 d and 28 d tests, respectively. Amphipod growth calculated as biomass resulted in IC20s of 4.1 and 6.3 ng/g for the 10 d and 28 d tests, respectively. Lack of a clear growth effect in the longer term test may be related to the lack of food adjustment to account for amphipod mortality in whole sediment exposures. The average C-corrected LC50s were 1.03 and 1.09 μg/g OC for the 10 d and 28 d tests, respectively. Interstitial water LC50s were determined as the measured dissolved concentration of bifenthrin relative to interstitial water dissolved organic carbon. The average LC50s for dissolved interstitial water bifenthrin were

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

    Science.gov (United States)

    2012-01-01

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

  16. Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

    Science.gov (United States)

    Rajendran, Narayanan; Hu, Shu-Chieh; Sullivan, Dennis; Muzzio, Miguel; Detrisac, Carol J; Venezia, Carmen

    2012-12-01

    The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

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

    Science.gov (United States)

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

    2008-04-01

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

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

    Science.gov (United States)

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

    2008-11-01

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

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

    Science.gov (United States)

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

    2016-07-25

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2015-12-28

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

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

    Science.gov (United States)

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

    2017-08-01

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

  3. Defining upper gastrointestinal bleeding from linked primary and secondary care data and the effect on occurrence and 28 day mortality

    Science.gov (United States)

    2012-01-01

    Background Primary care records from the UK have frequently been used to identify episodes of upper gastrointestinal bleeding in studies of drug toxicity because of their comprehensive population coverage and longitudinal recording of prescriptions and diagnoses. Recent linkage within England of primary and secondary care data has augmented this data but the timing and coding of concurrent events, and how the definition of events in linked data effects occurrence and 28 day mortality is not known. Methods We used the recently linked English Hospital Episodes Statistics and General Practice Research Database, 1997–2010, to define events by; a specific upper gastrointestinal bleed code in either dataset, a specific bleed code in both datasets, or a less specific but plausible code from the linked dataset. Results This approach resulted in 81% of secondary care defined bleeds having a corresponding plausible code within 2 months in primary care. However only 62% of primary care defined bleeds had a corresponding plausible HES admission within 2 months. The more restrictive and specific case definitions excluded severe events and almost halved the 28 day case fatality when compared to broader and more sensitive definitions. Conclusions Restrictive definitions of gastrointestinal bleeding in linked datasets fail to capture the full heterogeneity in coding possible following complex clinical events. Conversely too broad a definition in primary care introduces events not severe enough to warrant hospital admission. Ignoring these issues may unwittingly introduce selection bias into a study’s results. PMID:23148590

  4. Defining upper gastrointestinal bleeding from linked primary and secondary care data and the effect on occurrence and 28 day mortality

    Directory of Open Access Journals (Sweden)

    Crooks Colin

    2012-11-01

    Full Text Available Abstract Background Primary care records from the UK have frequently been used to identify episodes of upper gastrointestinal bleeding in studies of drug toxicity because of their comprehensive population coverage and longitudinal recording of prescriptions and diagnoses. Recent linkage within England of primary and secondary care data has augmented this data but the timing and coding of concurrent events, and how the definition of events in linked data effects occurrence and 28 day mortality is not known. Methods We used the recently linked English Hospital Episodes Statistics and General Practice Research Database, 1997–2010, to define events by; a specific upper gastrointestinal bleed code in either dataset, a specific bleed code in both datasets, or a less specific but plausible code from the linked dataset. Results This approach resulted in 81% of secondary care defined bleeds having a corresponding plausible code within 2 months in primary care. However only 62% of primary care defined bleeds had a corresponding plausible HES admission within 2 months. The more restrictive and specific case definitions excluded severe events and almost halved the 28 day case fatality when compared to broader and more sensitive definitions. Conclusions Restrictive definitions of gastrointestinal bleeding in linked datasets fail to capture the full heterogeneity in coding possible following complex clinical events. Conversely too broad a definition in primary care introduces events not severe enough to warrant hospital admission. Ignoring these issues may unwittingly introduce selection bias into a study’s results.

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

    Science.gov (United States)

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

    2014-01-01

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

  6. Absence of adverse effects of sodium metabisulphite in manufactured biscuits: results of subacute (28-days) and subchronic (85-days) feeding studies in rats.

    Science.gov (United States)

    Ribera, D; Jonker, D; Narbonne, J F; O'Brien, J; Antignac, E

    2001-02-01

    Sulphites are extensively used in the food and drinks industry. Their toxicity has been previously evaluated by addition to the diet or drinking water of laboratory animals. Because interactions between sulphites and food constituents occur, the present work was conducted to determine the subacute and subchronic toxicity of sulphite-bound compounds in a finished product: manufactured biscuits. The studies were performed on Sprague Dawley, rats for 28 and 85 days of dietary exposure. Diets were prepared from sulphited or untreated (controls) biscuits with the addition of sugar, protein, vitamins and minerals according to the nutritional requirements of the animals. Groups of 10 male and 10 female rats were administered diets containing sulphited biscuits at levels of 0, 10, 35 and 75%, corresponding to 10-15, 35-45, 150-170 and 310-340 mg SO2/kg diet. In both studies, no death or clinical abnormalities were reported. Growth rate, food consumption and food conversion efficiency were not affected by treatment. No dose-related changes were observed for haematology, clinical chemistry, ocular examination, renal-function, urinalysis, organ weights or gross and microscopic examinations. The liver concentrations of vitamins A, B1, C and E were not significantly changed except for an increase in vitamin E in high-dose males after 28 days' exposure. Based on these data, the no-observed-adverse-effect level (NOAEL) of sulphites in baked biscuits was judged to be 310 mg SO2/kg diet or 25 mg/kg body weight/day.

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

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed

    2015-01-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

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

    Science.gov (United States)

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

    2012-03-01

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

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

    Science.gov (United States)

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

    2015-08-01

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

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

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    Ryu HJ

    2014-12-01

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

  12. Downregulation of immediate-early genes linking to suppression of neuronal plasticity in rats after 28-day exposure to glycidol.

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    Akane, Hirotoshi; Saito, Fumiyo; Shiraki, Ayako; Takeyoshi, Masahiro; Imatanaka, Nobuya; Itahashi, Megu; Murakami, Tomoaki; Shibutani, Makoto

    2014-09-01

    We previously found that the 28-day oral toxicity study of glycidol at 200mg/kg/day in rats resulted in axonopathy in both the central and peripheral nervous systems and aberrations in the late-stage of hippocampal neurogenesis targeting the process of neurite extension. To capture the neuronal parameters in response to glycidol toxicity, these animals were subjected to region-specific global gene expression profiling in four regions of cerebral and cerebellar architectures, followed by immunohistochemical analysis of selected gene products. Expression changes of genes related to axonogenesis and synaptic transmission were observed in the hippocampal dentate gyrus, cingulate cortex and cerebellar vermis at 200mg/kg showing downregulation in most genes. In the corpus callosum, genes related to growth, survival and functions of glial cells fluctuated their expression. Immunohistochemically, neurons expressing gene products of immediate-early genes, i.e., Arc, Fos and Jun, decreased in their number in the dentate granule cell layer, cingulate cortex and cerebellar vermis. We also applied immunohistochemical analysis in rat offspring after developmental exposure to glycidol through maternal drinking water. The results revealed increases of Arc(+) neurons at 1000ppm and Fos(+) neurons at ≥300ppm in the dentate granule cell layer of offspring only at the adult stage. These results suggest that glycidol suppressed neuronal plasticity in the brain after 28-day exposure to young adult animals, in contrast to the operation of restoration mechanism to increase neuronal plasticity at the adult stage in response to aberrations in neurogenesis after developmental exposure.

  13. Usefulness of serial measurement of the red blood cell distribution width to predict 28-day mortality in patients with trauma.

    Science.gov (United States)

    Kong, Taeyoung; Park, Jong Eun; Park, Yoo Seok; Lee, Hye Sun; You, Je Sung; Chung, Hyun Soo; Park, Incheol; Chung, Sung Phil

    2017-06-08

    This is the first study to evaluate the association between the serially measured RDW values and clinical severity in patients surviving >24 h after sustaining trauma. We evaluated the serial measurement and cut-off values of RDW to determine its significance as a prognostic marker of early mortality in patients with suspected severe trauma. This study retrospectively analyzed prospective data of eligible adult patients who were admitted to the ED with suspected severe trauma. The RDW was determined on each day of hospitalization. The primary outcome was all-cause mortality within 28-days of ED admission. We included 305 patients who met our inclusion criteria. The multivariate Cox regression model demonstrated that higher RDW values on day 1 (hazard ratio [HR], 1.558; 95% confidence interval [CI], 1.09-2.227; p=0.015) and day 2 (HR, 1.549; 95% CI, 1.046-2.294; p=0.029) were strong independent predictors of short-term mortality among patients with suspected severe trauma. Considering the clinical course of severe trauma patients, the RDW is an important ancillary test for determining severity. Specifically, we found that RDW values >14.4% on day 1 (HR, 4.227; 95% CI: 1.672-10.942; p14.7% on day 2 (HR, 6.041; 95% CI: 2.361-15.458; pvalue is an independent predictor of 28-day mortality in patients with suspected severe trauma. The RDW, routinely obtained as part of the complete blood count without added cost or time, can be serially measured as indicator of severity after trauma. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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    Yoo-min Choi

    2015-03-01

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

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

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    Michelle R Newman

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

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

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    Wust Peter

    2010-05-01

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

  17. Intakes of culinary herbs and spices from a food frequency questionnaire evaluated against 28-days estimated records

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    Blomhoff Rune

    2011-05-01

    Full Text Available Abstract Background Worldwide, herbs and spices are much used food flavourings. However, little data exist regarding actual dietary intake of culinary herbs and spices. We developed a food frequency questionnaire (FFQ for the assessment of habitual diet the preceding year, with focus on phytochemical rich food, including herbs and spices. The aim of the present study was to evaluate the intakes of herbs and spices from the FFQ with estimates of intake from another dietary assessment method. Thus we compared the intake estimates from the FFQ with 28 days of estimated records of herb and spice consumption as a reference method. Methods The evaluation study was conducted among 146 free living adults, who filled in the FFQ and 2-4 weeks later carried out 28 days recording of herb and spice consumption. The FFQ included a section with questions about 27 individual culinary herbs and spices, while the records were open ended records for recording of herbs and spice consumption exclusively. Results Our study showed that the FFQ obtained slightly higher estimates of total intake of herbs and spices than the total intake assessed by the Herbs and Spice Records (HSR. The correlation between the two assessment methods with regard to total intake was good (r = 0.5, and the cross-classification suggests that the FFQ may be used to classify subjects according to total herb and spice intake. For the 8 most frequently consumed individual herbs and spices, the FFQ obtained good estimates of median frequency of intake for 2 herbs/spices, while good estimates of portion sizes were obtained for 4 out of 8 herbs/spices. Conclusions Our results suggested that the FFQ was able to give good estimates of frequency of intake and portion sizes on group level for several of the most frequently used herbs and spices. The FFQ was only able to fairly rank subjects according to frequency of intake of the 8 most frequently consumed herbs and spices. Other studies are warranted

  18. Assessing sediment toxicity from navigational pools of the Upper Mississippi River using a 28-day Hyalella azteca test

    Science.gov (United States)

    Kemble, N.E.; Brunson, E.L.; Canfield, T.J.; Dwyer, F.J.; Ingersoll, C.G.

    1998-01-01

    To assess the extent of sediment contamination in the Upper Mississippi River (UMR) system after the flood of 1993, sediment samples were collected from 24 of the 26 navigational pools in the river and from one site in the Saint Croix River in the summer of 1994. Whole-sediment tests were conducted with the amphipod Hyalella azteca for 28 days measuring the effects on survival, growth, and sexual maturation. Amphipod survival was significantly reduced in only one sediment (13B) relative to the control and reference sediments. Body length of amphipods was significantly reduced relative to the control and reference sediments in only one sample (26C). Sexual maturation was not significantly reduced in any treatment when compared to the control and reference sediments. No significant correlations were observed between survival, growth, and maturation to either the physical or chemical characteristics of the sediment samples from the river. When highly reliable effect range medians (ERMs) were used to evaluate sediment chemistry, 47 of 49 (96%) of the samples were correctly classified as nontoxic. These results indicate that sediment samples from the Upper Mississippi River are relatively uncontaminated compared to other areas of known contamination in the United States.

  19. Phenolic acid protects of renal damage induced by ochratoxin A in a 28-days-oral treatment in rats.

    Science.gov (United States)

    Cariddi, L N; Escobar, F M; Sabini, M C; Campra, N A; Bagnis, G; Decote-Ricardo, D; Freire-de-Lima, C G; Mañas, F; Sabini, L I; Dalcero, A M

    2016-04-01

    The present study aimed to characterize the chlorogenic acid (ChlA) capacity to reverse the toxic effects induced by ochratoxin A (OTA) in a subacute toxicity test in rats. Male Wistar rats were fed orally by gavage for 28 days with OTA (0.4mg/kg bw/day), ChlA (5mg/kg bw/day) or the combination OTA (0.4mg/kg bw/day)+ChlA (5mg/kg bw/day). No deaths, no decrease in feed intake or body weight in any experimental group were recorded. The negative control group and the animals treated with ChlA alone showed no changes in any parameters evaluated. In OTA-treated group significant changes such as decrease in urine volume, proteinuria, occult blood, increase in serum creatinine values; decrease in absolute and relative kidney weight and characteristics histopathological lesions that indicated kidney damage were observed. However, limited effect on oxidative stress parameters were detected in kidneys of OTA-treated group. Animals treated with the combination OTA+ChlA were showed as negative control group in the evaluation of several parameters of toxicity. In conclusion, ChlA, at given concentration, improved biochemical parameters altered in urine and serum and pathological damages in kidneys induced by OTA exposure, showing a good protective activity, but not by an apparent antioxidant mechanism.

  20. Psychomotor performance during a 28 day head-down tilt with and without lower body negative pressure

    Science.gov (United States)

    Traon, A. Pavy-le; de Feneyrols, A. Rous; Cornac, A.; Abdeseelam, R.; N'uygen, D.; Lazerges, M.; Güell, A.; Bes, A.

    Several factors may affect psychomotor performance in space: sensory-motor changes, sleep disturbances, psychological modifications induced by the social isolation and confinement. However, psychomotor performance is difficult to assess. A battery of standardized and computerized tests, so-called "Automated Portable Test System" (APTS) was devised to ascertain the cognitive, perceptive and motor abilities and their possible fluctuations according to environmental effects. Antiorthostatic bedrest, often used to simulate weightlessness, (particularly cardiovascular modifications) also constitutes a situation of social confinement and isolation. During two bedrest experiments (with head-down tilt of -6°) of 28 days each, we intended to assess psychomotor performance of 6 males so as to determine whether: —on the one hand, it could be altered by remaining in decubitus; —on the other, the Lower Body Negative Pressure sessions, designed to prevent orthostatic intolerance back on Earth, could improve the performance. To accomplish this, part of the APTS tests as well as an automated perceptive attention test were performed. No downgrading of psychomotor performance was observed. On the contrary, the tasks were more accurately performed over time. In order to assess the experimental conditions on the acquisition phase, the learning curves were modelled. A beneficial effect of the LBNP sessions on simple tests involving the visual-motor coordination and attention faculties can only be regarded as a mere trend. Methods used in this experiment are also discussed.

  1. Admission cell free DNA levels predict 28-day mortality in patients with severe sepsis in intensive care.

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    Avital Avriel

    Full Text Available The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD level at admission measured by a new simplified method.CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome.Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles were significantly associated with the mortality: odds ratio of 1.05, p = 0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone.CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT, suggests that CFD has the potential to improve clinical decision making.

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

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

    2015-04-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2009-01-15

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

  5. Effect of 28 days of creatine ingestion on muscle metabolism and performance of a simulated cycling road race

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    Hatley Holly

    2010-07-01

    Full Text Available Abstract Purpose The effects of creatine supplementation on muscle metabolism and exercise performance during a simulated endurance road race was investigated. Methods Twelve adult male (27.3 ± 1.0 yr, 178.6 ± 1.4 cm, 78.0 ± 2.5 kg, 8.9 ± 1.1 %fat endurance-trained (53.3 ± 2.0 ml* kg-1* min-1, cycling ~160 km/wk cyclists completed a simulated road race on a cycle ergometer (Lode, consisting of a two-hour cycling bout at 60% of peak aerobic capacity (VO2peak with three 10-second sprints performed at 110% VO2 peak every 15 minutes. Cyclists completed the 2-hr cycling bout before and after dietary creatine monohydrate or placebo supplementation (3 g/day for 28 days. Muscle biopsies were taken at rest and five minutes before the end of the two-hour ride. Results There was a 24.5 ± 10.0% increase in resting muscle total creatine and 38.4 ± 23.9% increase in muscle creatine phosphate in the creatine group (P 2 peak, were not affected by creatine supplementation. Submaximal oxygen consumption near the end of the two-hour ride was decreased by approximately 10% by creatine supplementation (P +14.0 ± 6.3% than the placebo group (-10.4 ± 4.4%; P Conclusions It can be concluded that although creatine supplementation may increase resting muscle total creatine, muscle creatine phosphate, and plasma volume, and may lead to a reduction in oxygen consumption during submaximal exercise, creatine supplementation does not improve sprint performance at the end of endurance cycling exercise.

  6. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days.

    Science.gov (United States)

    Witt, Kristine L; Malarkey, David E; Hobbs, Cheryl A; Davis, Jeffrey P; Kissling, Grace E; Caspary, William; Travlos, Gregory; Recio, Leslie

    2010-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. [2007]: Prog Neuropsychopharmacol Biol Psychiatry 31:1282-1288) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

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

    Science.gov (United States)

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

    2001-06-21

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2000-10-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

  13. Sex-based differences in clinical features, management, and 28-day and 7-year prognosis of first acute myocardial infarction. RESCATE II study.

    Science.gov (United States)

    García-García, Cosme; Molina, Lluís; Subirana, Isaac; Sala, Joan; Bruguera, Jordi; Arós, Fernando; Fiol, Miquel; Serra, Jordi; Marrugat, Jaume; Elosua, Roberto

    2014-01-01

    To analyze sex-based differences in clinical characteristics, management, and 28-day and 7-year prognosis after a first myocardial infarction. Between 2001 and 2003, 2042 first myocardial infarction patients were consecutively registered in 6 Spanish hospitals. Clinical characteristics, management, and 28-day case-fatality were prospectively recorded. Seven-year vital status was also ascertained by data linkage with the National Mortality Index. The registry included 449 women and 1593 men with a first myocardial infarction. Compared with men, women were older, had a higher prevalence of hypertension and diabetes, and were more likely to receive angiotensin-converting enzyme (ACE) inhibitors but were less likely to receive beta-blockers or thrombolysis. No differences were observed in use of invasive procedures. More women had non-ST-segment elevation and unclassified myocardial infarction than men (37.9% vs 31.3% and 9.8% vs 6.1%, respectively; both P<.001). Case-fatality at 28 days was similar in women and men (5.57% vs 4.46%; P=.39). After multivariate adjustment, the odds ratio of 28-day mortality for men was 1.06 (95% confidence interval: 0.49-2.27; P=.883) compared with women. After multivariate adjustment, men had higher 7-year mortality than women, hazard ratio 1.93 (95% confidence interval: 1.46-2.56; P<.001). There are demographic and clinical differences between men and women with a first myocardial infarction. The short-term prognosis of a first myocardial infarction in this century is similar in both sexes. However, the long-term vital prognosis after a first myocardial infarction is worse in men than in women. These results are observed in both ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction events. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  14. Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15 ppm formaldehyde vapor

    OpenAIRE

    Frieke Kuper, C.; Van Oostrum, Lidy; Ma-Hock, Lan; Durrer, Stefan; Woutersen, Ruud A.

    2010-01-01

    Abstract To investigate if local lymphoid tissues are a target of FA, nasopharynx-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice. Paraffin-embedded tissues were sectioned and stained with H&E or stained immunohistochemically for cell proliferation (BrdU incorporation). Light microscopy revealed simple hyperplasia of NALT lymphoepith...

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

    Science.gov (United States)

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

    2017-09-18

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

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

    Science.gov (United States)

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

    2015-04-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Adoke Yeka

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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

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

    1978-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-10-21

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

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

    Science.gov (United States)

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

    2008-10-01

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

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

    Science.gov (United States)

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

    2008-10-21

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

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

    Science.gov (United States)

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

    1992-06-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

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    ABR Thomson

    1997-01-01

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

  7. Safety assessments of subcutaneous doses of aragonite calcium carbonate nanocrystals in rats

    Science.gov (United States)

    Jaji, Alhaji Zubair; Zakaria, Zuki Abu Bakar; Mahmud, Rozi; Loqman, Mohamad Yusof; Hezmee, Mohamad Noor Mohamad; Abba, Yusuf; Isa, Tijani; Mahmood, Saffanah Khuder

    2017-05-01

    Calcium carbonate nanoparticles have shown promising potentials in the delivery of drugs and metabolites. There is however, a paucity of information on the safety of their intentional or accidental over exposures to biological systems and general health safety. To this end, this study aims at documenting information on the safety of subcutaneous doses of biogenic nanocrystals of aragonite polymorph of calcium carbonate derived from cockle shells (ANC) in Sprague-Dawley (SD) rats. ANC was synthesized using the top-down method, characterized using the transmission electron microscopy and field emission scanning electron microscope and its acute and repeated dose 28-day trial toxicities were evaluated in SD rats. The results showed that the homogenous 30 ± 5 nm-sized spherical pure aragonite nanocrystals were not associated with mortality in the rats. Severe clinical signs and gross and histopathological lesions, indicating organ toxicities, were recorded in the acute toxicity (29,500 mg/m2) group and the high dose (5900 mg/m2) group of the repeated dose 28-day trial. However, the medium- (590 mg/m2 body weight) and low (59 mg/m2)-dose groups showed moderate to mild lesions. The relatively mild lesions observed in the low toxicity dosage group marked the safety margin of ANC in SD rats. It was concluded from this study that the toxicity of CaCO3 was dependent on the particulate size (30 ± 5 nm) and concentration and the route of administration used.

  8. Longevity of SLE-prone mice increased by dietary 2-mercaptoethanol via a mechanism imprinted within the first 28 days of life.

    Science.gov (United States)

    Click, Robert E

    2010-01-01

    In the preceding report, moderately lived-mice fed dietary 2-mercaptoethanol (2-Me) had their life extended, whereas long-lived mice were found to have the quality of life improved, but not extended, and did not develop high fat-diet obesity. In the present report, alteration of longevity of mice prone to develop spontaneous, systemic lupus erythematosus (SLE) by dietary 2-Me was determined. NZB, NZW, (NZW x NZB) F₁-hybrid, BXSB/MpJ, BXSB-Yaa+/J, MRL/MpJ and MRL/MpJ-Faslpr mice received drinking water, without or with 2-Me at concentrations of 10⁻³ or 10⁻² M. Therapeutic benefit was assessed by changes in longevity. The median survival of MRL/MpJ males was increased from 443 to 615 days and those of (NZW x NZB) F₁ and NZB males and females were increased approximately 2-fold. The most unexpected finding was that longevity of F₁ males was significantly extended irrespective of whether dietary exposure to 2-Me was initiated at 28 days of age, at 50 days of age, or initiated during gestation (and then terminated at weaning--28 days of age). Survival of F₁-hybrids in which treatment was initiated in utero or at 28 days of age was not significantly different, whereas if initiation was delayed until 50 days of age, survival was >200 days shorter. Survival of male MRL/MpJ-Fas lpr and BXSB/MpJ (Yaa-), two strains with genetically controlled accelerated SLE, was not altered by 2-Me when started at 50 days. Various alternatives are discussed regarding potential long-lasting mechanisms imprinted early in life. Even though present day treatments of rodent SLE are generally aimed at controlling specific immunological events, with or without survival benefits, or are procedures presently unsuitable for therapeutic use in humans, the findings presented herein seem worthy of clinical evaluation.

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

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    Victoria Ríos

    2014-03-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-10-01

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

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

    Science.gov (United States)

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

    2008-01-01

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

  14. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs.

    Science.gov (United States)

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

    2016-07-01

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

  15. Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

    Science.gov (United States)

    Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

    2011-01-01

    Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.

  16. [Retrospective Analysis of the Afatinib Clinical Pathway during the 28-Day Introductory Period-The Japanese Style of Collaborative Drug Therapy Management(J-CDTM)].

    Science.gov (United States)

    Iwata, Kaori; Ryota, Noriko; Hikita, Ami; Sando, Masumi; Suzuki, Hidekazu; Tamiya, Motohiro; Azuma, Yuichiro; Tani, Eriko; Hamaguchi, Masanari; Tanaka, Ayako; Shiroyama, Takayuki; Morishita, Naoko; Okamoto, Norio; Futagami, Sumiko; Hirashima, Tomonori

    2015-08-01

    Afatinib is a newly approved second-generation epidermal growth factor receptor-tyrosine kinase inhibito r(EGFR-TKI). Afatinib has been shown to prolongthe overall survival of patients with non-small cell lungcancer (NSCLC) with EGFR mutations compared with the standard chemotherapy. However, Grade 3 or 4 toxicities, includingdiarrhea, rash, paronychia, and stomatitis, have been observed more frequently in patients treated with afatinib than in those treated with first-generation EGFR-TKIs. Accordingly, our institution developed an afatinib clinical pathway (the afatinib pathway), which was designed by certified nurses, medical physicians, and certified pharmacists, with the goal of reducing the severity of diarrhea and rash that occur most frequently duringthe 28-day introductory period of afatinib treatment. Between May and October 2014, afatinib was administered accordingto the afatinib pathway to 14 patients with NSCLC and EGFR mutations. Of these patients, only one (7.1%) experienced Grade 3 diarrhea. No other patient experienced Grade 3 or 4 toxicity. The afatinib pathway was effective in reducingthe severities of the diarrhea and rash duringthe 28-day introductory period of the afatinib treatment. Our implementation of the afatinib pathway could be considered the Japanese style of collaborative drugtherapy management (J-CDTM).

  17. Efficacy of Various Scoring Systems for Predicting the 28-Day Survival Rate among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Requiring Emergency Intensive Care

    Directory of Open Access Journals (Sweden)

    Zhihong Feng

    2017-01-01

    Full Text Available We aimed to investigate the efficacy of four severity-of-disease scoring systems in predicting the 28-day survival rate among patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD requiring emergency care. Clinical data of patients with AECOPD who required emergency care were recorded over 2 years. APACHE II, SAPS II, SOFA, and MEDS scores were calculated from severity-of-disease indicators recorded at admission and compared between patients who died within 28 days of admission (death group; 46 patients and those who did not (survival group; 336 patients. Compared to the survival group, the death group had a significantly higher GCS score, frequency of comorbidities including hypertension and heart failure, and age (P<0.05 for all. With all four systems, scores of age, gender, renal inadequacy, hypertension, coronary heart disease, heart failure, arrhythmia, anemia, fracture leading to bedridden status, tumor, and the GCS were significantly higher in the death group than the survival group. The prediction efficacy of the APACHE II and SAPS II scores was 88.4%. The survival rates did not differ significantly between APACHE II and SAPS II (P=1.519. Our results may guide triage for early identification of critically ill patients with AECOPD in the emergency department.

  18. Characterization of pulmonary protein profiles in response to zinc oxide nanoparticles in mice: a 24-hour and 28-day follow-up study

    Directory of Open Access Journals (Sweden)

    Pan CH

    2015-07-01

    Full Text Available Chih-Hong Pan,1,2,* Kai-Jen Chuang,3,4,* Jen-Kun Chen,5 Ta-Chih Hsiao,6 Ching-Huang Lai,2 Tim P Jones,7 Kelly A BéruBé,8 Gui-Bing Hong,9 Kin-Fai Ho,10,11 Hsiao-Chi Chuang12,13 1Institute of Occupational Safety and Health, Council of Labor Affairs, Executive Yuan, 2School of Public Health, National Defense Medical Center, 3School of Public Health, College of Public Health and Nutrition, 4Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, 6Graduate Institute of Environmental Engineering, National Central University, Taoyuan, Taiwan; 7School of Earth and Ocean Sciences, 8School of Biosciences, Cardiff University, Cardiff, Wales, UK; 9Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan; 10Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 11Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People’s Republic of China; 12School of Respiratory Therapy, College of Medicine, 13Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Abstract: Although zinc oxide nanoparticles (ZnONPs are recognized to cause systemic disorders, little is known about the mechanisms that underlie the time-dependent differences that occur after exposure. The objective of this study was to investigate the mechanistic differences at 24 hours and 28 days after the exposure of BALB/c mice to ZnONPs via intratracheal instillation. An isobaric tag for the relative and absolute quantitation coupled with liquid chromatography/tandem mass spectrometry was used to identify the differential

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Science.gov (United States)

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

    2010-04-01

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

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

    Directory of Open Access Journals (Sweden)

    S. A. Snopov

    2012-01-01

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

  2. Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats.

    Science.gov (United States)

    Klykken, P C; Galbraith, T W; Kolesar, G B; Jean, P A; Woolhiser, M R; Elwell, M R; Burns-Naas, L A; Mast, R W; McCay, J A; White, K L; Munson, A E

    1999-11-01

    Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels.

  3. Renal hemodynamic and morphological changes after 7 and 28 days of leptin treatment: the participation of angiotensin II via the AT1 receptor.

    Science.gov (United States)

    Thieme, Karina; Oliveira-Souza, Maria

    2015-01-01

    The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin's action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-α and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-α and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects.

  4. Acute and repeated inhalation lung injury by 3-methoxybutyl chloroformate in rats: CT-pathologic correlation

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    Lim, Yeon Soo [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Chung, Myung Hee [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)]. E-mail: mhchung@catholic.ac.kr; Park, Seog Hee [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Kim, Hyeon-Yeong [Industrial Chemicals Research Center, Industrial Safety and Health Research Institute KISCO, 104-8, Moonji-dong, Yusong-gu, Taejon-si 305-380 (Korea, Republic of); Choi, Byung Gil [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Lim, Hyun Wook [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Kim, Jin Ah [Department of Pathology, Holy Family Hospital, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon-si, Kyung gi-do 420-717 (Korea, Republic of); Yoo, Won Jong [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)

    2007-05-15

    Objectives: To investigate the acute and repeated pulmonary damage in Sprague-Dawley rats caused by the inhalation of 3-methoxybutyl chloroformate (3-MBCF) using computed tomography (CT), and to correlate these results with those obtained from a pathological study. Methods: Sixty, 7-week-old rats were exposed to 3-MBCF vapor via inhalation (6 h/day) for 1 day (N = 20), 3 days (N = 20), and 28 days (5 days/week) (N = 20) using whole body exposure chambers at a concentration of 0 (control), 3, 6 and 12 ppm. CT examinations including densitometry and histopathologic studies were carried out. For the follow-up study, the rats exposed for 3 days were scanned using CT and their pathology was examined at 7, 14, and 28 days. Results: There was a significant decrease in the parenchymal density in the groups exposed to the 3-MBCF vapors for 1 day at 3 ppm (p = 0.022) or 6 ppm (p = 0.010), compared with the control. The parenchymal density of the rats exposed to12 ppm was significantly higher. The pathological findings in this period, the grades of vascular congestion, tracheobronchial exfoliation, and alveolar rupture were significant. In the groups exposed for 3 days, there was a large decrease in the parenchymal density with increasing dose (control: -675.48 {+-} 32.82 HU, 3 ppm: -720.65 {+-} 34.21 HU, 6 ppm: -756.41 {+-} 41.68 HU, 12 ppm: -812.56 {+-} 53.48 HU) (p = 0.000). There were significant density differences between each dose in the groups exposed for 28 days (p = 0.000). The CT findings include an irregular lung surface, areas of multifocal, wedge-shaped increased density, a heterogeneous lung density, bronchial dilatation, and axial peribronchovascular bundle thickening. The histopathology examination revealed the development of alveolar interstitial thickening and vasculitis, and an aggravation of the mainstem bronchial exudates and bronchial inflammation. The alveolar wall ruptures and bronchial dilatation became severe during this period. On the follow

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

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

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

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

    Science.gov (United States)

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

    2016-11-10

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

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

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

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

  8. Effects of SiO₂, ZrO₂, and BaSO₄ nanomaterials with or without surface functionalization upon 28-day oral exposure to rats.

    Science.gov (United States)

    Buesen, Roland; Landsiedel, Robert; Sauer, Ursula G; Wohlleben, Wendel; Groeters, Sibylle; Strauss, Volker; Kamp, Hennicke; van Ravenzwaay, Bennard

    2014-10-01

    The effects of seven nanomaterials (four amorphous silicon dioxides with or without surface functionalization, two surface-functionalized zirconium dioxides, and barium sulfate) upon 28-day oral exposure to male or female rats were investigated. The studies were performed as limit tests in accordance with OECD Test Guideline 407 applying 1,000 mg test substance/kg body weight/day. Additionally, the acute phase proteins haptoglobin and α2-macroglobulin as well as cardiac troponin I were determined, and metabolome analysis was performed in plasma samples. There were no test substance-related adverse effects for any of the seven nanomaterials. Moreover, metabolomics changes were below the threshold of effects. Since test substance organ burden was not analyzed, it was not possible to establish whether the lack of findings related to the absence of systemic exposure of the tested nanomaterials or if the substances are devoid of any potential for toxicity. The few published subacute oral or short-term inhalation studies investigating comparable nanomaterials (SiO₂, ZrO₂, and BaSO₄) also do not report the occurrence of pronounced treatment-related findings. Overall, the results of the present survey provide a first indication that the tested nanomaterials neither cause local nor systemic effects upon subacute oral administration under the selected experimental conditions. Further investigations should aim at elucidating the extent of gastrointestinal absorption of surface-functionalized nanomaterials.

  9. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes

    Science.gov (United States)

    Garcia-Manero, G; Gore, S D; Kambhampati, S; Scott, B; Tefferi, A; Cogle, C R; Edenfield, W J; Hetzer, J; Kumar, K; Laille, E; Shi, T; MacBeth, K J; Skikne, B

    2016-01-01

    CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31–87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2–24) for the 14-day dosing schedule and 6 (1–24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS. PMID:26442612

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

    Directory of Open Access Journals (Sweden)

    Barry Aichatou

    2011-08-01

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

  11. Phase I Trial of Escalating-dose Cisplatin with 5-fluorouracil and Concurrent Radiotherapy in Chinese Patients with Esophageal Cancer

    Directory of Open Access Journals (Sweden)

    Zhao,Yan-Nan

    2008-02-01

    Full Text Available We defined the maximum-tolerated dose (MTD of chemoradiotherapy (cisplatin (CDDP with 5-fluorouracil (5-FU and concurrent chemoradiotherapy for Chinese patients with esophageal cancer. Twenty-one previously untreated patients with primary esophageal cancer were entered into this study. Escalating doses of CDDP with 5-FU were administered in a modified Fibonacci sequence, with concurrent conventional fractionation radiotherapy (CFR of 60 Gy or 50 Gy. The starting doses were CDDP 37.5 mg/m2 on day 1, and 5-FU 500 mg/m2 on days 1-5, respectively. The regimen was repeated 4 times every 28 days. If no dose-limiting toxicity (DLT was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be 1 dose level below the level at which DLT appeared. DLT was grade 3 radiation-induced esophagitis at a dose level of CDDP 60 mg/m2 with 5-FU 700 mg/m2 and concurrent 60 Gy CFR. MTD was defined as CDDP 52.5 mg/m2 with 5-FU 700 mg/m2 and concurrent 50 Gy CFR. The MTD of CDDP with 5-FU and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer is CDDP 52.5 mg/m2 on day 1 and 5FU 700 mg/m2 on days 1-5, repeated 4 times every 28 days, and concurrent 50 Gy CFR. Further evaluation of this regimen in a prospective phase II trial is ongoing.

  12. Phase I trial of escalating-dose cisplatin with 5-fluorouracil and concurrent radiotherapy in Chinese patients with esophageal cancer.

    Science.gov (United States)

    Lin, Qiang; Gao, Xian-Shu; Qiao, Xue-Ying; Zhou, Zhi-Guo; Zhang, Ping; Chen, Kun; Zhao, Yan-Nan; Asaumi, Junichi

    2008-02-01

    We defined the maximum-tolerated dose (MTD) of chemoradiotherapy (cisplatin (CDDP) with 5-fluorouracil (5-FU) and concurrent chemoradiotherapy) for Chinese patients with esophageal cancer. Twenty-one previously untreated patients with primary esophageal cancer were entered into this study. Escalating doses of CDDP with 5-FU were administered in a modified Fibonacci sequence, with concurrent conventional fractionation radiotherapy (CFR) of 60 Gy or 50 Gy. The starting doses were CDDP 37.5 mg/m2 on day 1, and 5-FU 500 mg/m2 on days 1-5, respectively. The regimen was repeated 4 times every 28 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be 1 dose level below the level at which DLT appeared. DLT was grade 3 radiation-induced esophagitis at a dose level of CDDP 60 mg/m2 with 5-FU 700 mg/m2 and concurrent 60 Gy CFR. MTD was defined as CDDP 52.5 mg/m2 with 5-FU 700 mg/m2 and concurrent 50 Gy CFR. The MTD of CDDP with 5-FU and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer is CDDP 52.5 mg/m2 on day 1 and 5FU 700 mg/m2 on days 1-5, repeated 4 times every 28 days, and concurrent 50 Gy CFR. Further evaluation of this regimen in a prospective phase II trial is ongoing.

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

    Science.gov (United States)

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

    2001-09-15

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

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

    Science.gov (United States)

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

    2014-05-01

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

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

    Science.gov (United States)

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

    2011-05-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2000-04-01

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

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

    Science.gov (United States)

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

    1998-07-01

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

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

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

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

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

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  2. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat.

    Science.gov (United States)

    Antkiewicz-Michaluk, Lucyna; Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy

    2014-07-01

    Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both

  3. Repeated low-dose 17β-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia.

    Science.gov (United States)

    Stanojlović, Miloš; Zlatković, Jelena; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zarić, Marina; Horvat, Anica; Drakulić, Dunja

    2015-01-01

    Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.

  4. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    Science.gov (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  5. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko

    2011-01-01

    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  6. Deployment Repeatability

    Science.gov (United States)

    2016-04-01

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

  7. Effects of 28 days of resistance exercise and consuming a commercially available pre-workout supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers in males

    Directory of Open Access Journals (Sweden)

    Leutholtz Brian

    2009-08-01

    Full Text Available Abstract Purpose This study determined the effects of 28 days of heavy resistance exercise combined with the nutritional supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers. Methods Eighteen non-resistance-trained males participated in a resistance training program (3 × 10-RM 4 times/wk for 28 days while also ingesting 27 g/day of placebo (PL or NO-Shotgun® (NO 30 min prior to exercise. Data were analyzed with separate 2 × 2 ANOVA and t-tests (p Results Total body mass was increased in both groups (p = 0.001, but without any significant increases in total body water (p = 0.77. No significant changes occurred with fat mass (p = 0.62; however fat-free mass did increase with training (p = 0.001, and NO was significantly greater than PL (p = 0.001. Bench press strength for NO was significantly greater than PL (p = 0.003. Myofibrillar protein increased with training (p = 0.001, with NO being significantly greater than PL (p = 0.019. Serum IGF-1 (p = 0.046 and HGF (p = 0.06 were significantly increased with training and for NO HGF was greater than PL (p = 0.002. Muscle phosphorylated c-met was increased with training for both groups (p = 0.019. Total DNA was increased in both groups (p = 0.006, while NO was significantly greater than PL (p = 0.038. For DNA/protein, PL was decreased and NO was not changed (p = 0.014. All of the myogenic regulatory factors were increased with training; however, NO was shown to be significantly greater than PL for Myo-D (p = 0.008 and MRF-4 (p = 0.022. No significant differences were located for any of the whole blood and serum clinical chemistry markers (p > 0.05. Conclusion When combined with heavy resistance training for 28 days, NO-Shotgun® is not associated with any negative side effects, nor does it abnormally impact any of the clinical chemistry markers. Rather, NO-Shotgun® effectively increases muscle strength and mass

  8. Identification of epigenetically downregulated Tmem70 and Ube2e2 in rat liver after 28-day treatment with hepatocarcinogenic thioacetamide showing gene product downregulation in hepatocellular preneoplastic and neoplastic lesions produced by tumor promotion.

    Science.gov (United States)

    Mizukami, Sayaka; Yafune, Atsunori; Watanabe, Yousuke; Nakajima, Kota; Jin, Meilan; Yoshida, Toshinori; Shibutani, Makoto

    2017-01-15

    The present study identified genes showing promoter region hypermethylation by CpG island microarrays in the liver of rats treated with hepatocarcinogen thioacetamide (TAA) for 28days. Among 47 hypermethylated genes, Hist1h2aa, Tmem70, Ube2e2, and Slk were confirmed to show hypermethylation by methylation-specific quantitative polymerase chain reaction (PCR) and pyrosequencing analyses as well as downregulation of transcript levels by real-time reverse transcription-PCR analysis in the livers of rats treated with TAA. All gene products of the 4 selected genes showed decreased immunoreactivity forming negative liver cell foci in a subpopulation of glutathione S-transferase placental form (GST-P)(+) foci in TAA-promoted rat livers in a two-stage hepatocarcinogenesis model. Among them, TMEM70 and UBE2E2 showed increased incidences of negative foci in GST-P(+) foci by promotion of all examined TAA, β-naphthoflavone, piperonyl butoxide, fenbendazole and phenobarbital, while HIST1H2AA and SLK did not respond to all promotive treatments. In the late stage of tumor promotion by TAA, the incidence of GST-P(+) proliferative lesions with downregulation of TMEM70 or UBE2E2 was higher in adenomas and carcinomas than liver cell foci. TMEM70 plays a role in mitochondrial oxidative phosphorylation, and UBE2E2 participates in the stabilization of cell cycle regulatory proteins. Therefore, our results indicate that aberrant epigenetic gene downregulation suggestive of a metabolic shift of cellular respiration from oxidative phosphorylation to glycolysis and aberrant cell cycle regulation facilitating cell proliferation from as early as 28days after hepatocarcinogen treatment contribute to tumor development.

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

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

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

  10. Comparison in the calculation of committed effective dose using the ICRP 30 and ICRP 60 models for a repeated incorporation by inhalation of I-125; Comparacion en el calculo de la dosis efectiva comprometida usando los modelos del ICRP 30 y del ICRP 60 para una incorporacion repetida por inhalacion de I-125

    Energy Technology Data Exchange (ETDEWEB)

    Carreno P, A.L.; Cortes C, A. [CNSNS, Dr. Barragan 779, Col. Narvarte, Mexico D.F. (Mexico); Alonso V, G.; Serrano P, F. [IPN, Edificio de Fisica Avanzada Zacatenco, 07300 Mexico D.F. (Mexico)

    2005-07-01

    Presently work, a comparison in the calculation of committed effective dose using the models of the ICRP 30 and those of the ICRP 60 for the analysis of internal dose due to repeated incorporation of I-125 is shown. The estimations of incorporated activity are obtained starting from the proportionate data for an exercise of inter comparison, with which it should be determined the internal dose later on. For to estimate the initial activity incorporated by repeated dose was assumed that this it was given through of multiple individual incorporations which happened in the middle points of the monitoring periods. The results using the models of the ICRP 30 and of the ICRP 60 are compared and the causes of the differences are analyzed. (Author)

  11. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days.

    Science.gov (United States)

    John, Kaarthik; Pratt, M Margaret; Beland, Frederick A; Churchwell, Mona I; McMullen, Gail; Olivero, Ofelia A; Pogribny, Igor P; Poirier, Miriam C

    2012-11-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.

  12. Oval pulsed high-dose dexamethasone for myositis

    NARCIS (Netherlands)

    Hoogendijk, JE; Wokke, JHJ; de Visser, M

    2000-01-01

    To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Sis patients responded. Side effects w

  13. The Efficacy of Magnesium Sulfate Loading on Microalbuminuria Following SIRS:One Step forward in Dosing

    Directory of Open Access Journals (Sweden)

    Atabak Najafi

    2012-10-01

    Full Text Available Backgrounds:Magnesium has been known for its antioxidative and antiinflammatory properties in many studies. In this study two dosing regimens of magnesium were compared with a placebocontrol group in order to investigate safety and efficacy of high doses of intravenous magnesium sulfate infusion on critically ill trauma patients. Inflammatory and oxidative factors were measured in this trial.Methods:45 trauma patients with systemic inflammatory response syndromes (SIRS were randomly assigned into 2 treatment and one placebo groups. The high dose group received 15 g MgSO4, low dose group received 7.5 g of MgSO4 over 4 hour infusion, and placebo groupreceived saline alone. The initial and post magnesium sulfate injections levels of tumor necrosis factor alpha (TNF-α, total antioxidant power and lipid peroxidation were measured after 6, 18 and 36 hours. The pre-infusion along with 6 and 36 hour level ofmicroalbuminuria were also determined.Results:Repeated measurements illustrated that there was no significant difference in TNF-α, total antioxidant power and lipid peroxidation levels among groups during the period of analysis.The microalbuminuria at 36 hour post infusion of high dose group was lower than that of control group (p = 0.024. Patient’s mortality (28 day was similar among all treatment groups. Both magnesium infusion groups tolerated the drug without experiencing anycomplications.Conclusion:No evidence for antioxidative and antiinflammatory effects of magnesium in traumatic SIRS positive patients was found. Magnesium in high doses may be recommended for traumaticpatients with SIRS status to prevent microalbuminuria.

  14. Repeat-until-success quantum repeaters

    Science.gov (United States)

    Bruschi, David Edward; Barlow, Thomas M.; Razavi, Mohsen; Beige, Almut

    2014-09-01

    We propose a repeat-until-success protocol to improve the performance of probabilistic quantum repeaters. Conventionally, these rely on passive static linear-optics elements and photodetectors to perform Bell-state measurements (BSMs) with a maximum success rate of 50%. This is a strong impediment for entanglement swapping between distant quantum memories. Every time a BSM fails, entanglement needs to be redistributed between the corresponding memories in the repeater link. The key ingredients of our scheme are repeatable BSMs. Under ideal conditions, these turn probabilistic quantum repeaters into deterministic ones. Under realistic conditions, our protocol too might fail. However, using additional threshold detectors now allows us to improve the entanglement generation rate by almost orders of magnitude, at a nominal distance of 1000 km, compared to schemes that rely on conventional BSMs. This improvement is sufficient to make the performance of our scheme comparable to the expected performance of some deterministic quantum repeaters.

  15. Effect of Beta alanine and sodium bicarbonate supplementation on repeated-sprint performance.

    Science.gov (United States)

    Ducker, Kagan J; Dawson, Brian; Wallman, Karen E

    2013-12-01

    This study aimed to investigate if combining beta alanine (BA) and sodium bicarbonate (NaHCO3) supplementation could lead to enhanced repeated-sprint performance in team-sport athletes, beyond what is possible with either supplement alone. Participants (n = 24) completed duplicate trials of a repeated-sprint test (3 sets; 6 × 20 m departing every 25 seconds, 4 minutes active recovery between sets) and were then allocated into 4 groups as follows: BA only (n = 6; 28 days BA, acute sodium chloride placebo); NaHCO3 only (n = 6; 28 days glucose placebo, acute NaHCO3); BA/NaHCO3 (n = 6; 28 days BA, acute NaHCO3); placebo only (n = 6; 28 days glucose placebo, acute sodium chloride placebo), then completed duplicate trials postsupplementation. Sodium bicarbonate alone resulted in moderate effect size (d = 0.40-0.71) and "likely" and "very likely" benefit for overall total sprint times (TST) and for each individual set and for first sprint (sets 2 and 3) and best sprint time (sets 2 and 3). Combining BA and NaHCO3 resulted in "possible" to "likely" benefits for overall TST and for sets 2 and 3. First sprint (set 3) and best sprint time (sets 2 and 3) also showed "likely" benefit after this trial. The BA and placebo groups showed no differences in performance after supplementation. In conclusion, these results indicate that supplementation with acute NaHCO3 improved repeated-sprint performance more than either a combination of NaHCO3 and BA or BA alone.

  16. [Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment].

    Science.gov (United States)

    Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi

    2008-12-01

    In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

  17. Repeat Gamma Knife Radiosurgery for Trigeminal Neuralgia

    Energy Technology Data Exchange (ETDEWEB)

    Aubuchon, Adam C., E-mail: acaubuchon@gmail.com [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Chan, Michael D. [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Lovato, James F. [Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (United States); Balamucki, Christopher J. [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States); Ellis, Thomas L.; Tatter, Stephen B. [Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, NC (United States); McMullen, Kevin P.; Munley, Michael T.; Deguzman, Allan F.; Ekstrand, Kenneth E.; Bourland, J. Daniel; Shaw, Edward G. [Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC (United States)

    2011-11-15

    Purpose: Repeat gamma knife stereotactic radiosurgery (GKRS) for recurrent or persistent trigeminal neuralgia induces an additional response but at the expense of an increased incidence of facial numbness. The present series summarized the results of a repeat treatment series at Wake Forest University Baptist Medical Center, including a multivariate analysis of the data to identify the prognostic factors for treatment success and toxicity. Methods and Materials: Between January 1999 and December 2007, 37 patients underwent a second GKRS application because of treatment failure after a first GKRS treatment. The mean initial dose in the series was 87.3 Gy (range, 80-90). The mean retreatment dose was 84.4 Gy (range, 60-90). The dosimetric variables recorded included the dorsal root entry zone dose, pons surface dose, and dose to the distal nerve. Results: Of the 37 patients, 81% achieved a >50% pain relief response to repeat GKRS, and 57% experienced some form of trigeminal dysfunction after repeat GKRS. Two patients (5%) experienced clinically significant toxicity: one with bothersome numbness and one with corneal dryness requiring tarsorraphy. A dorsal root entry zone dose at repeat treatment of >26.6 Gy predicted for treatment success (61% vs. 32%, p = .0716). A cumulative dorsal root entry zone dose of >84.3 Gy (72% vs. 44%, p = .091) and a cumulative pons surface dose of >108.5 Gy (78% vs. 44%, p = .018) predicted for post-GKRS numbness. The presence of any post-GKRS numbness predicted for a >50% decrease in pain intensity (100% vs. 60%, p = .0015). Conclusion: Repeat GKRS is a viable treatment option for recurrent trigeminal neuralgia, although the patient assumes a greater risk of nerve dysfunction to achieve maximal pain relief.

  18. The chemotherapy of onchocerciasis X. An assessment of four single dose treatment regimes of MK-933 (ivermectin) in human onchocerciasis.

    Science.gov (United States)

    Awadzi, K; Dadzie, K Y; Shulz-Key, H; Haddock, D R; Gilles, H M; Aziz, M A

    1985-02-01

    Nineteen patients from an area of vector control in the savanna region of Northern Ghana, all with moderate to heavy infections with Onchocerca volvulus and some with ocular involvement, were treated with 50, 100, 150 or 200 micrograms kg-1 of ivermectin. Detailed monitoring of clinical and ocular reactions and of alterations in skin microfilarial counts and laboratory indices were carried out during the first 28 days. Microfilarial counts in skin snips and detailed ocular examinations were then repeated at intervals over a period of nine months. Ivermectin slowly eliminated microfilariae from the skin and eye without serious adverse clinical or ocular reactions in all treated groups. There was little difference in efficacy between doses of 100, 150 and 200 micrograms kg-1, and these were more effective than the 50 micrograms kg-1 dose. Very low levels of skin microfilariae were maintained for nine months. Microfilariae were not eliminated from the eye for at least three months. The drug was neither macrofilaricidal nor embryotoxic. However, it produced a dose-dependent stimulation of embryogenesis manifest at one month and succeeded by a suppression of embryogenesis at three months after therapy. In areas where transmission of onchocerciasis has been interrupted, ivermectin may need not be given more often than once a year. The efficacy of the drug on single dosage and the mild adverse reactions produced, if confirmed in subsequent controlled studies, would greatly simplify the treatment of onchocerciasis and would reintroduce new concepts of the role of chemotherapy in the control of onchocerciasis.

  19. Twenty-eight-day repeated inhalation toxicity study of nano-sized lanthanum oxide in male sprague-dawley rats.

    Science.gov (United States)

    Shin, Seo-Ho; Lim, Cheol-Hong; Kim, Yong-Soon; Lee, Yong-Hoon; Kim, Sung-Hwan; Kim, Jong-Choon

    2017-04-01

    Although the use of lanthanum has increased in field of high-tech industry worldwide, potential adverse effects to human health and to the environment are largely unknown. The present study aimed to investigate the potential toxicity of nano-sized lanthanum oxide (La2 O3 ) following repeated inhalation exposure in male Sprague-Dawley rats. Male rats were exposed nose-only to nano-sized La2 O3 for 28 days (5 days/week) at doses of 0, 0.5, 2.5, and 10 mg/m(3) . In the experimental period, we evaluated treatment-related changes including clinical signs, body weight, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology findings. We also analyzed lanthanum distribution in the major organs and in the blood, bronchoalveolar lavage fluids (BALF), and oxidative stress in lung tissues. Lanthanum level was highest in lung tissues and showed a dose-dependent relation. Alveolar proteinosis was observed in all treatment groups and was accompanied by an increase in lung weight; moreover, lung inflammation was observed in the 2.5 mg/m(3) and higher dose groups and was accompanied by an increase in white blood cells. In the BALF, total cell counts including macrophages and neutrophils, lactate dehydrogenase, albumin, nitric oxide, and tumor necrosis factor-alpha increased significantly in all treatment groups. Furthermore, these changes tended to deteriorate in the 10 mg/m(3) group at the end of the recovery period. In the present experimental conditions, we found that the lowest-observed-adverse-effect level of nano-sized La2 O3 was 0.5 mg/m(3) in male rats, and the target organ was the lung. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1226-1240, 2017. © 2016 Wiley Periodicals, Inc.

  20. SHORT-TERM TOXICITY STUDY IN RATS DOSED WITH PULEGONE AND MENTHOL

    DEFF Research Database (Denmark)

    Thorup, I.; Würtzen, G.; Carstensen, J.

    1983-01-01

    Pulegone and menthol, components of peppermint oil, were investigated in rats. The substances were administered by gavage for 28 days at 0, 20, 80, 160 mg pulegone and 0, 200, 400, 800 mg menthol/kg body wt./day, respectively. At the two highest doses, pulegone induced atonia, decreased blood...

  1. SHORT-TERM TOXICITY STUDY IN RATS DOSED WITH PEPPERMINT OIL

    DEFF Research Database (Denmark)

    Thorup, I.; Würtzen, G.; Carstensen, J.

    1983-01-01

    Pulegone and menthol, components of peppermint oil, were investigated in rats. The substances were administered by gavage for 28 days at 0, 20, 80, 160 mg pulegone and 0, 200, 400, 800 mg menthol/kg body wt./day, respectively. At the two highest doses, pulegone induced atonia, decreased blood...

  2. Quantum repeated games revisited

    CERN Document Server

    Frackiewicz, Piotr

    2011-01-01

    We present a scheme for playing quantum repeated 2x2 games based on the Marinatto and Weber's approach to quantum games. As a potential application, we study twice repeated Prisoner's Dilemma game. We show that results not available in classical game can be obtained when the game is played in the quantum way. Before we present our idea, we comment on the previous scheme of playing quantum repeated games.

  3. Reconfigurable multiport EPON repeater

    Science.gov (United States)

    Oishi, Masayuki; Inohara, Ryo; Agata, Akira; Horiuchi, Yukio

    2009-11-01

    An extended reach EPON repeater is one of the solutions to effectively expand FTTH service areas. In this paper, we propose a reconfigurable multi-port EPON repeater for effective accommodation of multiple ODNs with a single OLT line card. The proposed repeater, which has multi-ports in both OLT and ODN sides, consists of TRs, BTRs with the CDR function and a reconfigurable electrical matrix switch, can accommodate multiple ODNs to a single OLT line card by controlling the connection of the matrix switch. Although conventional EPON repeaters require full OLT line cards to accommodate subscribers from the initial installation stage, the proposed repeater can dramatically reduce the number of required line cards especially when the number of subscribers is less than a half of the maximum registerable users per OLT. Numerical calculation results show that the extended reach EPON system with the proposed EPON repeater can save 17.5% of the initial installation cost compared with a conventional repeater, and can be less expensive than conventional systems up to the maximum subscribers especially when the percentage of ODNs in lightly-populated areas is higher.

  4. Revisiting the TALE repeat.

    Science.gov (United States)

    Deng, Dong; Yan, Chuangye; Wu, Jianping; Pan, Xiaojing; Yan, Nieng

    2014-04-01

    Transcription activator-like (TAL) effectors specifically bind to double stranded (ds) DNA through a central domain of tandem repeats. Each TAL effector (TALE) repeat comprises 33-35 amino acids and recognizes one specific DNA base through a highly variable residue at a fixed position in the repeat. Structural studies have revealed the molecular basis of DNA recognition by TALE repeats. Examination of the overall structure reveals that the basic building block of TALE protein, namely a helical hairpin, is one-helix shifted from the previously defined TALE motif. Here we wish to suggest a structure-based re-demarcation of the TALE repeat which starts with the residues that bind to the DNA backbone phosphate and concludes with the base-recognition hyper-variable residue. This new numbering system is consistent with the α-solenoid superfamily to which TALE belongs, and reflects the structural integrity of TAL effectors. In addition, it confers integral number of TALE repeats that matches the number of bound DNA bases. We then present fifteen crystal structures of engineered dHax3 variants in complex with target DNA molecules, which elucidate the structural basis for the recognition of bases adenine (A) and guanine (G) by reported or uncharacterized TALE codes. Finally, we analyzed the sequence-structure correlation of the amino acid residues within a TALE repeat. The structural analyses reported here may advance the mechanistic understanding of TALE proteins and facilitate the design of TALEN with improved affinity and specificity.

  5. 重症加强护理病房急性呼吸窘迫综合征患者28日死亡率影响因素分析%Risk factors of mortality within 28 days among patients with acute respiratory distress syndrome in Intensive Care Unit

    Institute of Scientific and Technical Information of China (English)

    林明强; 吕有凯; 王日兴

    2016-01-01

    Objective To investigate the mortality rate within 28 days among patients with acute respiratory distress syndrome (ARDS) in Intensive Care Unit (ICU), and to analyze the risk factors of mortality within 28 days. Methods The clinical data of 237 ARDS patients, aged above 12, admitted to ICU from May 2012 to May 2014 and stayed in ICU for longer than 24 h, were retrospectively studied. Single-factor and multi-factor logistic regression analy-sis were applied to evaluate the risk factors of mortality within 28 days. Results According to the Berlin Definition, the numbers of mild, moderate and severe patients were 47 cases, 112 cases and 78 cases, respectively, and the rate of mor-tality within 28 days were 17.1%, 49.1%and 65.4%, respectively. Extra pulmonary disease was the main primary disease of ARDS, accounting for 60.3%. Pneumonia had the highest rate of mortality within 28 days, which was 73.8%(31/42). Septic shock was the main direct factors of mortality, accounting for 34.5%. The risk factors of mild and moderate AR-DS patients' mortality within 28 days included duration of hospital stay before ARDS onset>48 h (OR=4.712, 4.773;P12岁的ARDS患者237例,统计其临床资料,采用单因素及多因素Logistic回归分析评价患者28日死亡危险因素.结果 根据柏林定义,轻度、中度、重度患者分别为47例、112例和78例,病死率分别为17.1%、49.1%和65.4%;ARDS原发病以肺外疾病为主,占60.3%;致死率最高的原发病为肺炎,42例中死亡31例,占73.8%;患者死亡的直接因素主要为脓毒性休克,占34.5%.轻度及中度ARDS患者28日死亡危险因素包括确诊前住院时间>48 h (OR=4.712,4.773;P<0.05)、急性生理学和慢性健康评价(APACHE)Ⅱ评分(OR=1.171,1.389;P<0.05);重度患者28日死亡危险因素包括序贯性器官功能衰竭(SOFA)评分(OR=1.447;P<0.05)和免疫抑制状态(OR=7.917;P<0.05).结论 ICU病房ARDS患者主要原发病为肺外疾病,致死率最高的原发病为肺炎,死

  6. Recursive quantum repeater networks

    CERN Document Server

    Van Meter, Rodney; Horsman, Clare

    2011-01-01

    Internet-scale quantum repeater networks will be heterogeneous in physical technology, repeater functionality, and management. The classical control necessary to use the network will therefore face similar issues as Internet data transmission. Many scalability and management problems that arose during the development of the Internet might have been solved in a more uniform fashion, improving flexibility and reducing redundant engineering effort. Quantum repeater network development is currently at the stage where we risk similar duplication when separate systems are combined. We propose a unifying framework that can be used with all existing repeater designs. We introduce the notion of a Quantum Recursive Network Architecture, developed from the emerging classical concept of 'recursive networks', extending recursive mechanisms from a focus on data forwarding to a more general distributed computing request framework. Recursion abstracts independent transit networks as single relay nodes, unifies software layer...

  7. Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial.

    Directory of Open Access Journals (Sweden)

    Chaoying Hu

    Full Text Available Darapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2 inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA2 activity and safety were evaluated.Systemic exposure (AUC(0-T, Cmax geometric mean (CVb% of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%, 34.4 ng/mL (49.9% compared to single-dose administration (153 ng.h/mL (69.0%, 17.9 ng/mL (55.2%. The steady-state accumulation ratio was less than unity (Rs = 0.80, indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib ratios for AUC(0-τ of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA2 activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA2 activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese

  8. Repeated fecal microbiota transplantation in a child with ulcerative colitis.

    Science.gov (United States)

    Shimizu, Hirotaka; Arai, Katsuhiro; Abe, Jun; Nakabayashi, Kazuhiko; Yoshioka, Takako; Hosoi, Kenji; Kuroda, Makoto

    2016-08-01

    We report the case of an 11-year-old girl with ulcerative colitis refractory to conventional therapy, who was subsequently treated successfully with repeated fecal microbiota transplantation (FMT). The patient was steroid dependent despite several infliximab treatments, and colectomy was proposed to improve quality of life. After repeated FMT, she was able to maintain remission with on minimal dose of steroid. Although her fecal microbiota was dysbiotic before FMT, it was restored to a similar pattern as the donor after repeated FMT.

  9. PERINATAL TUBERCULOSIS WITH MILLIARY PATTERN IN INFANT AGED 28 DAYS

    Directory of Open Access Journals (Sweden)

    Dian Savitri

    2015-07-01

    Full Text Available Perinatal  tuberculosis  (TB was a very  rare  case.  Its  clinical manifestations  could mimic bacterialinfection. The clinical course was often fulminant and characterized by dissemination and meningitis.Its mortality was very high, could achieve 100% in untreated patient. We reported a case of infant aged28  days  admitted with  breathlessness,  fever,  and  poor  feeding.  Physical  examination  showedbreathlessness, pale, lethargy, and hepatomegaly. Chest radiograph showed a feature of milliary patternwith fine tubercles in both lung, supported with positive result on gastric aspirates for acid fast bacilli3 days respectively. Gastric aspirate culture for Mycobacterium tuberculosis showed positive result.Patient then diagnosed with perinatal TB with milliary pattern. This condition was accompanied withsevere sepsis and meningitis. Four TB regimens (isoniazid, rifampisin, pirazinamide, and ethambutol,corticosteroid, antibiotics were given. The patient was eventually died after receiving TB therapy for 13days. [MEDICINA 2014;45:208-212].

  10. 注射用右旋雷贝拉唑钠大鼠13周重复给药毒性研究%Study on Repeated Dose Toxicity of Dexrabeprazole Sodium Injection in Rats for 13 Weeks

    Institute of Scientific and Technical Information of China (English)

    戴晓莉; 戴学栋; 郭峰; 胡建庭; 马玉奎

    2016-01-01

    taken the blood at ifrst and last injection for toxicokinetics. Results The rats in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 apperanced shortness of breath, unsteady gait, prone motionless and other symptoms. The levels of RBC,HGB,HCT in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 were significantly lower than those in vehicle control group at 13 weeks (P<0.05). The change of these parameters regained to normal at 4 weeks after withdrawal. The amount of small follicular in the thyroid gland increased at 13 weeks, and failed to fully recover at 4 weeks after the withdrawal.Conclusion Repeated administration of dexrabeprazole Sodium injection (80, 20 mg·kg-1) for 13 weeks could lead to abnormal indicators related erythrocyte and pathological lesions of thyroid in rats.

  11. Digital repeat analysis; setup and operation.

    Science.gov (United States)

    Nol, J; Isouard, G; Mirecki, J

    2006-06-01

    Since the emergence of digital imaging, there have been questions about the necessity of continuing reject analysis programs in imaging departments to evaluate performance and quality. As a marketing strategy, most suppliers of digital technology focus on the supremacy of the technology and its ability to reduce the number of repeats, resulting in less radiation doses given to patients and increased productivity in the department. On the other hand, quality assurance radiographers and radiologists believe that repeats are mainly related to positioning skills, and repeat analysis is the main tool to plan training needs to up-skill radiographers. A comparative study between conventional and digital imaging was undertaken to compare outcomes and evaluate the need for reject analysis. However, digital technology still being at its early development stages, setting a credible reject analysis program became the major task of the study. It took the department, with the help of the suppliers of the computed radiography reader and the picture archiving and communication system, over 2 years of software enhancement to build a reliable digital repeat analysis system. The results were supportive of both philosophies; the number of repeats as a result of exposure factors was reduced dramatically; however, the percentage of repeats as a result of positioning skills was slightly on the increase for the simple reason that some rejects in the conventional system qualifying for both exposure and positioning errors were classified as exposure error. The ability of digitally adjusting dark or light images reclassified some of those images as positioning errors.

  12. The Pentapeptide Repeat Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Vetting,M.; Hegde, S.; Fajardo, J.; Fiser, A.; Roderick, S.; Takiff, H.; Blanchard, J.

    2006-01-01

    The Pentapeptide Repeat Protein (PRP) family has over 500 members in the prokaryotic and eukaryotic kingdoms. These proteins are composed of, or contain domains composed of, tandemly repeated amino acid sequences with a consensus sequence of [S, T,A, V][D, N][L, F]-[S, T,R][G]. The biochemical function of the vast majority of PRP family members is unknown. The three-dimensional structure of the first member of the PRP family was determined for the fluoroquinolone resistance protein (MfpA) from Mycobacterium tuberculosis. The structure revealed that the pentapeptide repeats encode the folding of a novel right-handed quadrilateral {beta}-helix. MfpA binds to DNA gyrase and inhibits its activity. The rod-shaped, dimeric protein exhibits remarkable size, shape and electrostatic similarity to DNA.

  13. Repeating the Past

    Science.gov (United States)

    Moore, John W.

    1998-05-01

    As part of the celebration of the Journal 's 75th year, we are scanning each Journal issue from 25, 50, and 74 years ago. Many of the ideas and practices described are so similar to present-day "innovations" that George Santayana's adage (1) "Those who cannot remember the past are condemned to repeat it" comes to mind. But perhaps "condemned" is too strong - sometimes it may be valuable to repeat something that was done long ago. One example comes from the earliest days of the Division of Chemical Education and of the Journal.

  14. Effects of 28 days of resistance exercise while consuming commercially available pre- and post-workout supplements, NO-Shotgun® and NO-Synthesize® on body composition, muscle strength and mass, markers of protein synthesis, and clinical safety markers in males

    Directory of Open Access Journals (Sweden)

    Spillane Mike

    2011-11-01

    Full Text Available Abstract Purpose The effects of 28 days of heavy resistance training while ingesting the pre- and post-workout supplements, NO-Shotgun® and NO-Synthesize® were determined on body composition, muscle strength and mass, markers of protein synthesis, and clinical safety markers. Methods Nineteen non-resistance-trained males participated in a resistance training program 4 times/week for 28 days while either ingesting 27 g/day of carbohydrate (CARB or NO-Shotgun® 30 min pre-exercise and 27 g/day of carbohydrate or NO- Synthesize® 30 min post-exercise (NOSS. Data were analyzed with separate 2 × 2 ANOVA (p Results Total body mass was increased in both groups (p = 0.001, but not different between groups. Fat mass was unchanged with CARB, but NOSS decreased fat mass (p = 0.026. Both groups increased fat-free mass (p = 0.001; however, the increases were greater with NOSS (p = 0.023. NOSS underwent greater increases in upper-body (p = 0.023 and lower-body (p = 0.035 strength than CARB. Myofibrillar protein significantly increased in both groups (p = 0.041, with NOSS being greater than CARB (p = 0.049. All of the MHC isoforms were significantly increased in both groups; however, NOSS was greater than CARB for MHC 1 (p = 0.013 and MHC 2A (p = 0.046. All of the myogenic regulatory factors were significantly increased in both groups; however, NOSS was greater than CARB for Myo-D (p = 0.038 and MRF-4 (p = 0.001. For the whole blood and serum clinical chemistry markers, all variables remained within normal clinical ranges. Conclusions Heavy resistance training for 28 days, with NO-Shotgun® and NO-Synthesize® ingested before and after exercise, respectively, significantly improved body composition and increased muscle mass and performance without abnormally impacting any of the clinical chemistry markers.

  15. All-optical repeater.

    Science.gov (United States)

    Silberberg, Y

    1986-06-01

    An all-optical device containing saturable gain, saturable loss, and unsaturable loss is shown to transform weak, distorted optical pulses into uniform standard-shape pulses. The proposed device performs thresholding, amplification, and pulse shaping as required from an optical repeater. It is shown that such a device could be realized by existing semiconductor technology.

  16. Bidirectional Manchester repeater

    Science.gov (United States)

    Ferguson, J.

    1980-01-01

    Bidirectional Manchester repeater is inserted at periodic intervals along single bidirectional twisted pair transmission line to detect, amplify, and transmit bidirectional Manchester 11 code signals. Requiring only 18 TTL 7400 series IC's, some line receivers and drivers, and handful of passive components, circuit is simple and relatively inexpensive to build.

  17. Safety of Repeated Yttrium-90 Radioembolization

    Energy Technology Data Exchange (ETDEWEB)

    Lam, Marnix G. E. H.; Louie, John D. [Stanford University School of Medicine, Division of Interventional Radiology (United States); Iagaru, Andrei H.; Goris, Michael L. [Stanford University School of Medicine, Division of Nuclear Medicine (United States); Sze, Daniel Y., E-mail: dansze@stanford.edu [Stanford University School of Medicine, Division of Interventional Radiology (United States)

    2013-10-15

    Purpose: Repeated radioembolization (RE) treatments carry theoretically higher risk of radiation-induced hepatic injury because of the liver's cumulative memory of previous exposure. We performed a retrospective safety analysis on patients who underwent repeated RE. Methods: From 2004 to 2011, a total of 247 patients were treated by RE. Eight patients (5 men, 3 women, age range 51-71 years) underwent repeated treatment of a targeted territory, all with resin microspheres (SIR-Spheres; Sirtex, Lane Cove, Australia). Adverse events were graded during a standardized follow-up. In addition, the correlation between the occurrence of RE-induced liver disease (REILD) and multiple variables was investigated in univariate and multivariate analyses in all 247 patients who received RE. Results: Two patients died shortly after the second treatment (at 84 and 107 days) with signs and symptoms of REILD. Both patients underwent whole liver treatment twice (cumulative doses 3.08 and 2.66 GBq). The other 6 patients demonstrated only minor toxicities after receiving cumulative doses ranging from 2.41 to 3.88 GBq. All patients experienced objective tumor responses. In the whole population, multifactorial analysis identified three risk factors associated with REILD: repeated RE (p = 0.036), baseline serum total bilirubin (p = 0.048), and baseline serum aspartate aminotransferase (p = 0.043). Repeated RE proved to be the only independent risk factor for REILD in multivariate analysis (odds ratio 9.6; p = 0.002). Additionally, the administered activity per target volume (in GBq/L) was found to be an independent risk factor for REILD, but only in whole liver treatments (p = 0.033). Conclusion: The risk of REILD appears to be elevated for repeated RE. Objective tumor responses were observed, but establishment of safety limits will require improvement in dosimetric measurement and prediction.

  18. Flexibility of oral cholera vaccine dosing-a randomized controlled trial measuring immune responses following alternative vaccination schedules in a cholera hyper-endemic zone.

    Directory of Open Access Journals (Sweden)

    Suman Kanungo

    2015-03-01

    Full Text Available BACKGROUND: A bivalent killed whole cell oral cholera vaccine has been found to be safe and efficacious for five years in the cholera endemic setting of Kolkata, India, when given in a two dose schedule, two weeks apart. A randomized controlled trial revealed that the immune response was not significantly increased following the second dose compared to that after the first dose. We aimed to evaluate the impact of an extended four week dosing schedule on vibriocidal response. METHODOLOGY/PRINCIPAL FINDINGS: In this double blind randomized controlled non-inferiority trial, 356 Indian, non-pregnant residents aged 1 year or older were randomized to receive two doses of oral cholera vaccine at 14 and 28 day intervals. We compared vibriocidal immune responses between these schedules. Among adults, no significant differences were noted when comparing the rates of seroconversion for V. cholerae O1 Inaba following two dose regimens administered at a 14 day interval (55% vs the 28 day interval (58%. Similarly, no differences in seroconversion were demonstrated in children comparing the 14 (80% and 28 day intervals (77%. Following 14 and 28 day dosing intervals, vibriocidal response rates against V. cholerae O1 Ogawa were 45% and 49% in adults and 73% and 72% in children respectively. Responses were lower for V. cholerae O139, but similar between dosing schedules for adults (20%, 20% and children (28%, 20%. CONCLUSIONS/SIGNIFICANCE: Comparable immune responses and safety profiles between the two dosing schedules support the option for increased flexibility of current OCV dosing. Further operational research using a longer dosing regimen will provide answers to improve implementation and delivery of cholera vaccination in endemic and epidemic outbreak scenarios.

  19. Duct Leakage Repeatability Testing

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Iain [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sherman, Max [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2014-01-01

    Duct leakage often needs to be measured to demonstrate compliance with requirements or to determine energy or Indoor Air Quality (IAQ) impacts. Testing is often done using standards such as ASTM E1554 (ASTM 2013) or California Title 24 (California Energy Commission 2013 & 2013b), but there are several choices of methods available within the accepted standards. Determining which method to use or not use requires an evaluation of those methods in the context of the particular needs. Three factors that are important considerations are the cost of the measurement, the accuracy of the measurement and the repeatability of the measurement. The purpose of this report is to evaluate the repeatability of the three most significant measurement techniques using data from the literature and recently obtained field data. We will also briefly discuss the first two factors. The main question to be answered by this study is to determine if differences in the repeatability of these tests methods is sufficient to indicate that any of these methods is so poor that it should be excluded from consideration as an allowed procedure in codes and standards.

  20. Comparison of the repeated dose toxicity of isomers of dinitrotoluene.

    Science.gov (United States)

    Lent, Emily May; Crouse, Lee C B; Quinn, Michael J; Wallace, Shannon M

    2012-03-01

    Dinitrotoluene (DNT) is a nitroaromatic explosive used in propellant mixtures and in the production of plastics. Isomers of DNT were administered daily via oral gavage to male Sprague-Dawley rats for 14 days to determine the subacute toxicity of individual isomers of DNT. The 3,5-DNT isomer was the most toxic isomer, inducing weight loss and mortality within 3 days. Cyanosis and anemia were observed for all isomers. Exposure to 2,4-, 2,6-, and 3,5-DNT resulted in decreased testes mass and degenerative histopathological changes. Increased splenic mass was observed for 2,4-, 2,6-, and 2,5-DNT. Extramedullary hematopoiesis of the spleen was noted for all isomers, while lymphoid hyperplasia of the spleen was noted for all isomers except 2,5-DNT. Increased liver mass was observed for 2,3-DNT and 3,4-DNT. Hepatocellular lesions were observed for 2,6-DNT and 2,4-DNT. Neurotoxic effects were noted for 3,4-DNT, 2,4-DNT, and 3,5-DNT.

  1. Antithrombotic effect of repeated doses of the ethanolic extract of ...

    African Journals Online (AJOL)

    2013-05-22

    May 22, 2013 ... botic drugs for the prevention and treatment of arterial and venous ... 7), antidiabetic (8, 9) and anticancer effects (10, 11), and also to possesses .... Another possible explanation for non-adherence of the thrombi to the vessel ...

  2. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  3. The Effects of Repeated Low-Dose Sarin Exposure

    Science.gov (United States)

    2006-01-01

    and slight enzyme that breaks down the cholinergic neurotransmitter ataxia . It has been observed in rats and mice that (NT) acetylcholine (ACh). The...minutes) Latency to the first movement (see)_ Total # of rears (C) Total # of grooming episodes (C) Arousal: (R) (choose one) I. Very low (little or...description: (D) (choose one) 1. No movement 2. Normal 3. Impairment a. Uncoordinated movement ( ataxia ) b. Walking on toes c. Splayed hind limbs d

  4. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  5. Polymicrobial Gardnerella biofilm resists repeated intravaginal antiseptic treatment in a subset of women with bacterial vaginosis: a preliminary report.

    Science.gov (United States)

    Swidsinski, Alexander; Loening-Baucke, Vera; Swidsinski, Sonja; Verstraelen, Hans

    2015-03-01

    Bacterial vaginosis is a recalcitrant polymicrobial biofilm infection that often resists standard antibiotic treatment. We therefore considered repeated treatment with octenidine, a local antiseptic that has previously been shown to be highly effective in several biofilm-associated infections. Twenty-four patients with recurrent BV were treated with a 7-day course of octenidine (octenidine dihydrochloride spray application with the commercial product Octenisept). In case of treatment failure or relapse within 6 months, patients were re-treated with a 28-day course of octenidine. In case of recurrence within 6 months after the second treatment course, patients were treated again with a 28-day course followed by weekly applications for 2 months. Treatment effect was evaluated by assessment of the presence of the biofilm on voided vaginal epithelial cells through fluorescence in situ hybridisation. The initial cure rate following a 7-day course of octenidine was as high as 87.5%. The 6-month relapse rate was, however, as high as 66.6%. Repeated treatment for 28 days led to an overall cure rate of 75.0%; however, it was also associated with emergence of complete resistance to octenidine in a subset of women. The overall cure rate after three treatment courses with 1-year follow-up was 62.5 %, with 37.5 % of the patients showing complete resistance to octenidine. Our preliminary results showed that octenidine dihydrochloride was initially highly effective, but the efficacy of repeated and prolonged treatment dropped quickly as challenge with the antiseptic rapidly led to bacterial resistance in a considerable subset of women.

  6. Repeatability of Cryogenic Multilayer Insulation

    Science.gov (United States)

    Johnson, W. L.; Vanderlaan, M.; Wood, J. J.; Rhys, N. O.; Guo, W.; Van Sciver, S.; Chato, D. J.

    2017-01-01

    Due to the variety of requirements across aerospace platforms, and one off projects, the repeatability of cryogenic multilayer insulation has never been fully established. The objective of this test program is to provide a more basic understanding of the thermal performance repeatability of MLI systems that are applicable to large scale tanks. There are several different types of repeatability that can be accounted for: these include repeatability between multiple identical blankets, repeatability of installation of the same blanket, and repeatability of a test apparatus. The focus of the work in this report is on the first two types of repeatability. Statistically, repeatability can mean many different things. In simplest form, it refers to the range of performance that a population exhibits and the average of the population. However, as more and more identical components are made (i.e. the population of concern grows), the simple range morphs into a standard deviation from an average performance. Initial repeatability testing on MLI blankets has been completed at Florida State University. Repeatability of five GRC provided coupons with 25 layers was shown to be +/- 8.4 whereas repeatability of repeatedly installing a single coupon was shown to be +/- 8.0. A second group of 10 coupons have been fabricated by Yetispace and tested by Florida State University, through the first 4 tests, the repeatability has been shown to be +/- 16. Based on detailed statistical analysis, the data has been shown to be statistically significant.

  7. Evaluating dose response from flexible dose clinical trials

    Directory of Open Access Journals (Sweden)

    Baron David

    2008-01-01

    Full Text Available Abstract Background The true dose effect in flexible-dose clinical trials may be obscured and even reversed because dose and outcome are related. Methods To evaluate dose effect in response on primary efficacy scales from 2 randomized, double-blind, flexible-dose trials of patients with bipolar mania who received olanzapine (N = 234, 5–20 mg/day, or patients with schizophrenia who received olanzapine (N = 172, 10–20 mg/day, we used marginal structural models, inverse probability of treatment weighting (MSM, IPTW methodology. Dose profiles for mean changes from baseline were evaluated using weighted MSM with a repeated measures model. To adjust for selection bias due to non-random dose assignment and dropouts, patient-specific time-dependent weights were determined as products of (i stable weights based on inverse probability of receiving the sequence of dose assignments that was actually received by a patient up to given time multiplied by (ii stable weights based on inverse probability of patient remaining on treatment by that time. Results were compared with those by unweighted analyses. Results While the observed difference in efficacy scores for dose groups for the unweighted analysis strongly favored lower doses, the weighted analyses showed no strong dose effects and, in some cases, reversed the apparent "negative dose effect." Conclusion While naïve comparison of groups by last or modal dose in a flexible-dose trial may result in severely biased efficacy analyses, the MSM with IPTW estimators approach may be a valuable method of removing these biases and evaluating potential dose effect, which may prove useful for planning confirmatory trials.

  8. Heart failure re-admission: measuring the ever shortening gap between repeat heart failure hospitalizations.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Bakal

    Full Text Available Many quality-of-care and risk prediction metrics rely on time to first rehospitalization even though heart failure (HF patients may undergo several repeat hospitalizations. The aim of this study is to compare repeat hospitalization models. Using a population-based cohort of 40,667 patients, we examined both HF and all cause re-hospitalizations using up to five years of follow-up. Two models were examined: the gap-time model which estimates the adjusted time between hospitalizations and a multistate model which considered patients to be in one of four states; community-dwelling, in hospital for HF, in hospital for any reason, or dead. The transition probabilities and times were then modeled using patient characteristics and number of repeat hospitalizations. We found that during the five years of follow-up roughly half of the patients returned for a subsequent hospitalization for each repeat hospitalization. Additionally, we noted that the unadjusted time between hospitalizations was reduced ∼40% between each successive hospitalization. After adjustment each additional hospitalization was associated with a 28 day (95% CI: 22-35 reduction in time spent out of hospital. A similar pattern was seen when considering the four state model. A large proportion of patients had multiple repeat hospitalizations. Extending the gap between hospitalizations should be an important goal of treatment evaluation.

  9. Drug-induced interstitial pneumonitis due to low-dose lenalidomide.

    Science.gov (United States)

    Kunimasa, Kei; Ueda, Tomoaki; Arita, Machiko; Maeda, Takeshi; Hotta, Machiko; Ishida, Tadashi

    2012-01-01

    Lenalidomide is a second-generation immunomodulatory drug that has been approved to treat relapsed or refractory multiple myeloma. Here, we describe a patient who was treated with a low dose of lenalidomide (5 mg/day on days 1-21 of a 28-day cycle) because the standard dose of bortezomib was too toxic and adverse events persisted. However, he developed fever, dyspnea, hypoxia and pulmonary infiltrates. The results of an extensive workup for other causes including infections were negative and the final diagnosis was lenalidomide-induced interstitial pneumonitis. This is the first case report of lenalidomide-induced pneumonitis in a Japanese patient.

  10. Expansion of protein domain repeats.

    Directory of Open Access Journals (Sweden)

    Asa K Björklund

    2006-08-01

    Full Text Available Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e.g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  11. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis.

    Science.gov (United States)

    Tagami, Takashi; Matsui, Hiroki; Fushimi, Kiyohide; Yasunaga, Hideo

    2015-08-31

    The effectiveness of supplemental dose antithrombin administration (1,500 to 3,000 IU/ day) for patients with sepsis-associated disseminated intravascular coagulation (DIC), especially sepsis due to abdominal origin, remains uncertain. This was a retrospective cohort study of patients with mechanically ventilated septic shock and DIC after emergency surgery for perforation of the lower intestinal tract using a nationwide administrative database, Japanese Diagnosis Procedure Combination inpatient database. A total of 2,164 patients treated at 612 hospitals during the 33-month study period between 2010 and 2013 were divided into an antithrombin group (n=1,021) and a control group (n=1,143), from which 518 propensity score-matched pairs were generated. Although there was no significant 28-day mortality difference between the two groups in the unmatched groups (control vs antithrombin: 25.7 vs 22.9 %; difference, 2.8 %; 95 % confidence interval [CI], -0.8-6.4), a significant difference existed between the two groups in propensity-score weighted groups (26.3 vs 21.7 %; difference, 4.6 %; 95 % CI, 2.0-7.1) and propensity-score matched groups (27.6 vs 19.9 %; difference, 7.7 %; 95 % CI, 2.5-12.9). Logistic regression analyses showed a significant association between antithrombin use and lower 28-day mortality in propensity-matched groups (odds ratio, 0.65; 95 % CI, 0.49-0.87). Analysis using the hospital antithrombin-prescribing rate as an instrumental variable showed that receipt of antithrombin was associated with a 6.5 % (95 % CI, 0.05-13.0) reduction in 28-day mortality. Supplemental dose of antithrombin administration may be associated with reduced 28-day mortality in sepsis-associated DIC patients after emergency laparotomy for intestinal perforation.

  12. Lisina digestível em dietas de baixa proteína para frangos de corte tipo caipira de um aos 28 dias Digestible lysine in diets containing low protein concentrations for broiler type redneck from 1 to 28 days

    Directory of Open Access Journals (Sweden)

    H.G. Oliveira

    2013-04-01

    Full Text Available Avaliou-se a inclusão de diferentes porcentagens de lisina digestível em dietas de baixa proteína para frangos de corte tipo caipira, machos e fêmeas, com idade entre um e 28 dias. Utilizaram-se 792 machos e 792 fêmeas de linhagem comercial, de um dia de idade, distribuídos em delineamento inteiramente ao acaso, em esquema fatorial 2x6 (sexo x porcentagem de lisina digestível: 0,85; 0,90; 0,95; 1,00; 1,05 e 1,10% com seis repetições de 22 aves. Não foi constatada interação (P>0,05 de sexo versus inclusão de lisina. Observou-se superioridade (P0,05 para conversão alimentar. Da composição centesimal da carcaça, apenas o percentual de matéria mineral foi influenciada (PThe inclusion of different percentages of digestible lysine in low-protein diets was evaluated for male and female free-range broiler chickens, from 1 to 28 days. We used 792 female and 792 male naked neck chickens a day in a completely randomized 2x6 factorial scheme (sex x percentages of digestible lysine: 0.85, 0.90, 0.95, 1.00, 1.05 and1.10% with six replicates of 22 broilers. No interaction of sex versus lysine was found. Superiority was observed (P0.05 in food conversion.In the chemical composition of the carcass, only thepercentage of mineral matter was influenced (P<0.05 bydigestible lysine levels.It was concluded that the level of 0.85% for type redneck broiler meets the nutritional requirement of digestible lysine in diets containing lower protein concentrations.

  13. DWI Repeaters and Non-Repeaters: A Comparison.

    Science.gov (United States)

    Weeber, Stan

    1981-01-01

    Discussed how driving-while-intoxicated (DWI) repeaters differed signigicantly from nonrepeaters on 4 of 23 variables tested. Repeaters were more likely to have zero or two dependent children, attend church frequently, drink occasionally and have one or more arrests for public intoxication. (Author)

  14. To Repeat or Not to Repeat a Course

    Science.gov (United States)

    Armstrong, Michael J.; Biktimirov, Ernest N.

    2013-01-01

    The difficult transition from high school to university means that many students need to repeat (retake) 1 or more of their university courses. The authors examine the performance of students repeating first-year core courses in an undergraduate business program. They used data from university records for 116 students who took a total of 232…

  15. Repeated treatments of drooling with botulinum toxin B in neurology

    DEFF Research Database (Denmark)

    Møller, Eigild; Daugaard, Dorthe; Holm, Ole

    2015-01-01

    OBJECTIVES: To investigate efficacy, saliva flow, and composition in repeated BoNT-B treatments of drooling. MATERIALS AND METHODS: Seventeen neurological patients (median 66 years), referred for treatment of drooling participated in this observational study. Median total doses of 4000 units...

  16. Nifty Nines and Repeating Decimals

    Science.gov (United States)

    Brown, Scott A.

    2016-01-01

    The traditional technique for converting repeating decimals to common fractions can be found in nearly every algebra textbook that has been published, as well as in many precalculus texts. However, students generally encounter repeating decimal numerals earlier than high school when they study rational numbers in prealgebra classes. Therefore, how…

  17. Nifty Nines and Repeating Decimals

    Science.gov (United States)

    Brown, Scott A.

    2016-01-01

    The traditional technique for converting repeating decimals to common fractions can be found in nearly every algebra textbook that has been published, as well as in many precalculus texts. However, students generally encounter repeating decimal numerals earlier than high school when they study rational numbers in prealgebra classes. Therefore, how…

  18. All-photonic quantum repeaters

    Science.gov (United States)

    Azuma, Koji; Tamaki, Kiyoshi; Lo, Hoi-Kwong

    2015-01-01

    Quantum communication holds promise for unconditionally secure transmission of secret messages and faithful transfer of unknown quantum states. Photons appear to be the medium of choice for quantum communication. Owing to photon losses, robust quantum communication over long lossy channels requires quantum repeaters. It is widely believed that a necessary and highly demanding requirement for quantum repeaters is the existence of matter quantum memories. Here we show that such a requirement is, in fact, unnecessary by introducing the concept of all-photonic quantum repeaters based on flying qubits. In particular, we present a protocol based on photonic cluster-state machine guns and a loss-tolerant measurement equipped with local high-speed active feedforwards. We show that, with such all-photonic quantum repeaters, the communication efficiency scales polynomially with the channel distance. Our result paves a new route towards quantum repeaters with efficient single-photon sources rather than matter quantum memories. PMID:25873153

  19. Repeat Gamma Knife surgery for vestibular schwannomas

    Science.gov (United States)

    Lonneville, Sarah; Delbrouck, Carine; Renier, Cécile; Devriendt, Daniel; Massager, Nicolas

    2015-01-01

    Background: Gamma Knife (GK) surgery is a recognized treatment option for the management of small to medium-sized vestibular schwannoma (VS) associated with high-tumor control and low morbidity. When a radiosurgical treatment fails to stop tumor growth, repeat GK surgery can be proposed in selected cases. Methods: A series of 27 GK retreatments was performed in 25 patients with VS; 2 patients underwent three procedures. The median time interval between GK treatments was 45 months. The median margin dose used for the first, second, and third GK treatments was 12 Gy, 12 Gy, and 14 Gy, respectively. Six patients (4 patients for the second irradiation and 2 patients for the third irradiation) with partial tumor regrowth were treated only on the growing part of the tumor using a median margin dose of 13 Gy. The median tumor volume was 0.9, 2.3, and 0.7 cc for the first, second, and third treatments, respectively. Stereotactic positron emission tomography (PET) guidance was used for dose planning in 6 cases. Results: Mean follow-up duration was 46 months (range 24–110). At the last follow-up, 85% of schwannomas were controlled. The tumor volume decreased, remained unchanged, or increased after retreatment in 15, 8, and 4 cases, respectively. Four patients had PET during follow-up, and all showed a significant metabolic decrease of the tumor. Hearing was not preserved after retreatment in any patients. New facial or trigeminal palsy did not occur after retreatment. Conclusions: Our results support the long-term efficacy and low morbidity of repeat GK treatment for selected patients with tumor growth after initial treatment. PMID:26500799

  20. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

    Science.gov (United States)

    O'Sullivan, Amy; Kennedy, Ryan C.; Abbas, Mohammad; Dai, Lijun; Pregja, Silvana Lalo; Burt, Steve; Boyiadzis, Michael; Roodman, G. David; Mapara, Markus Y.; Agha, Mounzer; Waas, John; Shuai, Yongli; Normolle, Daniel; Zonder, Jeffrey A.

    2012-01-01

    This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704. PMID:22451423

  1. Dose-dependent adverse effects of salinomycin on male reproductive organs and fertility in mice.

    Directory of Open Access Journals (Sweden)

    Olajumoke Omolara Ojo

    Full Text Available Salinomycin is used as an antibiotic in animal husbandry. Its implication in cancer therapy has recently been proposed. Present study evaluated the toxic effects of Salinomycin on male reproductive system of mice. Doses of 1, 3 or 5 mg/kg of Salinomycin were administered daily for 28 days. Half of the mice were sacrificed after 24 h of the last treatment and other half were sacrificed 28 days after withdrawal of treatment. Effects of SAL on body and reproductive organ weights were studied. Histoarchitecture of testis and epididymis was evaluated along with ultrastructural changes in Leydig cells. Serum and testicular testosterone and luteinizing hormones were estimated. Superoxide dismutase, reduced glutathione, lipid peroxidation, catalase and lactate dehydrogenase activities were measured. Spermatozoa count, morphology, motility and fertility were evaluated. Expression patterns of steroidogenic acute regulatory protein (StAR and cytochrome P450 side chain cleavage proteins (CYP11A1 were assessed by Western blotting. Salinomycin treatment was lethal to few mice and retarded body growth in others with decreased weight of testes and seminal vesicles in a dose dependent manner. Seminiferous tubules in testes were disrupted and the epithelium of epididymis showed frequent occurrence of vacuolization and necrosis. Leydig cells showed hypertrophied cytoplasm with shrunken nuclei, condensed mitochondria, proliferated endoplasmic reticulum and increased number of lipid droplets. Salinomycin decreased motility and spermatozoa count with increased number of abnormal spermatozoa leading to infertility. The testosterone and luteinizing hormone levels were decreased in testis but increased in serum at higher doses. Depletion of superoxide dismutase and reduced glutathione with increased lipid peroxidation in both testis and epididymis indicated generation of oxidative stress. Suppressed expression of StAR and CYP11A1 proteins indicates inhibition of

  2. Dose-dependent adverse effects of salinomycin on male reproductive organs and fertility in mice.

    Science.gov (United States)

    Ojo, Olajumoke Omolara; Bhadauria, Smrati; Rath, Srikanta Kumar

    2013-01-01

    Salinomycin is used as an antibiotic in animal husbandry. Its implication in cancer therapy has recently been proposed. Present study evaluated the toxic effects of Salinomycin on male reproductive system of mice. Doses of 1, 3 or 5 mg/kg of Salinomycin were administered daily for 28 days. Half of the mice were sacrificed after 24 h of the last treatment and other half were sacrificed 28 days after withdrawal of treatment. Effects of SAL on body and reproductive organ weights were studied. Histoarchitecture of testis and epididymis was evaluated along with ultrastructural changes in Leydig cells. Serum and testicular testosterone and luteinizing hormones were estimated. Superoxide dismutase, reduced glutathione, lipid peroxidation, catalase and lactate dehydrogenase activities were measured. Spermatozoa count, morphology, motility and fertility were evaluated. Expression patterns of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage proteins (CYP11A1) were assessed by Western blotting. Salinomycin treatment was lethal to few mice and retarded body growth in others with decreased weight of testes and seminal vesicles in a dose dependent manner. Seminiferous tubules in testes were disrupted and the epithelium of epididymis showed frequent occurrence of vacuolization and necrosis. Leydig cells showed hypertrophied cytoplasm with shrunken nuclei, condensed mitochondria, proliferated endoplasmic reticulum and increased number of lipid droplets. Salinomycin decreased motility and spermatozoa count with increased number of abnormal spermatozoa leading to infertility. The testosterone and luteinizing hormone levels were decreased in testis but increased in serum at higher doses. Depletion of superoxide dismutase and reduced glutathione with increased lipid peroxidation in both testis and epididymis indicated generation of oxidative stress. Suppressed expression of StAR and CYP11A1 proteins indicates inhibition of steroidogenesis

  3. Analysis of repeated measures data

    CERN Document Server

    Islam, M Ataharul

    2017-01-01

    This book presents a broad range of statistical techniques to address emerging needs in the field of repeated measures. It also provides a comprehensive overview of extensions of generalized linear models for the bivariate exponential family of distributions, which represent a new development in analysing repeated measures data. The demand for statistical models for correlated outcomes has grown rapidly recently, mainly due to presence of two types of underlying associations: associations between outcomes, and associations between explanatory variables and outcomes. The book systematically addresses key problems arising in the modelling of repeated measures data, bearing in mind those factors that play a major role in estimating the underlying relationships between covariates and outcome variables for correlated outcome data. In addition, it presents new approaches to addressing current challenges in the field of repeated measures and models based on conditional and joint probabilities. Markov models of first...

  4. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice

    OpenAIRE

    Mahdieh Matinfar; Mahsa Masjedi Esfahani; Neda Aslany; Seyyed Hamid Reza Davoodi; Pouya Parsaei; Ghasem Zarei; Parham Reisi

    2013-01-01

    Background: One of the serious problems that opioid addicted people are facing is repeated withdrawal syndrome that is accompanying with a significant stress load for addicts. Therefore, the aim of this study was to evaluate the effects of repeated withdrawal on spatial learning, memory and serum cortisol levels in morphine-dependent mice. Materials and Methods: Male NMRI mice received morphine as daily increasing doses for 3 days. After that, the mice underwent one time or repeated spont...

  5. Methyldibromoglutaronitrile allergy: relationship between patch test and repeated open application test thresholds

    DEFF Research Database (Denmark)

    Fischer, L.A.; Johansen, J.D.; Menne, T.

    2008-01-01

    a significant relationship between the patch test and the repeated open application test (ROAT) reactivity. Objectives To study the relationship between elicitation threshold doses at single occluded exposure and repeated open application, using MDBGN as the allergen. Methods Eighteen subjects allergic to MDBGN...

  6. Persistence of the Oral Probiotic Streptococcus salivarius M18 Is Dose Dependent and Megaplasmid Transfer Can Augment Their Bacteriocin Production and Adhesion Characteristics

    OpenAIRE

    Burton, Jeremy P.; Wescombe, Philip A.; Macklaim, Jean M.; Chai, Melissa H. C.; Kyle Macdonald; Hale, John D. F.; John Tagg; Gregor Reid; Gloor, Gregory B.; Cadieux, Peter A.

    2013-01-01

    Bacteriocin-producing probiotic Streptococcus salivarius M18 offers beneficial modulatory capabilities within the oral microbiome, apparently through potent inhibitory activity against potentially deleterious bacteria, such as Streptococcus pyogenes. The oral cavity persistence of S. salivarius M18 was investigated in 75 subjects receiving four different doses for 28 days. Sixty per cent of the subjects already had some inhibitor-producing S. salivarius in their saliva prior to probiotic inte...

  7. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  8. Limitations on quantum key repeaters.

    Science.gov (United States)

    Bäuml, Stefan; Christandl, Matthias; Horodecki, Karol; Winter, Andreas

    2015-04-23

    A major application of quantum communication is the distribution of entangled particles for use in quantum key distribution. Owing to noise in the communication line, quantum key distribution is, in practice, limited to a distance of a few hundred kilometres, and can only be extended to longer distances by use of a quantum repeater, a device that performs entanglement distillation and quantum teleportation. The existence of noisy entangled states that are undistillable but nevertheless useful for quantum key distribution raises the question of the feasibility of a quantum key repeater, which would work beyond the limits of entanglement distillation, hence possibly tolerating higher noise levels than existing protocols. Here we exhibit fundamental limits on such a device in the form of bounds on the rate at which it may extract secure key. As a consequence, we give examples of states suitable for quantum key distribution but unsuitable for the most general quantum key repeater protocol.

  9. Hysteresis of magnetostructural transitions: Repeatable and non-repeatable processes

    Energy Technology Data Exchange (ETDEWEB)

    Provenzano, Virgil [National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States); Della Torre, Edward; Bennett, Lawrence H. [Department of Electrical and Computer Engineering, The George Washington University, Washington, DC 20052 (United States); ElBidweihy, Hatem, E-mail: Hatem@gwmail.gwu.edu [Department of Electrical and Computer Engineering, The George Washington University, Washington, DC 20052 (United States)

    2014-02-15

    The Gd{sub 5}Ge{sub 2}Si{sub 2} alloy and the off-stoichiometric Ni{sub 50}Mn{sub 35}In{sub 15} Heusler alloy belong to a special class of metallic materials that exhibit first-order magnetostructural transitions near room temperature. The magnetic properties of this class of materials have been extensively studied due to their interesting magnetic behavior and their potential for a number of technological applications such as refrigerants for near-room-temperature magnetic refrigeration. The thermally driven first-order transitions in these materials can be field-induced in the reverse order by applying a strong enough field. The field-induced transitions are typically accompanied by the presence of large magnetic hysteresis, the characteristics of which are a complicated function of temperature, field, and magneto-thermal history. In this study we show that the virgin curve, the major loop, and sequentially measured MH loops are the results of both repeatable and non-repeatable processes, in which the starting magnetostructural state, prior to the cycling of field, plays a major role. Using the Gd{sub 5}Ge{sub 2}Si{sub 2} and Ni{sub 50}Mn{sub 35}In{sub 15} alloys, as model materials, we show that a starting single phase state results in fully repeatable processes and large magnetic hysteresis, whereas a mixed phase starting state results in non-repeatable processes and smaller hysteresis.

  10. EAMJ Dec. Repeatability.indd

    African Journals Online (AJOL)

    2008-12-12

    Dec 12, 2008 ... Results:Kappa values for four-week repeatability for the wheeze and asthma questions were 0.61 ... for logistic, cultural and ethical reasons, to use ... individual with baseline forced expiratory volume in .... period is likely to also include the effects of true ... data, the writing of the manuscript or the decision.

  11. 75 FR 35977 - Significant New Use Rules on Certain Chemical Substances

    Science.gov (United States)

    2010-06-24

    ... eye irritation test (OECD 405 test guideline); a 28-day repeated dose (OECD 407 test guideline) gavage... (OECD 407 test guideline) gavage in rats. The order does not require submission of the fish early...

  12. Efeitos da relação metionina + cistina: lisina sobre os desempenhos produtivo e econômico e a qualidade interna e externa dos ovos antes e após 28 dias de armazenamento Effects of methionine + cystine: lysine ratio on the productive and economic performance and internal and external egg quality, before and 28 days after storage

    Directory of Open Access Journals (Sweden)

    José Jordão Filho

    2006-08-01

    .75% of total Lys; T4 = 0.86 Met+Cys: total Lys ratio or 0.70% of Met+Cys and 0.81% of total Lys. The performance variables and economical analysis were evaluated from 44 to 56 weeks old. At the end of trial, ten eggs per treatment were collected ad stored during 28 days for evaluation of internal/external egg quality before and after storage. With the exception of egg mass, no treatment effect on feed intake, egg production, egg weight and egg:mass ratio and egg:dozen ratio and egg shell specific quality was observed. The Met+Cys:Lys ratio of 0.76 or the estimate of 0.70% of total Met+Cys and 0.92% of total Lys can be recommended for the feeding of semiheavily laying hens. It was concluded that the storage affect internal egg quality.

  13. SU-E-T-315: The Change of Optically Stimulated Luminescent Dosimeters (OSLDs) Sensitivity by Accumulated Dose and High Dose

    Energy Technology Data Exchange (ETDEWEB)

    Han, S; Jung, H; Kim, M; Ji, Y; Kim, K [University of Science and Technology, Daejeon (Korea, Republic of); Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Choi, S; Park, S; Yoo, H [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Yi, C [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of)

    2014-06-01

    Purpose: The objective of this study is to evaluate radiation sensitivity of optical stimulated luminance dosimeters (OSLDs) by accumulated dose and high dose. Methods: This study was carried out in Co-60 unit (Theratron 780, AECL, and Canada) and used InLight MicroStar reader (Landauer, Inc., Glenwood, IL) for reading. We annealed for 30 min using optical annealing system which contained fluorescent lamps (Osram lumilux, 24 W, 280 ∼780 nm). To evaluate change of OSLDs sensitivity by repeated irradiation, the dosimeters were repeatedly irradiated with 1 Gy. And whenever a repeated irradiation, we evaluated OSLDs sensitivity. To evaluate OSLDs sensitivity after accumulated dose with 5 Gy, We irradiated dose accumulatively (from 1 Gy to 5 Gy) without annealing. And OSLDs was also irradiated with 15, 20, 30 Gy to certify change of OSLDs sensitivity after high dose irradiation. After annealing them, they were irradiated with 1Gy, repeatedly. Results: The OSLDs sensitivity increased up to 3% during irradiating seven times and decreased continuously above 8 times. That dropped by about 0.35 Gy per an irradiation. Finally, after 30 times irradiation, OSLDs sensitivity decreased by about 7%. For accumulated dose from 1 Gy to 5 Gy, OSLDs sensitivity about 1 Gy increased until 4.4% after second times accumulated dose compared with before that. OSLDs sensitivity about 1 Gy decreased by 1.6% in five times irradiation. When OSLDs were irradiated ten times with 1Gy after irradiating high dose (10, 15, 20 Gy), OSLDs sensitivity decreased until 6%, 9%, 12% compared with it before high dose irradiation, respectively. Conclusion: This study certified OSLDs sensitivity by accumulated dose and high dose. When irradiated with 1Gy, repeatedly, OSLDs sensitivity decreased linearly and the reduction rate of OSLDs sensitivity after high dose irradiation had dependence on irradiated dose.

  14. Effects of repeated restraint in Japanese quail genetically selected for contrasting adrenocortical responses.

    Science.gov (United States)

    Jones, R B; Satterlee, D G; Waddington, D; Cadd, G G

    2000-05-01

    Behavioral and adrenocortical responses to repeated mechanical restraint were compared in 28-day-old to 31-day-old male Japanese quail from two genetic lines divergently selected for reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone (C) responses to brief immobilization. Restraint in a metal crush cage for 5 min elicited immobility and silence in all the birds. Circulating C levels were considerably higher in quail of both lines following restraint than in the undisturbed controls of either line. As expected, both the behavioral and physiological effects were more pronounced in HS than in LS birds. Struggling increased with repeated restraint in HS and LS quail, thus suggesting behavioral habituation to the stressor in both lines. On the other hand, a line effect on the pattern of adrenocortical responses was revealed upon subtracting the change in plasma C concentrations from Day 1 to Day 4 in the undisturbed controls from the corresponding change in restrained birds. Thus, unlike LS quail, in which there were no detectable effects of repeated restraint, the adrenocortical responses of HS birds showed evidence of experience-dependent sensitization. Our results demonstrate the importance of the background genome in determining the patterns of the behavioral and adrenocortical responses elicited by repeated exposure to stressful stimulation. The present results and those of previous studies could be explained in one or both of two ways: that underlying fearfulness is lower in LS than HS quail or that they adopt active or passive coping strategies, respectively. Our findings may also have important implications for poultry welfare and productivity. @ 2000 Elsevier Science Inc.

  15. Directionality switchable gain stabilized linear repeater

    Science.gov (United States)

    Ota, Takayuki; Ohmachi, Tadashi; Aida, Kazuo

    2004-10-01

    We propose a new approach to realize a bidirectional linear repeater suitable for future optical internet networks and fault location in repeater chain with OTDR. The proposed approach is the linear repeater of simple configuration whose directionality is rearranged dynamically by electrical control signal. The repeater is composed of a magneto-optical switch, a circulator, a dynamically gain stabilized unidirectional EDFA, and control circuits. The repeater directionality is rearranged as fast as 0.1ms by an electrical control pulse. It is experimentally confirmed that OTDR with the directionality switchable repeater is feasible for repeater chain. The detailed design and performance of the repeater are also discussed, including the multi-pass interference (MPI) which may arise in the proposed repeater, the effect of the MPI on SNR degradation of the repeater chain and the feed-forward EDFA gain control circuit.

  16. Measurement-based quantum repeaters

    CERN Document Server

    Zwerger, M; Briegel, H J

    2012-01-01

    We introduce measurement-based quantum repeaters, where small-scale measurement-based quantum processors are used to perform entanglement purification and entanglement swapping in a long-range quantum communication protocol. In the scheme, pre-prepared entangled states stored at intermediate repeater stations are coupled with incoming photons by simple Bell-measurements, without the need of performing additional quantum gates or measurements. We show how to construct the required resource states, and how to minimize their size. We analyze the performance of the scheme under noise and imperfections, with focus on small-scale implementations involving entangled states of few qubits. We find measurement-based purification protocols with significantly improved noise thresholds. Furthermore we show that already resource states of small size suffice to significantly increase the maximal communication distance. We also discuss possible advantages of our scheme for different set-ups.

  17. A Repeating Fast Radio Burst

    CERN Document Server

    Spitler, L G; Hessels, J W T; Bogdanov, S; Brazier, A; Camilo, F; Chatterjee, S; Cordes, J M; Crawford, F; Deneva, J; Ferdman, R D; Freire, P C C; Kaspi, V M; Lazarus, P; Lynch, R; Madsen, E C; McLaughlin, M A; Patel, C; Ransom, S M; Seymour, A; Stairs, I H; Stappers, B W; van Leeuwen, J; Zhu, W W

    2016-01-01

    Fast Radio Bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measures (i.e. integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of the fast radio bursts has led several authors to hypothesise that they originate in cataclysmic astrophysical events. Here we report the detection of ten additional bursts from the direction of FRB121102, using the 305-m Arecibo telescope. These new bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and wh...

  18. Repeatability of Harris Corner Detector

    Institute of Scientific and Technical Information of China (English)

    HU Lili

    2003-01-01

    Interest point detectors are commonly employed to reduce the amount of data to be processed. The ideal interest point detector would robustly select those features which are most appropriate or salient for the application and data at hand. This paper shows that interest points are geometrically stable under different transformations.This property makes interest points very successful in the context of image matching. To measure this property quantatively, we introduce a evaluation criterion: repeatability rate.

  19. Hypoxic Repeat Sprint Training Improves Rugby Player's Repeated Sprint but Not Endurance Performance.

    Science.gov (United States)

    Hamlin, Michael J; Olsen, Peter D; Marshall, Helen C; Lizamore, Catherine A; Elliot, Catherine A

    2017-01-01

    This study aims to investigate the performance changes in 19 well-trained male rugby players after repeat-sprint training (six sessions of four sets of 5 × 5 s sprints with 25 s and 5 min of active recovery between reps and sets, respectively) in either normobaric hypoxia (HYP; n = 9; FIO2 = 14.5%) or normobaric normoxia (NORM; n = 10; FIO2 = 20.9%). Three weeks after the intervention, 2 additional repeat-sprint training sessions in hypoxia (FIO2 = 14.5%) was investigated in both groups to gauge the efficacy of using "top-up" sessions for previously hypoxic-trained subjects and whether a small hypoxic dose would be beneficial for the previously normoxic-trained group. Repeated sprint (8 × 20 m) and Yo-Yo Intermittent Recovery Level 1 (YYIR1) performances were tested twice at baseline (Pre 1 and Pre 2) and weekly after (Post 1-3) the initial intervention (intervention 1) and again weekly after the second "top-up" intervention (Post 4-5). After each training set, heart rate, oxygen saturation, and rate of perceived exertion were recorded. Compared to baseline (mean of Pre 1 and Pre 2), both the hypoxic and normoxic groups similarly lowered fatigue over the 8 sprints 1 week after the intervention (Post 1: -1.8 ± 1.6%, -1.5 ± 1.4%, mean change ± 90% CI in HYP and NORM groups, respectively). However, from Post 2 onwards, only the hypoxic group maintained the performance improvement compared to baseline (Post 2: -2.1 ± 1.8%, Post 3: -2.3 ± 1.7%, Post 4: -1.9 ± 1.8%, and Post 5: -1.2 ± 1.7%). Compared to the normoxic group, the hypoxic group was likely to have substantially less fatigue at Post 3-5 (-2.0 ± 2.4%, -2.2 ± 2.4%, -1.6 ± 2.4% Post 3, Post 4, Post 5, respectively). YYIR1 performances improved throughout the recovery period in both groups (13-37% compared to baseline) with unclear differences found between groups. The addition of two sessions of "top-up" training after intervention 1, had little effect on either group. Repeat-sprint training in

  20. Hypoxic Repeat Sprint Training Improves Rugby Player's Repeated Sprint but Not Endurance Performance

    Science.gov (United States)

    Hamlin, Michael J.; Olsen, Peter D.; Marshall, Helen C.; Lizamore, Catherine A.; Elliot, Catherine A.

    2017-01-01

    This study aims to investigate the performance changes in 19 well-trained male rugby players after repeat-sprint training (six sessions of four sets of 5 × 5 s sprints with 25 s and 5 min of active recovery between reps and sets, respectively) in either normobaric hypoxia (HYP; n = 9; FIO2 = 14.5%) or normobaric normoxia (NORM; n = 10; FIO2 = 20.9%). Three weeks after the intervention, 2 additional repeat-sprint training sessions in hypoxia (FIO2 = 14.5%) was investigated in both groups to gauge the efficacy of using “top-up” sessions for previously hypoxic-trained subjects and whether a small hypoxic dose would be beneficial for the previously normoxic-trained group. Repeated sprint (8 × 20 m) and Yo-Yo Intermittent Recovery Level 1 (YYIR1) performances were tested twice at baseline (Pre 1 and Pre 2) and weekly after (Post 1–3) the initial intervention (intervention 1) and again weekly after the second “top-up” intervention (Post 4–5). After each training set, heart rate, oxygen saturation, and rate of perceived exertion were recorded. Compared to baseline (mean of Pre 1 and Pre 2), both the hypoxic and normoxic groups similarly lowered fatigue over the 8 sprints 1 week after the intervention (Post 1: −1.8 ± 1.6%, −1.5 ± 1.4%, mean change ± 90% CI in HYP and NORM groups, respectively). However, from Post 2 onwards, only the hypoxic group maintained the performance improvement compared to baseline (Post 2: −2.1 ± 1.8%, Post 3: −2.3 ± 1.7%, Post 4: −1.9 ± 1.8%, and Post 5: −1.2 ± 1.7%). Compared to the normoxic group, the hypoxic group was likely to have substantially less fatigue at Post 3–5 (−2.0 ± 2.4%, −2.2 ± 2.4%, −1.6 ± 2.4% Post 3, Post 4, Post 5, respectively). YYIR1 performances improved throughout the recovery period in both groups (13–37% compared to baseline) with unclear differences found between groups. The addition of two sessions of “top-up” training after intervention 1, had little effect on either

  1. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  2. Origin and fate of repeats in bacteria.

    Science.gov (United States)

    Achaz, G; Rocha, E P C; Netter, P; Coissac, E

    2002-07-01

    We investigated 53 complete bacterial chromosomes for intrachromosomal repeats. In previous studies on eukaryote chromosomes, we proposed a model for the dynamics of repeats based on the continuous genesis of tandem repeats, followed by an active process of high deletion rate, counteracted by rearrangement events that may prevent the repeats from being deleted. The present study of long repeats in the genomes of Bacteria and Archaea suggests that our model of interspersed repeats dynamics may apply to them. Thus the duplication process might be a consequence of very ancient mechanisms shared by all three domains. Moreover, we show that there is a strong negative correlation between nucleotide composition bias and the repeat density of genomes. We hypothesise that in highly biased genomes, non-duplicated small repeats arise more frequently by random effects and are used as primers for duplication mechanisms, leading to a higher density of large repeats.

  3. Airway refractoriness to inhaled mannitol after repeated challenge.

    Science.gov (United States)

    Suh, Dong In; Lee, Ju Kyung; Kim, Jin-Tack; Koh, Young Yull

    2011-10-01

    Exercise and inhaled mannitol are thought to cause bronchoconstriction through a similar mechanism in asthma. The response to exercise becomes refractory with repeated challenges. This study aimed to investigate whether repeated challenge with mannitol induces refractoriness, as with exercise. Forty-one children with asthma underwent two consecutive dose-response mannitol challenges (Phase 1); the second challenge proceeded after recovery (FEV(1) : 95% or more of baseline value) from the first. The response to mannitol was expressed as a provocative dose causing a 15% fall in FEV(1) (PD(15) ) and the response-dose ratio (RDR) (% fall in FEV(1) /cumulative dose). In 18 subjects who were deemed to have mannitol refractoriness in Phase 1, a mannitol challenge was performed before and after a methacholine challenge (Phase 2). In Phase 1, the time taken for the FEV(1) to recover after the first mannitol challenge ranged from 20 to 100 min with a median of 50 min. In the 23 subjects with a measurable mannitol PD(15) in both challenges, the geometric mean (95%CI) PD(15) in the second challenge (163 mg [114-232]) was significantly higher than that in the first challenge (66 mg [50-88], P value of 0.083%/mg (0.055-0.125) in the first challenge to 0.029%/mg (0.017-0.048) in the second challenge (P challenge with methacholine or mannitol did not significantly alter subsequent bronchoconstriction to the opposite challenge. Repeated challenge with mannitol resulted in less bronchoconstriction when compared with the initial challenge. This refractoriness seems not to be attributable to functional loss of responsiveness or non-specific effect of prior bronchoconstriction.

  4. Improving repeatability by improving quality

    Energy Technology Data Exchange (ETDEWEB)

    Ronen, Shuki; Ackers, Mark; Schlumberger, Geco-Prakla; Brink, Mundy

    1998-12-31

    Time lapse (4-D) seismic is a promising tool for reservoir characterization and monitoring. The method is apparently simple: to acquire data repeatedly over the same reservoir, process and interpret the data sets, then changes between the data sets indicate changes in the reservoir. A problem with time lapse seismic data is that reservoirs are a relatively small part of the earth and important reservoir changes may cause very small differences to the time lapse data. The challenge is to acquire and process economical time lapse data such that reservoir changes can be detected above the noise of varying acquisition and environment. 7 refs., 9 figs.

  5. Coordinated hybrid automatic repeat request

    KAUST Repository

    Makki, Behrooz

    2014-11-01

    We develop a coordinated hybrid automatic repeat request (HARQ) approach. With the proposed scheme, if a user message is correctly decoded in the first HARQ rounds, its spectrum is allocated to other users, to improve the network outage probability and the users\\' fairness. The results, which are obtained for single- and multiple-antenna setups, demonstrate the efficiency of the proposed approach in different conditions. For instance, with a maximum of M retransmissions and single transmit/receive antennas, the diversity gain of a user increases from M to (J+1)(M-1)+1 where J is the number of users helping that user.

  6. Caffeine Ingestion Improves Repeated Freestyle Sprints in Elite Male Swimmers

    Science.gov (United States)

    Goods, Paul S.R.; Landers, Grant; Fulton, Sacha

    2017-01-01

    The purpose of this investigation was to determine the efficacy of a moderate dose of caffeine to improve repeat-sprint performance in elite freestyle sprinters. Nine highly trained male swimmers performed 6 x 75 m freestyle sprints on two occasions 1-h after consuming either 3 mg·kg-1 caffeine (CAF), or placebo, in a cross-over manner. Capillary blood samples for the analysis of blood lactate concentration and pH were collected after the 1st, 3rd, and 5th sprint, while heart rate and perceived exertion (RPE) were collected after every sprint. There was a moderate effect for improved mean sprint time in the CAF condition (0.52 s; 1.3%; d = 0.50). When assessed individually, there was a large effect for improved performance in sprints 3 (1.00 s; 2.5%; d = 1.02) and 4 (0.84 s; 2.1%; d = 0.84) in CAF compared to placebo, with worthwhile performance improvement found for each of the first 5 sprints. There was a significant treatment effect for higher blood lactate concentration for CAF (p = 0.029), and a significant treatment*time effect for reduced pH in the CAF condition (p = 0.004). Mean heart rate (167 ± 9 bpm vs 169 ± 7 bpm) and RPE (17 ± 1 vs 17 ± 1) were not different between placebo and CAF trials, respectively. This investigation is the first to demonstrate enhanced repeat-sprint ability in swimmers following acute caffeine ingestion. It appears likely that the combination of a moderate dose of caffeine (3-6 mg·kg-1) with trained athletes is most likely to enhance repeat-sprint ability in various athletic populations; however, the exact mechanism(s) for an improved repeat-sprint ability following acute caffeine ingestion remain unknown. Key points A moderate dose of caffeine (3 mg·kg-1) ingested 1 h before a repeat-sprint freestyle set significantly improves mean sprint time in elite swimmers. The combination of at least a moderate dose of caffeine (>3 mg·kg-1) with trained athletes appears the most likely to result in ergogenic benefit to anaerobic

  7. Crowding by a repeating pattern.

    Science.gov (United States)

    Rosen, Sarah; Pelli, Denis G

    2015-01-01

    Theinability to recognize a peripheral target among flankers is called crowding. For a foveal target, crowding can be distinguished from overlap masking by its sparing of detection, linear scaling with eccentricity, and invariance with target size.Crowding depends on the proximity and similarity of the flankers to the target. Flankers that are far from or dissimilar to the target do not crowd it. On a gray page, text whose neighboring letters have different colors, alternately black and white, has enough dissimilarity that it might escape crowding. Since reading speed is normally limited by crowding, escape from crowding should allow faster reading. Yet reading speed is unchanged (Chung & Mansfield, 2009). Why? A recent vernier study found that using alternating-color flankers produces strong crowding (Manassi, Sayim, & Herzog, 2012). Might that effect occur with letters and reading? Critical spacing is the minimum center-to-center target-flanker spacing needed to correctly identify the target. We measure it for a target letter surrounded by several equidistant flanker letters of the same polarity, opposite polarity, or mixed polarity: alternately white and black. We find strong crowding in the alternating condition, even though each flanker letter is beyond its own critical spacing (as measured in a separate condition). Thus a periodic repeating pattern can produce crowding even when the individual elements do not. Further, in all conditions we find that, once a periodic pattern repeats (two cycles), further repetition does not affect critical spacing of the innermost flanker.

  8. Immunogenicity of a Live Attenuated Chimeric Japanese Encephalitis Vaccine as a Booster Dose After Primary Vaccination With Live Attenuated SA14-14-2 Vaccine: A Phase IV Study in Thai Children.

    Science.gov (United States)

    Sricharoenchai, Sirintip; Lapphra, Keswadee; Chuenkitmongkol, Sunate; Phongsamart, Wanatpreeya; Bouckenooghe, Alain; Wittawatmongkol, Orasri; Rungmaitree, Supattra; Chokephaibulkit, Kulkanya

    2017-02-01

    This single-group study investigated the immunogenicity and safety of a booster dose of the recently licensed live attenuated chimeric Japanese encephalitis vaccine in 50 healthy children (1-5 years old) who were primed with the live attenuated SA14-14-2 vaccine. A strong anamnestic response was induced 28 days postbooster: geometric mean titer, 9144 (95% confidence interval: 7365-11353); and seroprotection rate, 49 of 49 (100%) children.

  9. Automatization and familiarity in repeated checking

    NARCIS (Netherlands)

    Dek, Eliane C P; van den Hout, Marcel A.; Giele, Catharina L.; Engelhard, Iris M.

    2014-01-01

    Repeated checking paradoxically increases memory uncertainty. This study investigated the underlying mechanism of this effect. We hypothesized that as a result of repeated checking, familiarity with stimuli increases, and automatization of the checking procedure occurs, which should result in decrea

  10. CDC Vital Signs: Preventing Repeat Teen Births

    Science.gov (United States)

    ... file Error processing SSI file Preventing Repeat Teen Births Recommend on Facebook Tweet Share Compartir On this ... Too many teens, ages 15–19, have repeat births. Nearly 1 in 5 births to teens, ages ...

  11. Acoustic dose and acoustic dose-rate.

    Science.gov (United States)

    Duck, Francis

    2009-10-01

    Acoustic dose is defined as the energy deposited by absorption of an acoustic wave per unit mass of the medium supporting the wave. Expressions for acoustic dose and acoustic dose-rate are given for plane-wave conditions, including temporal and frequency dependencies of energy deposition. The relationship between the acoustic dose-rate and the resulting temperature increase is explored, as is the relationship between acoustic dose-rate and radiation force. Energy transfer from the wave to the medium by means of acoustic cavitation is considered, and an approach is proposed in principle that could allow cavitation to be included within the proposed definitions of acoustic dose and acoustic dose-rate.

  12. Expanded complexity of unstable repeat diseases

    OpenAIRE

    Polak, Urszula; McIvor, Elizabeth; Dent, Sharon Y.R.; Wells, Robert D.; Napierala, Marek.

    2012-01-01

    Unstable Repeat Diseases (URDs) share a common mutational phenomenon of changes in the copy number of short, tandemly repeated DNA sequences. More than 20 human neurological diseases are caused by instability, predominantly expansion, of microsatellite sequences. Changes in the repeat size initiate a cascade of pathological processes, frequently characteristic of a unique disease or a small subgroup of the URDs. Understanding of both the mechanism of repeat instability and molecular consequen...

  13. 47 CFR 97.205 - Repeater station.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Repeater station. 97.205 Section 97.205... SERVICE Special Operations § 97.205 Repeater station. (a) Any amateur station licensed to a holder of a Technician, General, Advanced or Amateur Extra Class operator license may be a repeater. A holder of...

  14. 47 CFR 22.1015 - Repeater operation.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 2 2010-10-01 2010-10-01 false Repeater operation. 22.1015 Section 22.1015... Offshore Radiotelephone Service § 22.1015 Repeater operation. Offshore central stations may be used as repeater stations provided that the licensee is able to maintain control of the station, and in...

  15. ProtRepeatsDB: a database of amino acid repeats in genomes

    Directory of Open Access Journals (Sweden)

    Chauhan Virander S

    2006-07-01

    Full Text Available Abstract Background Genome wide and cross species comparisons of amino acid repeats is an intriguing problem in biology mainly due to the highly polymorphic nature and diverse functions of amino acid repeats. Innate protein repeats constitute vital functional and structural regions in proteins. Repeats are of great consequence in evolution of proteins, as evident from analysis of repeats in different organisms. In the post genomic era, availability of protein sequences encoded in different genomes provides a unique opportunity to perform large scale comparative studies of amino acid repeats. ProtRepeatsDB http://bioinfo.icgeb.res.in/repeats/ is a relational database of perfect and mismatch repeats, access to which is designed as a resource and collection of tools for detection and cross species comparisons of different types of amino acid repeats. Description ProtRepeatsDB (v1.2 consists of perfect as well as mismatch amino acid repeats in the protein sequences of 141 organisms, the genomes of which are now available. The web interface of ProtRepeatsDB consists of different tools to perform repeat s; based on protein IDs, organism name, repeat sequences, and keywords as in FASTA headers, size, frequency, gene ontology (GO annotation IDs and regular expressions (REGEXP describing repeats. These tools also allow formulation of a variety of simple, complex and logical queries to facilitate mining and large-scale cross-species comparisons of amino acid repeats. In addition to this, the database also contains sequence analysis tools to determine repeats in user input sequences. Conclusion ProtRepeatsDB is a multi-organism database of different types of amino acid repeats present in proteins. It integrates useful tools to perform genome wide queries for rapid screening and identification of amino acid repeats and facilitates comparative and evolutionary studies of the repeats. The database is useful for identification of species or organism specific

  16. Pentatricopeptide repeat proteins in plants.

    Science.gov (United States)

    Barkan, Alice; Small, Ian

    2014-01-01

    Pentatricopeptide repeat (PPR) proteins constitute one of the largest protein families in land plants, with more than 400 members in most species. Over the past decade, much has been learned about the molecular functions of these proteins, where they act in the cell, and what physiological roles they play during plant growth and development. A typical PPR protein is targeted to mitochondria or chloroplasts, binds one or several organellar transcripts, and influences their expression by altering RNA sequence, turnover, processing, or translation. Their combined action has profound effects on organelle biogenesis and function and, consequently, on photosynthesis, respiration, plant development, and environmental responses. Recent breakthroughs in understanding how PPR proteins recognize RNA sequences through modular base-specific contacts will help match proteins to potential binding sites and provide a pathway toward designing synthetic RNA-binding proteins aimed at desired targets.

  17. Two-dimensional quantum repeaters

    Science.gov (United States)

    Wallnöfer, J.; Zwerger, M.; Muschik, C.; Sangouard, N.; Dür, W.

    2016-11-01

    The endeavor to develop quantum networks gave rise to a rapidly developing field with far-reaching applications such as secure communication and the realization of distributed computing tasks. This ultimately calls for the creation of flexible multiuser structures that allow for quantum communication between arbitrary pairs of parties in the network and facilitate also multiuser applications. To address this challenge, we propose a two-dimensional quantum repeater architecture to establish long-distance entanglement shared between multiple communication partners in the presence of channel noise and imperfect local control operations. The scheme is based on the creation of self-similar multiqubit entanglement structures at growing scale, where variants of entanglement swapping and multiparty entanglement purification are combined to create high-fidelity entangled states. We show how such networks can be implemented using trapped ions in cavities.

  18. General benchmarks for quantum repeaters

    CERN Document Server

    Pirandola, Stefano

    2015-01-01

    Using a technique based on quantum teleportation, we simplify the most general adaptive protocols for key distribution, entanglement distillation and quantum communication over a wide class of quantum channels in arbitrary dimension. Thanks to this method, we bound the ultimate rates for secret key generation and quantum communication through single-mode Gaussian channels and several discrete-variable channels. In particular, we derive exact formulas for the two-way assisted capacities of the bosonic quantum-limited amplifier and the dephasing channel in arbitrary dimension, as well as the secret key capacity of the qubit erasure channel. Our results establish the limits of quantum communication with arbitrary systems and set the most general and precise benchmarks for testing quantum repeaters in both discrete- and continuous-variable settings.

  19. Hungarian repeat station survey, 2010

    Directory of Open Access Journals (Sweden)

    Péter Kovács

    2013-03-01

    Full Text Available The last Hungarian repeat station survey was completed between October 2010 and February 2011. Declination, inclination and the total field were observed using one-axial DMI fluxgate magnetometer mounted on Zeiss20A theodolite and GSM 19 Overhauser magnetometer. The magnetic elements of the sites were reduced to the epoch of 2010.5 on the basis of the continuous recordings of Tihany Geophysical Observatory. In stations located far from the reference observatory, the observations were carried out in the morning and afternoon in order to decrease the effect of the distant temporal correction. To further increase the accuracy, on-site dIdD variometer has also been installed near the Aggtelek station, in the Baradla cave, during the survey of the easternmost sites. The paper presents the technical details and the results of our last campaign. The improvement of the accuracy of the temporal reduction by the use of the local variometer is also reported.

  20. Quality control during repeated fryings

    Directory of Open Access Journals (Sweden)

    Cuesta, C.

    1998-08-01

    Full Text Available Most of the debate ¡s about how the slow or frequent turnover of fresh fat affects the deterioration, of fat used in frying. Then, the modification of different oils used in repeated fryings of potatoes without or with turnover of fresh oil, under similar frying conditions, was evaluated by two criteria: by measuring the total polar component isolated by column chromatography and by the evaluation of the specific compounds related to thermoxidative and hydrolytic alteration by High Performance Size Exclusion Chromatography (HPSEC. The results indicate that with frequent turnover of fresh oil, the critical level of 25% of polar material is rarely reached, and there are fewer problems with fat deterioration because the frying tended to increase the level of polar material and thermoxidative compounds (polymers and dimers of triglycerides and oxidized triglycerides in the fryer oil during the first fryings, followed by minor changes and a tendency to reach a near-steady state in successive fryings. However, in repeated frying of potatoes using a null turnover the alteration rate was higher being linear the relationship found between polar material or the different thermoxidative compounds and the number of fryings. On the other hand chemical reactions produced during deep-fat frying can be minimized by using proper oils. In addition the increased level of consumers awareness toward fat composition and its impact on human health could had an impact on the selection of fats for snacks and for industry. In this way monoenic fats are the most adequate from a nutritional point of view and for its oxidative stability during frying.

  1. Two-year follow-up of a randomised trial with repeated antenatal betamethasone.

    Science.gov (United States)

    Peltoniemi, O M; Kari, M A; Lano, A; Yliherva, A; Puosi, R; Lehtonen, L; Tammela, O; Hallman, M

    2009-11-01

    Weekly repeated antenatal corticosteroid treatment improves respiratory outcome but decreases fetal growth and may impair neurodevelopmental outcome. We have previously reported that a single repeat betamethasone (BM) dose neither decreased fetal growth nor improved the outcome of preterm infants during the first hospitalisation. To study prospectively whether a single repeat dose of BM influences neurodevelopment and growth within 2 years. Women with imminent delivery before 34.0 gestational weeks were eligible if they remained undelivered for >7 days after a single course of antenatal BM. After stratification, a single repeat dose of BM (12 mg) or placebo was given. The children underwent neurological and psychometric examinations and a speech evaluation at a corrected age of 2 years. Prospective, blinded evaluation following the randomised multicentre trial. 259 (82%) surviving infants completed the 2-year follow-up, 120 in the BM group and 139 in the placebo group. The rate of survival without severe neurodevelopmental impairment was similar in both groups (BM 98%, placebo 99%). The risk of cerebral palsy (BM 2%, placebo 1%), growth or re-hospitalisation rates (BM 60%, placebo 50%) did not differ between the groups. A single repeat dose of antenatal BM tended not to influence physical growth or neurodevelopment at 2 years of age.

  2. Caffeine Ingestion Improves Repeated Freestyle Sprints in Elite Male Swimmers

    Directory of Open Access Journals (Sweden)

    Paul S.R. Goods, Grant Landers, Sacha Fulton

    2017-03-01

    Full Text Available The purpose of this investigation was to determine the efficacy of a moderate dose of caffeine to improve repeat-sprint performance in elite freestyle sprinters. Nine highly trained male swimmers performed 6 x 75 m freestyle sprints on two occasions 1-h after consuming either 3 mg·kg-1 caffeine (CAF, or placebo, in a cross-over manner. Capillary blood samples for the analysis of blood lactate concentration and pH were collected after the 1st, 3rd, and 5th sprint, while heart rate and perceived exertion (RPE were collected after every sprint. There was a moderate effect for improved mean sprint time in the CAF condition (0.52 s; 1.3%; d = 0.50. When assessed individually, there was a large effect for improved performance in sprints 3 (1.00 s; 2.5%; d = 1.02 and 4 (0.84 s; 2.1%; d = 0.84 in CAF compared to placebo, with worthwhile performance improvement found for each of the first 5 sprints. There was a significant treatment effect for higher blood lactate concentration for CAF (p = 0.029, and a significant treatment*time effect for reduced pH in the CAF condition (p = 0.004. Mean heart rate (167 ± 9 bpm vs 169 ± 7 bpm and RPE (17 ± 1 vs 17 ± 1 were not different between placebo and CAF trials, respectively. This investigation is the first to demonstrate enhanced repeat-sprint ability in swimmers following acute caffeine ingestion. It appears likely that the combination of a moderate dose of caffeine (3-6 mg·kg-1 with trained athletes is most likely to enhance repeat-sprint ability in various athletic populations; however, the exact mechanism(s for an improved repeat-sprint ability following acute caffeine ingestion remain unknown.

  3. A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures.

    Science.gov (United States)

    Elger, Christian E; Stefan, Hermann; Mann, Allison; Narurkar, Milind; Sun, Yijun; Perdomo, Carlos

    2010-02-01

    To assess the efficacy, safety, tolerability, and pharmacokinetics of adjunctive rufinamide in adults and adolescents with inadequately controlled partial seizures receiving treatment with one to three concomitant antiepileptic drugs (AEDs). A 24-week multicenter Phase II clinical study was conducted (n=647), comprising a 12-week prospective baseline phase and a 12-week randomized double-blind, parallel-group, five-arm (placebo and rufinamide 200, 400, 800, and 1600mg/day) treatment phase. The linear trend of dose response for seizure frequency per 28 days in the double-blind treatment phase - the primary efficacy outcome measure - was statistically significant in favor of rufinamide (estimated slope=-0.049, P=0.003; minimally efficacious dose, 400mg/day). Response rates, defined as a >or=50% reduction in seizure frequency per 28 days, also revealed a significant linear trend of dose response (P=0.0019, logistic regression analysis). Adverse events were comparable between placebo and all rufinamide groups except the 1600mg/day group; no safety signals were observed. These results suggest that in the dose range of 400-1600mg/day, add-on rufinamide therapy may benefit patients with inadequately controlled partial seizures and is generally well tolerated. These data also suggest that higher doses may confer additional efficacy without adversely affecting safety and tolerability.

  4. Benchmark Dose Modeling

    Science.gov (United States)

    Finite doses are employed in experimental toxicology studies. Under the traditional methodology, the point of departure (POD) value for low dose extrapolation is identified as one of these doses. Dose spacing necessarily precludes a more accurate description of the POD value. ...

  5. Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gillies, R.S. [Oxford Cancer and Haematology Centre, Department of Oncology, Oxford (United Kingdom); Oxford Cancer and Haematology Centre, Department of Oesophagogastric Surgery, Oxford (United Kingdom); NIHR Biomedical Research Centre, Oxford (United Kingdom); Middleton, M.R. [Oxford Cancer and Haematology Centre, Department of Oncology, Oxford (United Kingdom); NIHR Biomedical Research Centre, Oxford (United Kingdom); Blesing, C.; Patel, K.; Warner, N. [Oxford Cancer and Haematology Centre, Department of Oncology, Oxford (United Kingdom); Marshall, R.E.K.; Maynard, N.D. [Oxford Cancer and Haematology Centre, Department of Oesophagogastric Surgery, Oxford (United Kingdom); Bradley, K.M. [Oxford Cancer and Haematology Centre, Department of Radiology, Oxford (United Kingdom); Gleeson, F.V. [Oxford Cancer and Haematology Centre, Department of Radiology, Oxford (United Kingdom); NIHR Biomedical Research Centre, Oxford (United Kingdom)

    2012-09-15

    Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5-fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. Forty-eight subjects were included: mean age 65 years; 37 male. Using the median percentage reduction in SUV{sub max} (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P = 0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P = 0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low. (orig.)

  6. Cataract after repeated daily in vivo exposure to ultraviolet radiation.

    Science.gov (United States)

    Galichanin, Konstantin; Löfgren, Stefan; Söderberg, Per

    2014-12-01

    Epidemiological data indicate a correlation between lifelong exposure to ultraviolet radiation and cortical cataract. However, there is no quantitative experimental data on the effect of daily repeated in vivo exposures of the eye to UVR. Therefore, this experiment was designed to verify whether the dose additivity for UVR exposures holds through periods of time up to 30 d. Eighty rats were conditioned to a rat restrainer 5 d prior to exposure. All animals were divided into four exposure period groups of 1, 3, 10, and 30 d of exposure to UVR. Each exposure period group of 20 animals was randomly divided into five cumulated UVR dose subgroups. Eighteen-wk-old non-anesthetized albino Sprague-Dawley rats were exposed daily to UVR-300 nm for 15 min. One week after the last exposure, animals were sacrificed. The lenses were extracted for macroscopic imaging of dark-field anatomy, and degree of cataract was quantified by measurement of the intensity of forward lens light scattering. Maximum tolerable dose (MTD(2.3:16)), a statistically defined standard for sensitivity for the threshold for UVR cataract, was estimated for each exposure period. Exposed lenses developed cataract with varying appearance on the anterior surface. Single low doses of UVR accumulated to cause cataract during periods up to 30 d. MTD(2.3:16) for 1, 3, 10, and 30 d of repeated exposures was estimated to 4.70, 4.74, 4.80, and 6.00 kJ m(-2), respectively. In conclusion, the lens sensitivity to UVR-B for 18-wk-old Sprague-Dawley rats decreases with the increasing number of days being exposed.

  7. Strengthening concept learning by repeated testing.

    Science.gov (United States)

    Wiklund-Hörnqvist, Carola; Jonsson, Bert; Nyberg, Lars

    2014-02-01

    The aim of this study was to examine whether repeated testing with feedback benefits learning compared to rereading of introductory psychology key-concepts in an educational context. The testing effect was examined immediately after practice, after 18 days, and at a five-week delay in a sample of undergraduate students (n = 83). The results revealed that repeated testing with feedback significantly enhanced learning compared to rereading at all delays, demonstrating that repeated retrieval enhances retention compared to repeated encoding in the short- and the long-term. In addition, the effect of repeated testing was beneficial for students irrespectively of working memory capacity. It is argued that teaching methods involving repeated retrieval are important to consider by the educational system.

  8. Repeat concussions in the national football league.

    Science.gov (United States)

    Casson, Ira R; Viano, David C; Powell, John W; Pellman, Elliot J

    2011-01-01

    Repeat concussion is an important issue in the National Football League (NFL). An initial description of repeat injuries was published for 6 years (1996-2001). The characteristics and frequency of repeat concussion in the NFL have not changed in the subsequent 6 years (2002-2007). Case control. From 1996 to 2007, concussions were reported using a standardized form documenting signs and symptoms, loss of consciousness and medical action taken. Data on repeat concussions were analyzed for the 12 years and compared between the 2 periods. In 2002-2007, 152 players had repeat concussions (vs 160 in 1996-2001); 44 had 3+ head injuries (vs 52). The positions most often associated with repeat concussion in 2002-2007 were the defensive secondary, kick unit, running back, and linebacker. The odds for repeat concussion were elevated for wide receivers, tight ends, and linebackers but lower than in the earlier period. During 2002-2007, over half of players with repeat concussion were removed from play, and fewer immediately returned (vs 1996-2001). The average duration between concussions was 1.25 years for 2002-2007 and 1.65 years for the 12-year period. Over 12 years, 7.6% of all repeat concussions occurred within 2 weeks of the prior concussion. The defensive secondary, kick unit, running back, and linebacker have the highest incidence of repeat concussion. During 2002-2007, more than half of players with repeat concussion were removed from play, and only a fraction immediately returned. Although concussion was managed more conservatively by team physicians in the recent 6 years, repeat concussions occurred at similar rates during both periods.

  9. Automated quality checks on repeat prescribing.

    OpenAIRE

    Rogers, Jeremy E; Wroe, Christopher J; Roberts, Angus; Swallow, Angela; Stables, David; Cantrill, Judith A; Rector, Alan L.

    2003-01-01

    BACKGROUND: Good clinical practice in primary care includes periodic review of repeat prescriptions. Markers of prescriptions that may need review have been described, but manually checking all repeat prescriptions against the markers would be impractical. AIM: To investigate the feasibility of computerising the application of repeat prescribing quality checks to electronic patient records in United Kingdom (UK) primary care. DESIGN OF STUDY: Software performance test against benchmark manual...

  10. Short Tandem Repeat DNA Internet Database

    Science.gov (United States)

    SRD 130 Short Tandem Repeat DNA Internet Database (Web, free access)   Short Tandem Repeat DNA Internet Database is intended to benefit research and application of short tandem repeat DNA markers for human identity testing. Facts and sequence information on each STR system, population data, commonly used multiplex STR systems, PCR primers and conditions, and a review of various technologies for analysis of STR alleles have been included.

  11. Competition impedes the recovery of Daphnia magna from repeated insecticide pulses.

    Science.gov (United States)

    Dolciotti, Ida; Foit, Kaarina; Herkelrath, Anna; Liess, Matthias

    2014-02-01

    The effects of multiple insecticide pulses on non-target organisms have rarely been investigated in combination with relevant biotic interactions, such as competition. In this study, we examined the effects of two repeated pulses of the insecticide pirimicarb (3, 10, 24 μg/L) on populations of Daphnia magna with or without competition. To investigate the influence of competition, half of the test systems were supplemented with the pirimicarb-insensitive species Culex pipiens. The pesticide pulses were followed by a recovery period of 28 days, which corresponded to approximately three generation times for D. magna. The one-species setup with the Daphnia populations and the two-species setup with both the Daphnia and Culex populations had a precontamination period of 30 days so that intra- and interspecific competitions were present prior to the insecticide pulse. Short-term effects on the survival of the Daphnia population were observed in both setups immediately after each insecticide pulse at the highest concentration level. In the one-species setup, the short-term effects on population survival were increased by intraspecific competition. However, the Daphnia populations in the one-species setup recovered and reached the control level within approximately two weeks after each insecticide pulse. In contrast, in the two-species setup at the highest concentration, we observed culmination of insecticide effects: the Daphnia populations did not recover and their abundance was below the control level until the end of the observation time. Their recovery was impeded by the presence of the competing species C. pipiens for at least four weeks. At low concentrations, no culmination of effects was observed. We conclude that repeated toxicant pulses on populations that are challenged with interspecific competition may result in a multigenerational culmination of toxicant effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies.

    Directory of Open Access Journals (Sweden)

    Eric Laille

    Full Text Available CC-486 (oral azacitidine is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK and pharmacodynamic (PD profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS, chronic myelomonocytic leukemia (CMML or acute myeloid leukemia (AML from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05 reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle, with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle.ClinicalTrials.gov NCT00528983.

  13. Efficacy of dose-reduced lenalidomide in patients with refractory or recurrent multiple myeloma

    Directory of Open Access Journals (Sweden)

    Schmidt-Wolf, Ingo G. H.

    2011-01-01

    Full Text Available Purpose: Introduction of lenalidomide has expanded the therapeutic options for refractory and recurrent multiple myeloma (MM patients. However, the application of the approved doses may be difficult in some patients due to adverse effects. Experimental design: Therefore, we evaluated the efficacy and safety of lenalidomide in 10 patients with relapsed and refractory MM who received a reduced dose due to leukopenia (4, polyneuropathy (1, muscle cramps (1, thrombocytopenia (1, renal insufficiency (1, at the request of patient (1, as continuous therapy (1, either from the beginning (2 or during treatment (8. They received lenalidomide at a mean (median daily dose of 14 (15 mg/d once a day (days 1–21 every 28 days in combination with dexamethasone at a mean (median dose of 17.6 (28 mg per day (4–40 mg on days 1–4, 9–12 and 17–20. Results: Mean (median duration of treatment with lenalidomide was 15.1 (15 months. Partial response or better was reported in seven and minimal response or better was reported in eight patients. Mean (median values for time-to-progression (TTP and for progression-free survival (PFS were 8.7 (4 months. Mean overall survival (OS has not been reached, all patients are still alive. Conclusion: In conclusion, dose-reduced lenalidomide is an effective and well tolerated treatment for patients with recurrent or refractory MM who cannot tolerate full doses.

  14. Acid and alkaline phosphatase activities in a novel phosphorothionate (RPR-11) treated male and female rats. Evidence of dose and time-dependent response.

    Science.gov (United States)

    Rahman, M F; Siddiqui, M K; Jamil, K

    2000-08-01

    The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high)mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.

  15. Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats.

    Science.gov (United States)

    Hooth, Michelle J; Nyska, Abraham; Fomby, Laurene M; Vasconcelos, Daphne Y; Vallant, Molly; DeVito, Michael J; Walker, Nigel J

    2012-11-15

    In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague-Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015-0.0072, for PCN 66 and 0.00029-0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO toxic equivalency factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity.

  16. Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Husain, Mainul, E-mail: mainul.husain@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Saber, Anne T., E-mail: ats@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Guo, Charles, E-mail: charles.guo@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Jacobsen, Nicklas R., E-mail: nrj@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Jensen, Keld A., E-mail: kaj@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Yauk, Carole L., E-mail: carole.yauk@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada); Williams, Andrew, E-mail: andrew.williams@hc-sc.gc.ca [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Vogel, Ulla, E-mail: ubv@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Department of Micro- and Nanotechnology, Technical University of Denmark, Kgs. Lyngby DK-2800 (Denmark); Wallin, Hakan, E-mail: hwa@nrcwe.dk [The Danish NanoSafety Centre, National Research Centre for the Working Environment, Copenhagen DK-2100 (Denmark); Institute of Public Health, University of Copenhagen, Copenhagen DK-1014 (Denmark); Halappanavar, Sabina, E-mail: sabina.halappanavar@hc-sc.gc.ca [Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9 (Canada)

    2013-06-15

    We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO{sub 2}). Female C57BL/6 mice were exposed to rutile nano-TiO{sub 2} via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO{sub 2} in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO{sub 2} in the lungs up to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (± 1.3 fold; p < 0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO{sub 2} in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities. - Highlights: • Pulmonary effects following exposure to low doses of nano-TiO{sub 2} were examined. • Particle retention in lungs was assessed using nanoscale hyperspectral microscopy. • Particles persisted up to 28 days in lungs in all dose groups. • Inflammation was the pathway affected in the high dose group at all time points. • Ion homeostasis and muscle activity pathways were affected in the low dose

  17. Repeated challenge with virulent Newcastle Disease Virus does not decrease the efficacy of vaccines

    Science.gov (United States)

    In the field, well-vaccinated birds may be repeatedly exposed to challenges with virulent strains of Newcastle disease virus (vNDV), which may infect macrophages and cause damage to the immune system. In this study, we evaluated the hypothesis that daily challenges with high doses of vNDV may overwh...

  18. Nephrotoxicity in mice after repeated imaging using 111In- labeled peptides

    NARCIS (Netherlands)

    M.L. Melis (Marleen); E. Vegt (Erik); M.W. Konijnenberg (Mark); M. de Visser (Monique); M. Bijster (Magda); M. Vermeij (Marcel); E.P. Krenning (Eric); O.C. Boerman (Otto); M. de Jong (Marion)

    2010-01-01

    textabstractWe determined the renal radiation dose of a series of111Inlabeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. Methods: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention a

  19. Nephrotoxicity in mice after repeated imaging using 111In-labeled peptides.

    NARCIS (Netherlands)

    Melis, M.; Vegt, E.; Konijnenberg, M.W.; Visser, M. de; Bijster, M.; Vermeij, M.; Krenning, E.P.; Boerman, O.C.; Jong, M. de

    2010-01-01

    We determined the renal radiation dose of a series of (111)In-labeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. METHODS: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after inj

  20. Effect of high-dose growth hormone and glutamine on body composition, urine creatinine excretion, fatty acid absorption, and essential fatty acids status in short bowel patients - A randomized, double-blind, crossover, placebo-controlled study

    DEFF Research Database (Denmark)

    Jeppesen, P.B.; Szkudlarek, J.; Høy, Carl-Erik;

    2001-01-01

    Background: Positive effects of high dose growth hormone and glutamine (GH+GLN) on body composition in short bowel patients have been described. Lack of effects on intestinal absorption found in some studies has been ascribed to concomitant essential fatty acid (EFA) deficiency. This study...... describes changes in body weight (BW) and composition, 24-h urine creatinine excretion, intestinal fatty acid absorption (total, saturated, unsaturated and EFA), and EFA status in relation to treatment with GH+GLN in s short bowel patients. Methods: A double-blind, crossover study between placebo and growth...... hormone (mean, 0.12 mg/kg/day) plus oral (mean, 28 g/day) and parenteral glutamine (mean, 5.28/day) for 28 days. Body composition was measured by dual-energy absorptiometry (DEXA) scans. intestinal fatty acid absorption was evaluated in balance studies, and EFAs were measured in plasma phospholipids...

  1. Repeatability & Workability Evaluation of SIGMOD 2009

    KAUST Repository

    Manegold, Stefan

    2010-12-15

    SIGMOD 2008 was the first database conference that offered to test submitters\\' programs against their data to verify the repeatability of the experiments published [1]. Given the positive feedback concerning the SIGMOD 2008 repeatability initiative, SIGMOD 2009 modified and expanded the initiative with a workability assessment.

  2. Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships

    Directory of Open Access Journals (Sweden)

    Thompson Sally

    2010-11-01

    Full Text Available Abstract Background To compare the efficacy of pregabalin and gabapentin at comparable effective dose levels in patients with refractory partial epilepsy. Methods Eight randomized placebo controlled trials investigating the efficacy of pregabalin (4 studies and gabapentin (4 studies over 12 weeks were identified with a systematic literature search. The endpoints of interest were "responder rate" (where response was defined as at least a 50% reduction from baseline in the number of seizures and "change from baseline in seizure-free days over the last 28 days (SFD". Results of all trials were analyzed using an indirect comparison approach with placebo as the common comparator. The base-case analysis used the intention-to-treat last observation carried forward method. Two sensitivity analyses were conducted among completer and responder populations. Results The base-case analysis revealed statistically significant differences in response rate in favor of pregabalin 300 mg versus gabapentin 1200 mg (odds ratio, 1.82; 95% confidence interval, 1.02, 3.25 and pregabalin 600 mg versus gabapentin 1800 mg (odds ratio, 2.52; 95% confidence interval, 1.21, 5.27. Both sensitivity analyses supported the findings of the base-case analysis, although statistical significance was not demonstrated. All dose levels of pregabalin (150 mg to 600 mg were more efficacious than corresponding dosages of gabapentin (900 mg to 2400 mg in terms of SFD over the last 28 days. Conclusion In patients with refractory partial epilepsy, pregabalin is likely to be more effective than gabapentin at comparable effective doses, based on clinical response and the number of SFD.

  3. Reward modulation of contextual cueing: Repeated context overshadows repeated target location.

    Science.gov (United States)

    Sharifian, Fariba; Contier, Oliver; Preuschhof, Claudia; Pollmann, Stefan

    2017-08-07

    Contextual cueing can be enhanced by reward. However, there is a debate if reward is associated with the repeated target-distractor configurations or with the repeated target locations that occur in both repeated and new displays. Based on neuroimaging evidence, we hypothesized that reward becomes associated with the target location only in new displays, but not in repeated displays, where the repeated target location is overshadowed by the more salient repeated target-distractor configuration. To test this hypothesis, we varied the reward value associated with the same target location in repeated and new displays. The results confirmed the overshadowing hypothesis in that search facilitation in repeated target-distractor configurations was modulated by the variable value associated with the target location. This effect was observed mainly in early learning.

  4. Childhood experiences and repeated suicidal behavior

    DEFF Research Database (Denmark)

    Krarup, Gertrud; Nielsen, Bent; Rask, P

    1991-01-01

    The aim of this study was to elucidate the influence of various events in childhood on suicidal behavior in adult age. For this purpose, 99 patients admitted to the Department of Psychiatry of Odense University Hospital after making a suicide attempt were followed for 5 years, to register repeated...... suicidal behavior. The results showed that three fourths of the patients attempted suicide more than once (62% nonfatal and 14% fatal outcome). The sex distribution was about the same among the first-evers as among the repeaters. Most repeaters were younger people in their twenties and thirties......, and the first-evers on average were past the age of 40. Somewhat unexpectedly, significantly more repeaters than first-evers had grown up with both their parents. However, the results also showed that significantly more repeaters than first-evers had had an unhappy childhood. This indicates...

  5. UK 2009-2010 repeat station report

    Directory of Open Access Journals (Sweden)

    Thomas J.G. Shanahan

    2013-03-01

    Full Text Available The British Geological Survey is responsible for conducting the UK geomagnetic repeat station programme. Measurements made at the UK repeat station sites are used in conjunction with the three UK magnetic observatories: Hartland, Eskdalemuir and Lerwick, to produce a regional model of the local field each year. The UK network of repeat stations comprises 41 stations which are occupied at approximately 3-4 year intervals. Practices for conducting repeat station measurements continue to evolve as advances are made in survey instrumentation and as the usage of the data continues to change. Here, a summary of the 2009 and 2010 UK repeat station surveys is presented, highlighting the measurement process and techniques, density of network, reduction process and recent results.

  6. Cannabis and motor function: fMRI changes following 28 days of discontinuation.

    Science.gov (United States)

    Pillay, Srinivasan S; Rogowska, Jadwiga; Kanayama, Gen; Gruber, Staci; Simpson, Norah; Pope, Harrison G; Yurgelun-Todd, Deborah A

    2008-02-01

    The authors hypothesized that supplementary motor cortex (SMA) and anterior cingulate cortex (ACC) activation in chronic cannabis users, studied 4 to 36 hours after their last episode of use, would disappear by Day 28 of abstinence during finger-tapping tests. Eleven cannabis users and 16 comparison subjects were scanned during right (RFT) and left (LFT) finger-tapping tasks on a GE 1.5 Tesla scanner retrofitted with a whole body echo planar coil. Image analyses were conducted in SPM99 using an ROI approach to define each Brodmann area (BA). Differences in cerebral activation were examined in the left and right primary motor cortex (BA4), SMA (BA6), and ACC (BA24 and BA32 separately). The authors found diminished activation for contralateral BA6 from Day 0 to Day 28. For LFT, the authors also found: ipsilaterally diminished BA6 activation on Day 7, but not Day 0 or Day 28; ipsilaterally diminished BA32 activation on Day 0, but not Day 7 or Day 28; contralaterally diminished BA 4 activation on Day 28, but not Day 0 or Day 7; and contralaterally diminished BA32 activation on Day 0 and Day 28, but not Day 7. For RFT, the authors found ipsilaterally diminished BA32 activation on Days 0 and 7 but not on Day 28; contralaterally diminished BA32 activation on Days 0, 7, and 28; and ipsilaterally diminished BA6 activation on Days 0, 7, and 28. These results suggest that residual diminished brain activation is still observed after discontinuing cannabis use in motor cortical circuits. 2008 APA

  7. Jet fuel kerosene is not immunosuppressive in mice or rats following inhalation for 28 days.

    Science.gov (United States)

    White, Kimber L; DeLorme, Michael P; Beatty, Patrick W; Smith, Matthew J; Peachee, Vanessa L

    2013-01-01

    Previous reports indicated that inhalation of JP-8 aviation turbine fuel is immunosuppressive. However, in some of those studies, the exposure concentrations were underestimated, and percent of test article as vapor or aerosol was not determined. Furthermore, it is unknown whether the observed effects are attributable to the base hydrocarbon fuel (jet fuel kerosene) or to the various fuel additives in jet fuels. The present studies were conducted, in compliance with Good Laboratory Practice (GLP) regulations, to evaluate the effects of jet fuel kerosene on the immune system, in conjunction with an accurate, quantitative characterization of the aerosol and vapor exposure concentrations. Two female rodent species (B6C3F1 mice and Crl:CD rats) were exposed by nose-only inhalation to jet fuel kerosene at targeted concentrations of 0, 500, 1000, or 2000 mg/m(3) for 6 h daily for 28 d. Humoral, cell-mediated, and innate immune functions were subsequently evaluated. No marked effects were observed in either species on body weights, spleen or thymus weights, the T-dependent antibody-forming cell response (plaque assay), or the delayed-type hypersensitivity (DTH) response. With a few exceptions, spleen cell numbers and phenotypes were also unaffected. Natural killer (NK) cell activity in mice was unaffected, while the NK assessment in rats was not usable due to an unusually low response in all groups. These studies demonstrate that inhalation of jet fuel kerosene for 28 d at levels up to 2000 mg/m(3) did not adversely affect the functional immune responses of female mice and rats.

  8. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    Science.gov (United States)

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  9. Validation of a track repeating algorithm for intensity modulated proton therapy: clinical cases study

    Science.gov (United States)

    Yepes, Pablo P.; Eley, John G.; Liu, Amy; Mirkovic, Dragan; Randeniya, Sharmalee; Titt, Uwe; Mohan, Radhe

    2016-04-01

    Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or for large retrospective studies. Track-repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 μs.

  10. The preventive effect of vitamin C on the cellular and functional integrity of kidney cells in rats following repeated exposure to paraquat

    Directory of Open Access Journals (Sweden)

    Benjamin Nnamdi Okolonkwo

    2014-11-01

    Full Text Available Paraquat (PQ is a bipyridylium herbicide that is applied around trees in orchards and between crop rows to control broad-leaved and grassy weeds. Its oxidation results in the formation of superoxides which causes damage to cellular components. In this study, we determined the antioxidant effect vitamin C has on the cellular integrity of kidney function in rats following repeated exposure to PQ. Ninety-six male rats, grouped twelve rats per subgroup (A, Avit.c, B, Bvit.c, C, Cvit.c, D and Dvit.c were intraperitoneally injected with different sublethal increasing doses (0, 0, 2, 2, 4, 4, 6 and 6 mg/kg body weight of PQ respectively on biweekly (14 days intervals over a period of three months (84 days. Subsequently, the subgrouped animals (Avit.c, Bvit.c, Cvit.c and Dvit.c were maintained orally with 1 g/L vitamin C, while the other subgrouped animals (A, B, C and D received drinking water with negligible vitamin content throughout the study period. At the end of each monthly (28 days treatment, four animals per subgroup were selected. Urine samples were collected from each of the selected rats, after which each of the animals were anaesthetized with gaseous isoflurane and 5 mL of blood samples were collected using cardiac puncture procedure. The animals were later decapitated and their kidneys harvested. The samples collected were analyzed for urine [specific gravity (SG, pH, protein and glucose], blood (urea, creatinine, total protein and glucose, and the histological studies on kidney slides. The dose and exposure- time dependent PQ toxicity resulted in the reduction in urinary pH, elevation in urinary SG, and the detectable presence of protein and glucose in urine. It also caused marked elevation in serum urea and creatinine levels with reduction in serum protein and glucose levels and alterations in the cellular integrity of the renal architecture, especially the glomeruli and tubular tissues. Treatments on the PQ insulted animals with vitamin

  11. DNA Replication Dynamics of the GGGGCC Repeat of the C9orf72 Gene.

    Science.gov (United States)

    Thys, Ryan Griffin; Wang, Yuh-Hwa

    2015-11-27

    DNA has the ability to form a variety of secondary structures in addition to the normal B-form DNA, including hairpins and quadruplexes. These structures are implicated in a number of neurological diseases and cancer. Expansion of a GGGGCC repeat located at C9orf72 is associated with familial amyotrophic lateral sclerosis and frontotemporal dementia. This repeat expands from two to 24 copies in normal individuals to several hundreds or thousands of repeats in individuals with the disease. Biochemical studies have demonstrated that as little as four repeats have the ability to form a stable DNA secondary structure known as a G-quadruplex. Quadruplex structures have the ability to disrupt normal DNA processes such as DNA replication and transcription. Here we examine the role of GGGGCC repeat length and orientation on DNA replication using an SV40 replication system in human cells. Replication through GGGGCC repeats leads to a decrease in overall replication efficiency and an increase in instability in a length-dependent manner. Both repeat expansions and contractions are observed, and replication orientation is found to influence the propensity for expansions or contractions. The presence of replication stress, such as low-dose aphidicolin, diminishes replication efficiency but has no effect on instability. Two-dimensional gel electrophoresis analysis demonstrates a replication stall with as few as 20 GGGGCC repeats. These results suggest that replication of the GGGGCC repeat at C9orf72 is perturbed by the presence of expanded repeats, which has the potential to result in further expansion, leading to disease.

  12. Sensitization and Tolerance Following Repeated Exposure to Caffeine and Alcohol in Mice

    Science.gov (United States)

    May, Christina E.; Haun, Harold L.; Griffin, William C.

    2015-01-01

    Introduction Energy drinks are popular mixers with alcohol. While energy drinks contain many ingredients, caffeine is an important pharmacologically active component and is generally present in larger amounts than in other caffeinated beverages. In these studies, we investigated the hypothesis that caffeine would influence the effects of alcohol (ethanol) on conditioned taste aversion, ataxia and locomotor activity after repeated exposure. Methods Four groups of mice were exposed by oral gavage twice daily to vehicle, ethanol (4 g/kg), caffeine (15 mg/kg), or the ethanol/caffeine combination. Conditioned taste aversion to saccharin and ataxia in the parallel rod task were evaluated after 8 or 16 gavages, respectively, using ethanol (1–3 g/kg) or ethanol/caffeine (3mg/kg + 2 g/kg) challenges. In addition, locomotor activity was evaluated initially and after repeated exposure to oral gavage of these drugs and doses. Results Repeated oral gavage of ethanol produced significant locomotor sensitization, with those mice increasing total distance traveled by 2-fold. The locomotor response to caffeine, while significantly greater than vehicle gavage, did not change with repeated exposure. On the other hand, repeated gavage of caffeine/ethanol combination produced a substantial increase in total distance traveled after repeated exposure (~4-fold increase). After repeated ethanol exposure, there was significant tolerance to ethanol in the conditioned taste aversion and parallel rod tests. However, neither a history of caffeine exposure nor including caffeine influenced ethanol-induced conditioned taste aversion. Interestingly, a history of caffeine exposure increased the ataxic response to the caffeine/ethanol combination and appeared to reduce the ataxic response to high doses of ethanol. Conclusion The data support the general hypothesis that repeated exposure to caffeine influences the response to ethanol. Together with previously published work, these data indicate

  13. Repeated Nrf2 stimulation using sulforaphane protects fibroblasts from ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Mathew, Sherin T.; Bergström, Petra; Hammarsten, Ola, E-mail: ola.hammarsten@clinchem.gu.se

    2014-05-01

    Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA and reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2′-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage. - Highlights: • Repeated treatment with sulforaphane protects fibroblasts from ionizing radiation • Repeated sulforaphane treatment attenuates radiation induced ROS and DNA damage • Sulforaphane mediated protection is Nrf2 dependent.

  14. The child accident repeater: a review.

    Science.gov (United States)

    Jones, J G

    1980-04-01

    The child accident repeater is defined as one who has at least three accidents that come to medical attention within a year. The accident situation has features in common with those of the child who has a single accident through simple "bad luck", but other factors predispose him to repeated injury. In the child who has a susceptible personality, a tendency for accident repetition may be due to a breakdown in adjustment to a stressful environment. Prevention of repeat accidents should involve the usual measures considered appropriate for all children as well as an attempt to provide treatment of significant maladjustment and modification of a stressful environment.

  15. The Moral Maturity of Repeater Delinquents.

    Science.gov (United States)

    Petronio, Richard J.

    1980-01-01

    Differences in moral development (as conceived by Kohlberg) were examined in a sample of delinquent teenagers. The repeater group was not found, as had been hypothesized, to be lower on moral maturity than those who engaged in less delinquency. (GC)

  16. Development of Real-Time Measurement of Effective Dose for High Dose Rate Neutron Fields

    CERN Document Server

    Braby, L A; Reece, W D

    2003-01-01

    Studies of the effects of low doses of ionizing radiation require sources of radiation which are well characterized in terms of the dose and the quality of the radiation. One of the best measures of the quality of neutron irradiation is the dose mean lineal energy. At very low dose rates this can be determined by measuring individual energy deposition events, and calculating the dose mean of the event size. However, at the dose rates that are normally required for biology experiments, the individual events can not be separated by radiation detectors. However, the total energy deposited in a specified time interval can be measured. This total energy has a random variation which depends on the size of the individual events, so the dose mean lineal energy can be calculated from the variance of repeated measurements of the energy deposited in a fixed time. We have developed a specialized charge integration circuit for the measurement of the charge produced in a small ion chamber in typical neutron irradiation exp...

  17. Star repeaters for fiber optic links.

    Science.gov (United States)

    McMahon, D H; Gravel, R L

    1977-02-01

    A star repeater combines the functions of a passive star coupler and a signal regenerating amplifier. By more effectively utilizing the light power radiated by a light emitting diode, the star repeater can, when used with small diameter channels, couple as much power to all receivers of a multiterminal link as would be coupled to the single receiver of a simple point-to-point link.

  18. Quantum Key Distribution over Probabilistic Quantum Repeaters

    CERN Document Server

    Amirloo, Jeyran; Majedi, A Hamed

    2010-01-01

    A feasible route towards implementing long-distance quantum key distribution (QKD) systems relies on probabilistic schemes for entanglement distribution and swapping as proposed in the work of Duan, Lukin, Cirac, and Zoller (DLCZ) [Nature 414, 413 (2001)]. Here, we calculate the conditional throughput and fidelity of entanglement for DLCZ quantum repeaters, by accounting for the DLCZ self-purification property, in the presence of multiple excitations in the ensemble memories as well as loss and other sources of inefficiency in the channel and measurement modules. We then use our results to find the generation rate of secure key bits for QKD systems that rely on DLCZ quantum repeaters. We compare the key generation rate per logical memory employed in the two cases of with and without a repeater node. We find the cross-over distance beyond which the repeater system outperforms the non-repeater one. That provides us with the optimum inter-node distancing in quantum repeater systems. We also find the optimal exci...

  19. Remarkable selective constraints on exonic dinucleotide repeats.

    Science.gov (United States)

    Haasl, Ryan J; Payseur, Bret A

    2014-09-01

    Long dinucleotide repeats found in exons present a substantial mutational hazard: mutations at these loci occur often and generate frameshifts. Here, we provide clear and compelling evidence that exonic dinucleotides experience strong selective constraint. In humans, only 18 exonic dinucleotides have repeat lengths greater than six, which contrasts sharply with the genome-wide distribution of dinucleotides. We genotyped each of these dinucleotides in 200 humans from eight 1000 Genomes Project populations and found a near-absence of polymorphism. More remarkably, divergence data demonstrate that repeat lengths have been conserved across the primate phylogeny in spite of what is likely considerable mutational pressure. Coalescent simulations show that even a very low mutation rate at these loci fails to explain the anomalous patterns of polymorphism and divergence. Our data support two related selective constraints on the evolution of exonic dinucleotides: a short-term intolerance for any change to repeat length and a long-term prevention of increases to repeat length. In general, our results implicate purifying selection as the force that eliminates new, deleterious mutants at exonic dinucleotides. We briefly discuss the evolution of the longest exonic dinucleotide in the human genome--a 10 x CA repeat in fibroblast growth factor receptor-like 1 (FGFRL1)--that should possess a considerably greater mutation rate than any other exonic dinucleotide and therefore generate a large number of deleterious variants. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  20. Dynamic combinatorial libraries of artificial repeat proteins.

    Science.gov (United States)

    Eisenberg, Margarita; Shumacher, Inbal; Cohen-Luria, Rivka; Ashkenasy, Gonen

    2013-06-15

    Repeat proteins are found in almost all cellular systems, where they are involved in diverse molecular recognition processes. Recent studies have suggested that de novo designed repeat proteins may serve as universal binders, and might potentially be used as practical alternative to antibodies. We describe here a novel chemical methodology for producing small libraries of repeat proteins, and screening in parallel the ligand binding of library members. The first stage of this research involved the total synthesis of a consensus-based three-repeat tetratricopeptide (TPR) protein (~14 kDa), via sequential attachment of the respective peptides. Despite the effectiveness of the synthesis and ligation steps, this method was found to be too demanding for the production of proteins containing variable number of repeats. Additionally, the analysis of binding of the individual proteins was time consuming. Therefore, we designed and prepared novel dynamic combinatorial libraries (DCLs), and show that their equilibration can facilitate the formation of TPR proteins containing up to eight repeating units. Interestingly, equilibration of the library building blocks in the presence of the biologically relevant ligands, Hsp90 and Hsp70, induced their oligomerization into forming more of the proteins with large recognition surfaces. We suggest that this work presents a novel simple and rapid tool for the simultaneous screening of protein mixtures with variable binding surfaces, and for identifying new binders for ligands of interest.

  1. Eye lens radiation exposure and repeated head CT scans: A problem to keep in mind

    Energy Technology Data Exchange (ETDEWEB)

    Michel, Morgane; Jacob, Sophie [Institute for Radiological Protection and Nuclear Safety, IRSN/DRPH/SRBE/Laboratoire d' Epidemiologie, BP 17, 92 262 Fontenay-aux-Roses (France); Roger, Gilles [Otolaryngology Department, Trousseau Hospital, Paris (France); Pelosse, Beatrice [Ophthalmology Department, Trousseau Hospital, Paris (France); Laurier, Dominique [Institute for Radiological Protection and Nuclear Safety, IRSN/DRPH/SRBE/Laboratoire d' Epidemiologie, BP 17, 92 262 Fontenay-aux-Roses (France); Le Pointe, Hubert Ducou [Radiology Department, Trousseau Hospital, Paris (France); Bernier, Marie-Odile, E-mail: marie-odile.bernier@irsn.fr [Institute for Radiological Protection and Nuclear Safety, IRSN/DRPH/SRBE/Laboratoire d' Epidemiologie, BP 17, 92 262 Fontenay-aux-Roses (France)

    2012-08-15

    Objectives: The deterministic character of radiation-induced cataract is being called into question, raising the possibility of a risk in patients, especially children, exposed to ionizing radiation in case of repeated head CT-scans. This study aims to estimate the eye lens doses of a pediatric population exposed to repeated head CTs and to assess the feasibility of an epidemiological study. Methods: Children treated for a cholesteatoma, who had had at least one CT-scan of the middle ear before their tenth birthday, were included. Radiation exposure has been assessed from medical records and telephone interviews. Results: Out of the 39 subjects contacted, 32 accepted to participate. A total of 76 CT-scans were retrieved from medical records. At the time of the interview (mean age: 16 years), the mean number of CT per child was 3. Cumulative mean effective and eye lens doses were 1.7 mSv and 168 mGy, respectively. Conclusion: A relatively high lens radiation dose was observed in children exposed to repeated CT-scans. Due to that exposure and despite the difficulties met when trying to reach patients' families, a large scale epidemiological study should be performed in order to assess the risk of radiation-induced cataracts associated with repeated head CT.

  2. Effects of Four Weeks of β-Alanine Supplementation on Repeated Sprint Ability in Water Polo Players.

    Science.gov (United States)

    Brisola, Gabriel Motta Pinheiro; Artioli, Guilherme Giannini; Papoti, Marcelo; Zagatto, Alessandro Moura

    2016-01-01

    The purpose of this study was to investigate the effect of four weeks of β-alanine supplementation on repeated sprint ability in water polo players. Twenty-two male water polo players participated in the study, divided randomly into two homogeneous groups (placebo and β-alanine groups). The study design was double-blind, parallel and placebo controlled. Before and after the supplementation period (28 days), the athletes performed two specific repeated sprint ability tests interspaced by a 30-minute swimming test. Participants received 4.8g∙day-1 of the supplement (dextrose or β-alanine) on the first 10 days and 6.4g∙day-1 on the final 18 days. There was no significant group-time interaction for any variable. The qualitative inference for substantial changes demonstrated a likely beneficial effect in the β-alanine group (β-alanine vs placebo) for mean time (6.6±0.4s vs 6.7±0.4s; 81% likely beneficial), worst time (6.9±0.5s vs 7.1±0.5s; 78% likely beneficial) and total time (39.3±2.5s vs 40.4±2.5s; 81% likely beneficial) in the first repeated sprint ability set and for worst time (7.2±0.6s vs 7.5±0.6s; 57% possible beneficial) in the second repeated sprint ability set. Further, was found substantial change for total time for both repeated sprint ability tests (80.8±5.7s vs 83.4±5.6s; 52% possible beneficial). To conclude, four weeks of β-alanine supplementation had a likely beneficial effect in the first set of repeated sprint ability tests and a possible beneficial effect for worst time in the second set performed in a specific protocol in water polo players.

  3. Effects of Four Weeks of β-Alanine Supplementation on Repeated Sprint Ability in Water Polo Players

    Science.gov (United States)

    Brisola, Gabriel Motta Pinheiro; Artioli, Guilherme Giannini; Papoti, Marcelo; Zagatto, Alessandro Moura

    2016-01-01

    The purpose of this study was to investigate the effect of four weeks of β-alanine supplementation on repeated sprint ability in water polo players. Twenty-two male water polo players participated in the study, divided randomly into two homogeneous groups (placebo and β-alanine groups). The study design was double-blind, parallel and placebo controlled. Before and after the supplementation period (28 days), the athletes performed two specific repeated sprint ability tests interspaced by a 30-minute swimming test. Participants received 4.8g∙day-1 of the supplement (dextrose or β-alanine) on the first 10 days and 6.4g∙day-1 on the final 18 days. There was no significant group-time interaction for any variable. The qualitative inference for substantial changes demonstrated a likely beneficial effect in the β-alanine group (β-alanine vs placebo) for mean time (6.6±0.4s vs 6.7±0.4s; 81% likely beneficial), worst time (6.9±0.5s vs 7.1±0.5s; 78% likely beneficial) and total time (39.3±2.5s vs 40.4±2.5s; 81% likely beneficial) in the first repeated sprint ability set and for worst time (7.2±0.6s vs 7.5±0.6s; 57% possible beneficial) in the second repeated sprint ability set. Further, was found substantial change for total time for both repeated sprint ability tests (80.8±5.7s vs 83.4±5.6s; 52% possible beneficial). To conclude, four weeks of β-alanine supplementation had a likely beneficial effect in the first set of repeated sprint ability tests and a possible beneficial effect for worst time in the second set performed in a specific protocol in water polo players. PMID:27930743

  4. New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine▿

    Science.gov (United States)

    Krudsood, S.; Looareesuwan, S.; Tangpukdee, N.; Wilairatana, P.; Phumratanaprapin, W.; Leowattana, W.; Chalermrut, K.; Ramanathan, S.; Navaratnam, V.; Olliaro, P.; Vaillant, M.; Kiechel, J. R.; Taylor, W. R. J.

    2010-01-01

    A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement. PMID:20547795

  5. Antenatal steroids: can we optimize the dose?

    Science.gov (United States)

    Romejko-Wolniewicz, Ewa; Teliga-Czajkowska, Justyna; Czajkowski, Krzysztof

    2014-01-01

    Purpose of review The beneficial effects of antenatal steroids in women at risk of preterm birth are evident. A dose of 24 mg appears sufficient, but there are insufficient data to recommend betamethasone or dexamethasone, a single steroid dose, the optimal interval between doses and repeated courses, the gestational age at which treatment is beneficial and the long-term effects of steroid treatment. This review addresses these aspects of antenatal steroid treatment. Recent findings Although the 12-h and 24-h dosing intervals are equivalent with respect to prevention of respiratory distress syndrome, the former enables the completion of treatment in 50% more neonates delivered prematurely. Reducing the single steroid dose in patients at risk for premature birth reduces the associated maternal side effects. An inverse relationship has been demonstrated between the number of corticosteroid courses and foetal growth. The reduced size of exposed foetuses has been attributed to birth at earlier gestational ages and decreased foetal growth. Evidence suggests that antenatal exposure to synthetic glucocorticoids in term-born children has long-lasting effects, which may have important implications in the recommendation of steroids before elective caesarean at term. Summary The short-term and long-term effects of the dosage regimen on the pregnant mother and foetus remain unclear. PMID:24463225

  6. Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli.

    Science.gov (United States)

    Gibson, Gabrielle A; Bauer, Seth R; Neuner, Elizabeth A; Bass, Stephanie N; Lam, Simon W

    2015-11-02

    The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure. Copyright © 2015, American Society for Microbiology. All Rights

  7. Radiotherapy for a repeatedly recurrent ameloblastoma with malignant transformation.

    Science.gov (United States)

    Huang, Chun-Ming; Chen, Jin-Yi; Chen, Chung-Ho; Huang, Chih-Jen

    2014-01-01

    The role of radiation therapy (RT) for ameloblastoma remains controversial and undetermined due to the rarity of the disease. A case of repeatedly recurrent ameloblastoma with malignant transformation is presented. The clinical course and managements are described. The 63-year-old man had a recurrent ameloblastoma in the left mandible. Five years after the first surgical resection, he underwent 8 more rounds of surgical excision of the recurrent tumors. The malignant transformation occurred and the unresectable tumor invaded the masticator space, parapharyngeal space, and skull base. He received 3-dimensional conformal RT, at the dose of 66 Gray (Gy) in 33 fractions. The ulcerative exophytic mass had regressed gradually. After follow-up of 28 months, the tumor was well controlled. RT seems to be a feasible treatment option for recurrent ameloblastoma with malignant transformation. Copyright © 2013 Wiley Periodicals, Inc.

  8. Impact of repeat computerized tomography replans in the radiation therapy of head and neck cancers

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    Virendra Bhandari

    2014-01-01

    Full Text Available Anatomical changes can occur during course of head-and-neck (H and N radiotherapy like tumor shrinkage, decreased edema and/or weight loss. This can lead to discrepancies in planned and delivered dose increasing the dose to organs at risk. A study was conducted to determine the volumetric and dosimetric changes with the help of repeat computed tomography (CT and replanning for selected H and N cancer patients treated with IMRT plans to see for these effects. In 15 patients with primary H and N cancer, a repeat CT scan after 3 rd week of radiotherapy was done when it was clinically indicated and then two plans were generated on repeat CT scan, actual plan (AP planned on repeat CT scan, and hybrid plan (HP, which was generated by applying the first intensity-modulated radiation therapy (IMRT plan (including monitoring units to the images of second CT scan. Both plans (AP and HP on repeat CT scan were compared for volumetric and dosimetric parameter. The mean variation in volumes between CT and repeat CT were 44.32 cc, 82.2 cc, and 149.83 cc for gross tumor volume (GTV, clinical target volumes (CTV, and planning target volume (PTV, respectively. Mean conformity index and homogeneity index was 0.68 and 1.07, respectively for AP and 0.5 and 1.16, respectively for HP. Mean D 95 and D 99 of PTV was 97.92% (standard deviation, SD 2.32 and 93.4% (SD 3.75, respectively for AP and 92.8% (SD 3.83 and 82.8% (SD 8.0, respectively for HP. Increase in mean doses to right parotid, left parotid, spine, and brainstem were 5.56 Gy (D mean , 3.28 Gy (D mean , 1.25 Gy (D max , and 3.88 Gy (D max , respectively in HP compared to AP. Repeat CT and replanning reduces the chance of discrepancies in delivered dose due to volume changes and also improves coverage to target volume and further reduces dose to organ at risk.

  9. The effects of high-dose ivermectin regimens on Onchocerca volvulus in onchocerciasis patients.

    Science.gov (United States)

    Awadzi, K; Attah, S K; Addy, E T; Opoku, N O; Quartey, B T

    1999-01-01

    Ivermectin, at the standard dose of 150 micrograms/kg bodyweight, does not kill the adult worms of Onchocerca volvulus and does not disrupt embryogenesis or spermatogenesis. Repeated standard doses, if maintained, arrest microfilarial production but result in only a mild-to-modest macrofilaricidal effect. We investigated whether high doses would effectively kill the adult worms, and whether cessation of microfilarial production could be reproduced by an equivalent, single, high dose. One hundred men participated in a double-blind placebo-controlled trial and received increasing doses of ivermectin from 150 micrograms/kg to 1600 micrograms/kg bodyweight. Nodules were excised at day 180 and examined by histopathology. Total doses of ivermectin up to 1600 micrograms/kg were not significantly more effective than 150 micrograms/kg. Moreover, they did not reproduce the marked inhibitory effects of the repeat standard-dose regimens on embryogenesis, nor the modest effect on adult worm viability, at comparable total doses. These effects may be functions of multiplicities of dosages rather than of the total dose. Our findings also suggest that repeated high-dose regimens are unlikely to be more effective than a similar number of 150 micrograms/kg doses. This deficiency of ivermectin requires that the search for macrofilaricides remains a top priority.

  10. Automated genotyping of dinucleotide repeat markers

    Energy Technology Data Exchange (ETDEWEB)

    Perlin, M.W.; Hoffman, E.P. [Carnegie Mellon Univ., Pittsburgh, PA (United States)]|[Univ. of Pittsburgh, PA (United States)

    1994-09-01

    The dinucleotide repeats (i.e., microsatellites) such as CA-repeats are a highly polymorphic, highly abundant class of PCR-amplifiable markers that have greatly streamlined genetic mapping experimentation. It is expected that over 30,000 such markers (including tri- and tetranucleotide repeats) will be characterized for routine use in the next few years. Since only size determination, and not sequencing, is required to determine alleles, in principle, dinucleotide repeat genotyping is easily performed on electrophoretic gels, and can be automated using DNA sequencers. Unfortunately, PCR stuttering with these markers generates not one band for each allele, but a pattern of bands. Since closely spaced alleles must be disambiguated by human scoring, this poses a key obstacle to full automation. We have developed methods that overcome this obstacle. Our model is that the observed data is generated by arithmetic superposition (i.e., convolution) of multiple allele patterns. By quantitatively measuring the size of each component band, and exploiting the unique stutter pattern associated with each marker, closely spaced alleles can be deconvolved; this unambiguously reconstructs the {open_quotes}true{close_quotes} allele bands, with stutter artifact removed. We used this approach in a system for automated diagnosis of (X-linked) Duchenne muscular dystrophy; four multiplexed CA-repeats within the dystrophin gene were assayed on a DNA sequencer. Our method accurately detected small variations in gel migration that shifted the allele size estimate. In 167 nonmutated alleles, 89% (149/167) showed no size variation, 9% (15/167) showed 1 bp variation, and 2% (3/167) showed 2 bp variation. We are currently developing a library of dinucleotide repeat patterns; together with our deconvolution methods, this library will enable fully automated genotyping of dinucleotide repeats from sizing data.

  11. Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats.

    Science.gov (United States)

    Moreno-Rocha, Luis Alfonso; López-Muñoz, Francisco Javier; Medina-López, José Raúl; Domínguez-Ramírez, Adriana Miriam

    2016-11-01

    Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P metamizol and tramadol was found under acute treatment (P > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites' pharmacokinetics (P < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

  12. Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats

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    Luis Alfonso Moreno-Rocha

    2016-11-01

    Full Text Available Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P  0.05. The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites’ pharmacokinetics (P < 0.05 were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

  13. Carbohydrate mouth rinse does not improve repeated sprint performance

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    Leandro Ricardo Altimari

    2013-09-01

    Full Text Available The objective of this study was to evaluate the effect of a carbohydrate mouth rinse on the repeated sprint ability (RSA of young soccer players. Nine youth soccer players (15.0 ± 1.5 years; 60.7 ± 4.84 kg; 1.72 ± 0.05 m; 20.5 ± 1.25 kg/m2 were selected. The athletes were submitted to an RSA test consisting of six sprints of 40 m (going/return = 20 m + 20 m, separated by 20 s of passive recovery, under three experimental conditions: carbohydrate mouth rinse (CHO or placebo (PLA and control (CON. The mouth rinses containing CHO or PLA were administered 5 min and immediately before the beginning of the test in doses of 100 mL. The best sprint time (RSAbest, mean sprint time (RSAmean, and drop-off in sprint performance (fatigue index were determined for the different treatments. One-not identify significant differences (p> 0.05 in RSAbest (CHO way ANOVA for repeated measures did = 7.30 ± 0.31 s; PLA = 7.30 ± 0.30 s; CON = 7.26 ±0.16 s, RSA mean (CHO = 7.71 ± 0.30 s; PLA = 7.71 ± 0.25 s; CON = 7.66 ± 0.24s, or fatigue index (CHO = 5.58 ± 2.16%; PLA = 5.77 ± 3.04%; CON = 5.55 ±3.72%. The results suggest that a carbohydrate mouth rinse does not improve the repeated sprint performance of young soccer players.

  14. [Effect of dosed diet restriction on physiological remodeling and bioelectric properties of bone].

    Science.gov (United States)

    Levashov, M I; Ianko, R V; Chaka, E G; Safonov, S L

    2014-07-01

    The effect of dosed diet restriction on the physiological remodeling and bioelectric properties of bone tissue was studied in 48 male Wistar rats 3- and 18-months of age. The rate of bone tissue apposition was studied by the dynamic histomorphometry method (intravital tetracycline labeling). Electric potentials on the periosteal surface of the freshly isolated femurs were recorded. The magnitude of dielectric loss factor was determined to assess the quality of bone tissue. The control rats received a standard diet. The experimental rats received a limited diet (60 % of the standard mass) for 28 days. The magnitude and rate of the bone tissue apposition on the endosteal and periosteal surface of the tibia were less by 38.4% and 122.7% respectively in experimental rats after dosed diet restriction. Electric potential in the metaphyseal-epiphyseal growth zones of the femur was 29.7% lower, and the dielectric loss factor increased by 15.8%. The bone tissue apposition rate and the electric potential magnitude were increased 10 days after completion of the dosed diet restriction. The magnitude of the dielectric loss factor decreased after returning to the standard diet. Key words: dosed diet restriction, bone, remodelling, bioelectric properties.

  15. Repeatability and heritability of response to superovulation in Holstein cows.

    Science.gov (United States)

    Tonhati, H; Lôbo, R B; Oliveira, H N

    1999-04-15

    The objective of this study was to estimate the relative effects of genetic and phenotypic factors on the efficacy and efficiency of superovulation for Holstein-Friesian cows reared in Brazil. A database, established by the Associacao Brasileira de Criadores de Bovinos da Raca Holandesa, consisting of a total of 5387 superovulations of 2941 cows distributed over 473 herds and sired by 690 bulls was used for the analysis. The records were analyzed by MTDFREML (Multiple Trait Derivative-Free Restricted Maximum Likelihood), using a repeatability animal model. The fixed effects included in the model were contemporaneous group (veterinarian, herd, year and season of the superovulation); number of semen doses; cow age; and superovulation order. The estimated repeatability of the number of the transferable embryos was low (0.13), and the estimated heritability was 0.03. These results indicate that environmental factors play a critical role in the response of a cow to a superovulation treatment. There is little evidence that future responses to superovulation by individual females can be predicted by previous treatment(s) or that superovulation response is an heritable trait.

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

    Science.gov (United States)

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

    1986-08-01

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

  17. Polychlorinated biphenyls as oxidative stress inducers in liver of subacutely exposed rats: implication for dose-dependence toxicity and benchmark dose concept.

    Science.gov (United States)

    Buha, Aleksandra; Antonijević, Biljana; Milovanović, Vesna; Janković, Saša; Bulat, Zorica; Matović, Vesna

    2015-01-01

    Hepatotoxicity is one of the well-documented adverse health effects of polychlorinated biphenyls (PCBs)-persistent organic pollutants widely present in the environment. Although previous studies suggest possible role of oxidative stress, the precise mechanisms of PCB-induced ROS production in liver still remain to be fully assessed. The aim of this study was to evaluate the effects of different doses of PCBs on the parameters of oxidative stress and to investigate whether these effects are dose dependent. Furthermore, a comparison between calculated benchmark doses (BMD) and estimated NOAEL values for investigated parameters, was made. Six groups of male albino Wistar rats (7 animals per group) were receiving Aroclor 1254 dissolved in corn oil in the doses of 0.5, 1, 2, 4, 8, 16 mg PCBs/kg b.w./day by oral gavage during 28 days while control animals were receiving corn oil only. The following parameters of oxidative stress were analyzed in liver homogenates: superoxide dismutase activity, glutathione, malondialdehyde (MDA) and total protein thiol levels. Hepatic enzymes AST, ALT, ALP and protein albumin were also determined in serum as clinical parameters of liver function. Collected data on the investigated parameters were analyzed by the BMD method. The results of this study demonstrate that subacute exposure to PCBs causes induction of oxidative stress in liver with dose-dependent changes of the investigated parameters, although more pronounced adverse effects were observed on enzymatic than on non-enzymatic components of antioxidant protection. The obtained values for BMD and NOAEL support the use of BMD concept in the prediction of health risks associated with PCBs exposure. Furthermore, our results implicate possible use of MDA in PCBs risk assessment, since MDA was the most sensitive investigated parameter with calculated low critical effect dose of 0.07 mg/kg b.w.

  18. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice

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    Mahdieh Matinfar

    2013-01-01

    Full Text Available Background: One of the serious problems that opioid addicted people are facing is repeated withdrawal syndrome that is accompanying with a significant stress load for addicts. Therefore, the aim of this study was to evaluate the effects of repeated withdrawal on spatial learning, memory and serum cortisol levels in morphine-dependent mice. Materials and Methods: Male NMRI mice received morphine as daily increasing doses for 3 days. After that, the mice underwent one time or repeated spontaneous or pharmacologic (naloxone-precipitated withdrawal. Then spatial learning and memory were investigated by morris water maze test, and at the end trunk blood samples were collected for measurement of serum cortisol levels. Results: The results showed that only repeated spontaneous withdrawal significantly increases escape latency ( P < 0.05, and in other models of withdrawal, spatial learning and memory were intact. The results of probe trial were intact in all groups. Radioimmunoassay showed that serum cortisol levels were increased significantly in all models of withdrawal ( P < 0.05 and P < 0.01 except the repeated spontaneous withdrawal. Conclusion: The results showed that short periods of withdrawal syndrome can increase serum cortisol levels; however they do not affect spatial learning and memory. Nevertheless, repeated spontaneous withdrawal can make learning slow.

  19. Mining of simple sequence repeats in the Genome of Gentianaceae

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    R Sathishkumar

    2011-01-01

    Full Text Available Simple sequence repeats (SSRs or short tandem repeats are short repeat motifs that show high level of length polymorphism due to insertion or deletion mutations of one or more repeat types. Here, we present the detection and abundance of microsatellites or SSRs in nucleotide sequences of Gentianaceae family. A total of 545 SSRs were mined in 4698 nucleotide sequences downloaded from the National Center for Biotechnology Information (NCBI. Among the SSR sequences, the frequency of repeat type was about 429 -mono repeats, 99 -di repeats, 15 -tri repeats, and 2 --hexa repeats. Mononucleotide repeats were found to be abundant repeat types, about 78%, followed by dinucleotide repeats (18.16% among the SSR sequences. An attempt was made to design primer pairs for 545 identified SSRs but these were found only for 169 sequences.

  20. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats.

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    Zhenming Yu

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ repeats of 27-33 in ATAXIN-2 (ATXN2, encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥ 34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1-3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT, while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC. Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2.

  1. A Phase I Study of High-Dose Calcitriol in Combination with Temozolomide for Patients with Metastatic Melanoma

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    Erin Pettijohn

    2014-10-01

    Full Text Available Background: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM. Calcitriol has anti-proliferative properties and vitamin D receptor (VDR polymorphisms are associated with alterations in melanoma susceptibility and progression. Methods: Tem 150 mg/m2 was administered on days 2–8 and 16–22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP and overall survival (OS. Results: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/−ff (n = 6 had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11, although not statistically significant (HR = 1.20, 95% CI 0.41–3.53, p = 0.74. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.

  2. Repeatability of peripheral aberrations in young emmetropes.

    Science.gov (United States)

    Baskaran, Karthikeyan; Theagarayan, Baskar; Carius, Staffan; Gustafsson, Jörgen

    2010-10-01

    The purpose of this study is to assess the intrasession repeatability of ocular aberration measurements in the peripheral visual field with a commercially available Shack-Hartmann aberrometer (complete ophthalmic analysis system-high definition-vision research). The higher-order off-axis aberrations data in young healthy emmetropic eyes are also reported. The aberrations of the right eye of 18 emmetropes were measured using an aberrometer with an open field of view that allows peripheral measurements. Five repeated measures of ocular aberrations were obtained and assessed in steps of 10° out to ±40° in the horizontal visual field (nasal + and temporal -) and -20° in the inferior visual field. The coefficient of repeatability, coefficient of variation, and the intraclass correlation coefficient were calculated as a measure of intrasession repeatability. In all eccentric angles, the repeatability of the third- and fourth-order aberrations was better than the fifth and sixth order aberrations. The coefficient of variation was coefficient was >0.90 for the third and fourth order but reduced gradually for higher orders. There was no statistical significant difference in variance of total higher-order root mean square between on- and off-axis measurements (p > 0.05). The aberration data in this group of young emmetropes showed that the horizontal coma (C(3)(1)) was most positive at 40° in the temporal field, decreasing linearly toward negative values with increasing off-axis angle into the nasal field, whereas all other higher-order aberrations showed little or no change. The complete ophthalmic analysis system-high definition-vision research provides fast, repeatable, and valid peripheral aberration measurements and can be used efficiently to measure off-axis aberrations in the peripheral visual field.

  3. Effect of a single dose of mesoglycan on the human fibrinolytic system, and the profibrinolytic action of nine daily doses.

    Science.gov (United States)

    Vittoria, A; Messa, G L; Frigerio, C; Celasco, G; Auteri, A

    1988-01-01

    The profibrinolytic activity of orally administered Mesoglycan was evaluated in 18 patients affected by impaired plasma fibrinolytic activity. Mesoglycan was administered by a single oral dose of 24, 48 or 72 mg on 1 day, and by repeated doses of 48 mg twice a day for 9 consecutive days. After the single administration all the fibrinolytic parameters were significantly and positively influenced with an order of magnitude and a duration of effects proportional to the dose employed. After the repeated administration, a constant and reproducible activation of the fibrinolytic system was observed without any interference with haemocoagulative parameters. These results confirm that Mesoglycan is endowed with a relevant profibrinolytic activity in man after oral administration. The pharmacological activity of Mesoglycan could possibly involve the liberation of a certain amount of plasminogen tissue activator.

  4. Controllable dose; Dosis controlable

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez R, J.T.; Anaya M, R.A. [ININ, A.P. 18-1027, 11801 Mexico D.F. (Mexico)]. E-mail: jtar@nuclear.inin.mx

    2004-07-01

    With the purpose of eliminating the controversy about the lineal hypothesis without threshold which found the systems of dose limitation of the recommendations of ICRP 26 and 60, at the end of last decade R. Clarke president of the ICRP proposed the concept of Controllable Dose: as the dose or dose sum that an individual receives from a particular source which can be reasonably controllable by means of any means; said concept proposes a change in the philosophy of the radiological protection of its concern by social approaches to an individual focus. In this work a panorama of the foundations is presented, convenient and inconveniences that this proposal has loosened in the international community of the radiological protection, with the purpose of to familiarize to our Mexican community in radiological protection with these new concepts. (Author)

  5. Copy number of tandem direct repeats within the inverted repeats of Marek's disease virus DNA.

    Science.gov (United States)

    Kanamori, A; Nakajima, K; Ikuta, K; Ueda, S; Kato, S; Hirai, K

    1986-12-01

    We previously reported that DNA of the oncogenic strain BC-1 of Marek's disease virus serotype 1 (MDV1) contains three units of tandem direct repeats with 132 base pair (bp) repeats within the inverted repeats of the long regions of the MDV1 genome, whereas the attenuated, nononcogenic viral DNA contains multiple units of tandem direct repeats (Maotani et al., 1986). In the present study, the difference in the copy numbers of 132 bp repeats of oncogenic and nononcogenic MDV1 DNAs in other strains of MDV1 was investigated by Southern blot hybridization. The main copy numbers in different oncogenic MDV1 strains differed: those of BC-1, JM and highly oncogenic Md5 were 3, 5 to 12 and 2, respectively. The viral DNA population with two units of repeats was small, but detectable, in cells infected with either the oncogenic BC-1 or JM strain. The MDV1 DNA in various MD cell lines contained either two units or both two and three units of repeats. The significance of the copy number of repeats in oncogenicity of MDV1 is discussed.

  6. [Immune response to one booster dose of inactivated hepatitis A vaccine in college students].

    Science.gov (United States)

    Liao, Z; Feng, X W; Liu, X E; Zhou, Y S; Wen, H R; Peng, S H; Zhang, Y X; Xu, B; Zhuang, H; Chen, H Y

    2017-05-10

    Objective: To evaluate the safety and immunogenicity of one booster dose of inactivated hepatitis A vaccine in young adults. Methods: The subjects were selected from participants in the clinical trial of immunogenicity of inactivated and attenuated live hepatitis A vaccine in young adults. Eligible subjects were those who had received one dose of inactivated or attenuated hepatitis A vaccine, could be contacted and were sero-negative before primary vaccination. All qualified subjects were immunized with one booster dose of inactivated hepatitis A vaccine. The blood samples were collected before booster dose vaccination and 28 days after the immunization. Anti-HAV antibody titer ≥20 mIU/ml was considered to be sero-protected against hepatitis A virus. Results: The GMCs in the inactivated HAV vaccine group and attenuated live vaccine group before booster dose vaccination were 70.80 mIU/ml and 50.12 mIU/ml, respectively, and the sero-protection rates were 94.7% and 65.0%, respectively. After the vaccination of the booster dose, the sero-protection rates in both groups were 100.0%, and the GMCs were 2 816.09 mIU/ml and 2 654.55 mIU/ml, respectively. Conclusion: The GMCs and sero-protection rates of anti-HAV antibody in young adults declined after three years of the primary vaccination. However, the higher GMC and sero-protection rate were observed in the inactivated vaccine group than in the attenuated live vaccine group. Significant increases of GMC levels were observed in both groups after one booster dose vaccination.

  7. Measuring pacemaker dose: A clinical perspective

    Energy Technology Data Exchange (ETDEWEB)

    Studenski, Matthew T., E-mail: matthew.studenski@jeffersonhospital.org [Department of Radiation Oncology at the Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Xiao Ying; Harrison, Amy S. [Department of Radiation Oncology at the Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States)

    2012-07-01

    Recently in our clinic, we have seen an increased number of patients presenting with pacemakers and defibrillators. Precautions are taken to develop a treatment plan that minimizes the dose to the pacemaker because of the adverse effects of radiation on the electronics. Here we analyze different dosimeters to determine which is the most accurate in measuring pacemaker or defibrillator dose while at the same time not requiring a significant investment in time to maintain an efficient workflow in the clinic. The dosimeters analyzed here were ion chambers, diodes, metal-oxide-semiconductor field effect transistor (MOSFETs), and optically stimulated luminescence (OSL) dosimeters. A simple phantom was used to quantify the angular and energy dependence of each dosimeter. Next, 8 patients plans were delivered to a Rando phantom with all the dosimeters located where the pacemaker would be, and the measurements were compared with the predicted dose. A cone beam computed tomography (CBCT) image was obtained to determine the dosimeter response in the kilovoltage energy range. In terms of the angular and energy dependence of the dosimeters, the ion chamber and diode were the most stable. For the clinical cases, all the dosimeters match relatively well with the predicted dose, although the ideal dosimeter to use is case dependent. The dosimeters, especially the MOSFETS, tend to be less accurate for the plans, with many lateral beams. Because of their efficiency, we recommend using a MOSFET or a diode to measure the dose. If a discrepancy is observed between the measured and expected dose (especially when the pacemaker to field edge is <10 cm), we recommend analyzing the treatment plan to see whether there are many lateral beams. Follow-up with another dosimeter rather than repeating multiple times with the same type of dosimeter. All dosimeters should be placed after the CBCT has been acquired.

  8. Y Se Repite = And It Repeats Itself

    Science.gov (United States)

    Katzew, Adriana

    2010-01-01

    In this article, the author discusses Y Se Repite [And It Repeats Itself], a project she conceptualized due to the growing number of Latino/a Mexican migrant workers in dairy farms in the state of Vermont. In 2006, approximately 2,000 Latinos/as--most of them undocumented Mexican migrant workers--worked throughout the state's dairy farms, yet…

  9. Repeater For A Digital-Communication Bus

    Science.gov (United States)

    Torres-Guzman, Esteban; Olson, Stephen; Heaps, Tim

    1993-01-01

    Digital repeater circuit designed to extend range of communication on MIL-STD-1553 bus beyond original maximum allowable length of 300 ft. Circuit provides two-way communication, one way at time, and conforms to specifications of MIL-STD-1553. Crosstalk and instability eliminated.

  10. Episodes of repeated sudden deafness following pregnancies.

    Science.gov (United States)

    Pawlak-Osinska, Katarzyna; Burduk, Pawel K; Kopczynski, Andrzej

    2009-04-01

    Sex hormones influence and provoke changes in hearing levels. Sudden deafness is rarely observed in pregnant women. The effective treatment of sudden deafness in pregnant women is a challenging problem. We present a case of repeatable, completely regressed sudden deafness in a woman during her first and second pregnancies.

  11. Repeated sprint training in normobaric hypoxia.

    Science.gov (United States)

    Galvin, Harvey M; Cooke, Karl; Sumners, David P; Mileva, Katya N; Bowtell, Joanna L

    2013-12-01

    Repeated sprint ability (RSA) is a critical success factor for intermittent sport performance. Repeated sprint training has been shown to improve RSA, we hypothesised that hypoxia would augment these training adaptations. Thirty male well-trained academy rugby union and rugby league players (18.4 ± 1.5 years, 1.83 ± 0.07 m, 88.1 ± 8.9 kg) participated in this single-blind repeated sprint training study. Participants completed 12 sessions of repeated sprint training (10 × 6 s, 30 s recovery) over 4 weeks in either hypoxia (13% FiO₂) or normoxia (21% FiO₂). Pretraining and post-training, participants completed sports specific endurance and sprint field tests and a 10 × 6 s RSA test on a non-motorised treadmill while measuring speed, heart rate, capillary blood lactate, muscle and cerebral deoxygenation and respiratory measures. Yo-Yo Intermittent Recovery Level 1 test performance improved after RS training in both groups, but gains were significantly greater in the hypoxic (33 ± 12%) than the normoxic group (14 ± 10%, prepeated aerobic high intensity workout than an equivalent normoxic training. Performance gains are evident in the short term (4 weeks), a period similar to a preseason training block.

  12. Adaptation and complexity in repeated games

    DEFF Research Database (Denmark)

    Maenner, Eliot Alexander

    2008-01-01

    The paper presents a learning model for two-player infinitely repeated games. In an inference step players construct minimally complex inferences of strategies based on observed play, and in an adaptation step players choose minimally complex best responses to an inference. When players randomly ...

  13. A Structured Group Program for Repeat Dieters.

    Science.gov (United States)

    McNamara, Kathleen

    1989-01-01

    Describes a structured group program for women who repeatedly diet and may be at risk of developing more serious eating disorders. Discusses sessions focusing on eating behavior as well as internal factors that contribute to low body esteem and food and weight preoccupation. Evaluates effectiveness of program by self-reports of members of two…

  14. Why Do Students Repeat Admissions Tests?

    Science.gov (United States)

    Jones, Martha S.

    Attitudes and beliefs about the admissions process, especially the role of standardized testing in admissions, were examined for students who took a standardized admissions test more than once. Their attitudes were compared with those of students who did not repeat the test. About 200 preveterinary students who had taken the Veterinary Aptitude…

  15. The Effect of Repeaters on Equating

    Science.gov (United States)

    Kim, HeeKyoung; Kolen, Michael J.

    2010-01-01

    Test equating might be affected by including in the equating analyses examinees who have taken the test previously. This study evaluated the effect of including such repeaters on Medical College Admission Test (MCAT) equating using a population invariance approach. Three-parameter logistic (3-PL) item response theory (IRT) true score and…

  16. Triggering of repeating earthquakes in central California

    Science.gov (United States)

    Wu, Chunquan; Gomberg, Joan; Ben-Naim, Eli; Johnson, Paul

    2014-01-01

    Dynamic stresses carried by transient seismic waves have been found capable of triggering earthquakes instantly in various tectonic settings. Delayed triggering may be even more common, but the mechanisms are not well understood. Catalogs of repeating earthquakes, earthquakes that recur repeatedly at the same location, provide ideal data sets to test the effects of transient dynamic perturbations on the timing of earthquake occurrence. Here we employ a catalog of 165 families containing ~2500 total repeating earthquakes to test whether dynamic perturbations from local, regional, and teleseismic earthquakes change recurrence intervals. The distance to the earthquake generating the perturbing waves is a proxy for the relative potential contributions of static and dynamic deformations, because static deformations decay more rapidly with distance. Clear changes followed the nearby 2004 Mw6 Parkfield earthquake, so we study only repeaters prior to its origin time. We apply a Monte Carlo approach to compare the observed number of shortened recurrence intervals following dynamic perturbations with the distribution of this number estimated for randomized perturbation times. We examine the comparison for a series of dynamic stress peak amplitude and distance thresholds. The results suggest a weak correlation between dynamic perturbations in excess of ~20 kPa and shortened recurrence intervals, for both nearby and remote perturbations.

  17. A Repeater in the Language Laboratory

    Science.gov (United States)

    Griffiths, B. T.

    1969-01-01

    Discusses the feasilility of the use of repeater devices in the language laboratory in order to enable the student to "recapitulate effortlessly and and indefinitely any utterance of any length which is causing him difficulty or is of special interest. (FWB)

  18. The Differential Effects of Repeating Kindergarten

    Science.gov (United States)

    Burkam, David T.; LoGerfo, Laura; Ready, Doug; Lee, Valerie E.

    2007-01-01

    We use the Early Childhood Longitudinal Study to investigate national patterns addressing (a) who repeats kindergarten, and (b) the subsequent cognitive effects of this event. Using OLS regression techniques, we investigate 1st-time kindergartners who are promoted, 1st-time kindergartners who are retained, and children who are already repeating…

  19. Preventing Repeat Teen Births PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    2013-04-02

    This 60 second public service announcement is based on the April 2013 CDC Vital Signs report, which discusses repeat teen births and ways teens, parents and guardians, health care providers, and communities can help prevent them.  Created: 4/2/2013 by Centers for Disease Control and Prevention (CDC).   Date Released: 4/2/2013.

  20. Epigenetics and triplet repeat neurological diseases

    Directory of Open Access Journals (Sweden)

    Sathiji eNageshwaran

    2015-12-01

    Full Text Available The term ‘junk DNA’ has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterchromatinised resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide and tetranucleotide repeats. The association between repetitive regions and disease was emphasised following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy’s disease and fragile X syndrome of mental retardation (FRAXA in 1991. In this review we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.

  1. Costly renegotiation in repeated Bertand games

    DEFF Research Database (Denmark)

    Andersson, Ola; Wengström, Erik Roland

    2010-01-01

    This paper extends the concept of weak renegotiation-proof equilibrium (WRP) to allow for costly renegotiation and shows that even small renegotiation costs can have dramatic effects on the set of equilibria. More specifically, the paper analyzes the infinitely repeated Bertrand game. It is shown...

  2. EVOLUTION AND RECOMBINATION OF BOVINE DNA REPEATS

    NARCIS (Netherlands)

    JOBSE, C; BUNTJER, JB; HAAGSMA, N; BREUKELMAN, HJ; BEINTEMA, JJ; LENSTRA, JA

    The history of the abundant repeat elements in the bovine genome has been studied by comparative hybridization and PCR. The Bov-A and Bov-B SINE elements both emerged just after the divergence of the Camelidae and the true ruminants. A 31-bp subrepeat motif in satellites of the Bovidae species

  3. Building Fluency through the Repeated Reading Method

    Science.gov (United States)

    Cohen, Joshua

    2011-01-01

    For the last two years the author has used Repeated Reading (RR) to teach reading fluency in English as a Foreign Language classrooms in colleges and universities in Japan. RR is a method where the student reads and rereads a text silently or aloud from two to four times to reach a predetermined level of speed, accuracy, and comprehension. RR…

  4. History repeats itself: genomic divergence in copepods.

    Science.gov (United States)

    Renaut, Sébastien; Dion-Côté, Anne-Marie

    2016-04-01

    Press stop, erase everything from now till some arbitrary time in the past and start recording life as it evolves once again. Would you see the same tape of life playing itself over and over, or would a different story unfold every time? The late Steven Jay Gould called this experiment replaying the tape of life and argued that any replay of the tape would lead evolution down a pathway radically different from the road actually taken (Gould 1989). This thought experiment has puzzled evolutionary biologists for a long time: how repeatable are evolutionary events? And if history does indeed repeat itself, what are the factors that may help us predict the path taken? A powerful means to address these questions at a small evolutionary scale is to study closely related populations that have evolved independently, under similar environmental conditions. This is precisely what Pereira et al. (2016) set out to do using marine copepods Tigriopus californicus, and present their results in this issue of Molecular Ecology. They show that evolution can be repeatable and even partly predictable, at least at the molecular level. As expected from theory, patterns of divergence were shaped by natural selection. At the same time, strong genetic drift due to small population sizes also constrained evolution down a similar evolutionary road, and probably contributed to repeatable patterns of genomic divergence.

  5. Costly renegotiation in repeated Bertand games

    DEFF Research Database (Denmark)

    Andersson, Ola; Wengström, Erik Roland

    2010-01-01

    This paper extends the concept of weak renegotiation-proof equilibrium (WRP) to allow for costly renegotiation and shows that even small renegotiation costs can have dramatic effects on the set of equilibria. More specifically, the paper analyzes the infinitely repeated Bertrand game. It is shown...

  6. Photometric Repeatability of Scanned Imagery: UVIS

    Science.gov (United States)

    Shanahan, Clare E.; McCullough, Peter; Baggett, Sylvia

    2017-08-01

    We provide the preliminary results of a study on the photometric repeatability of spatial scans of bright, isolated white dwarf stars with the UVIS channel of the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope (HST). We analyze straight-line scans from the first pair of identical orbits of HST program 14878 to assess if sub 0.1% repeatability can be attained with WFC3/UVIS. This study is motivated by the desire to achieve better signal-to-noise in the UVIS contamination and stability monitor, in which observations of standard stars in staring mode have been taken from the installation of WFC3 in 2009 to the present to assess temporal photometric stability. Higher signal to noise in this program would greatly benefit the sensitivity to detect contamination, and to better characterize the observed small throughput drifts over time. We find excellent repeatability between identical visits of program 14878, with sub 0.1% repeatability achieved in most filters. These! results support the initiative to transition the staring mode UVIS contamination and photometric stability monitor from staring mode images to spatial scans.

  7. Repeat surgery after failed midurethral slings

    DEFF Research Database (Denmark)

    Foss Hansen, Margrethe; Lose, Gunnar; Kesmodel, Ulrik Schiøler

    2016-01-01

    MUS from 1998 through 2007. The outcome was repeat surgery with any subsequent procedure code for urinary incontinence within a 5-year period of the first procedure. RESULTS: A total of 5,820 women (mean age 55.4 years, ± 12.1) were registered with a synthetic MUS, and 354 (6 %) underwent reoperation...

  8. EVOLUTION AND RECOMBINATION OF BOVINE DNA REPEATS

    NARCIS (Netherlands)

    JOBSE, C; BUNTJER, JB; HAAGSMA, N; BREUKELMAN, HJ; BEINTEMA, JJ; LENSTRA, JA

    1995-01-01

    The history of the abundant repeat elements in the bovine genome has been studied by comparative hybridization and PCR. The Bov-A and Bov-B SINE elements both emerged just after the divergence of the Camelidae and the true ruminants. A 31-bp subrepeat motif in satellites of the Bovidae species cattl

  9. Multivariate linear models and repeated measurements revisited

    DEFF Research Database (Denmark)

    Dalgaard, Peter

    2009-01-01

    Methods for generalized analysis of variance based on multivariate normal theory have been known for many years. In a repeated measurements context, it is most often of interest to consider transformed responses, typically within-subject contrasts or averages. Efficiency considerations leads...

  10. On balanced minimal repeated measurements designs

    Directory of Open Access Journals (Sweden)

    Shakeel Ahmad Mir

    2014-10-01

    Full Text Available Repeated Measurements designs are concerned with scientific experiments in which each experimental unit is assigned more than once to a treatment either different or identical. This class of designs has the property that the unbiased estimators for elementary contrasts among direct and residual effects are obtainable. Afsarinejad (1983 provided a method of constructing balanced Minimal Repeated Measurements designs p < t , when t is an odd or prime power, one or more than one treatment may occur more than once in some sequences and  designs so constructed no longer remain uniform in periods. In this paper an attempt has been made to provide a new method to overcome this drawback. Specifically, two cases have been considered                RM[t,n=t(t-t/(p-1,p], λ2=1 for balanced minimal repeated measurements designs and  RM[t,n=2t(t-t/(p-1,p], λ2=2 for balanced  repeated measurements designs. In addition , a method has been provided for constructing              extra-balanced minimal designs for special case RM[t,n=t2/(p-1,p], λ2=1.

  11. Repeated Nrf2 stimulation using sulforaphane protects fibroblasts from ionizing radiation.

    Science.gov (United States)

    Mathew, Sherin T; Bergström, Petra; Hammarsten, Ola

    2014-05-01

    Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA and reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2'-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Repeated toluene exposure increases c-Fos in catecholaminergic cells of the nucleus accumbens shell.

    Science.gov (United States)

    Tomaszycki, Michelle L; Aulerich, Kelsey E; Bowen, Scott E

    2013-01-01

    Toluene is a frequently abused solvent. Previous studies have suggested that toluene acts like other drugs of abuse, specifically on the dopaminergic system in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of the mesolimbic pathway. Although changes in dopamine (DA) levels and c-Fos have been observed in both acute and repeated exposure paradigms, the extent to which c-Fos is localized to catecholaminergic cells is unknown. The present study tested the effects of repeated toluene exposure (1000-4000ppm) on locomotor activity and cells containing c-Fos, tyrosine hydroxylase (TH), or both in the core and shell of the NAc, as well as the anterior and posterior VTA. We focused our study on adolescents, since adolescence is a time of great neural change and a time when individuals tend to be more susceptible to drug abuse. In early tests, toluene dose-dependently increased locomotor activity. Repeated exposure to the highest concentration of toluene resulted in sensitization to toluene's effects on locomotor activity. Although the number of cells immunopositive for c-Fos or TH did not significantly differ across groups, cells immunopositive for TH+c-Fos were higher in the NAc shell of animals exposed to 4000ppm than in animals exposed to air (control) or 1000ppm. Taken together, these findings demonstrate that repeated high dose toluene exposure increases locomotor activity as well as activation of catecholaminergic cells in the shell of the NAc. © 2013 Elsevier Inc. All rights reserved.

  13. RepeatsDB 2.0: improved annotation, classification, search and visualization of repeat protein structures

    Science.gov (United States)

    Paladin, Lisanna; Hirsh, Layla; Piovesan, Damiano; Andrade-Navarro, Miguel A.; Kajava, Andrey V.; Tosatto, Silvio C.E.

    2017-01-01

    RepeatsDB 2.0 (URL: http://repeatsdb.bio.unipd.it/) is an update of the database of annotated tandem repeat protein structures. Repeat proteins are a widespread class of non-globular proteins carrying heterogeneous functions involved in several diseases. Here we provide a new version of RepeatsDB with an improved classification schema including high quality annotations for ∼5400 protein structures. RepeatsDB 2.0 features information on start and end positions for the repeat regions and units for all entries. The extensive growth of repeat unit characterization was possible by applying the novel ReUPred annotation method over the entire Protein Data Bank, with data quality is guaranteed by an extensive manual validation for >60% of the entries. The updated web interface includes a new search engine for complex queries and a fully re-designed entry page for a better overview of structural data. It is now possible to compare unit positions, together with secondary structure, fold information and Pfam domains. Moreover, a new classification level has been introduced on top of the existing scheme as an independent layer for sequence similarity relationships at 40%, 60% and 90% identity. PMID:27899671

  14. Dose-Dependent Model of Caffeine Effects on Human Vigilance during Total Sleep Deprivation

    Science.gov (United States)

    2014-05-20

    Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation Sridhar Ramakrishnan a, Srinivas Laxminarayan a, Nancy J...We modeled the dose-dependent effects of caffeine on human vigilance. The model predicted the effects of both single and repeated caffeine doses...We developed and validated the model using two laboratory studies. Individual-specific caffeine models outperformed population-average models. a

  15. Utirik Atoll Dose Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Robison, W.L.; Conrado, C.L.; Bogen, K.T

    1999-10-06

    On March 1, 1954, radioactive fallout from the nuclear test at Bikini Atoll code-named BRAVO was deposited on Utirik Atoll which lies about 187 km (300 miles) east of Bikini Atoll. The residents of Utirik were evacuated three days after the fallout started and returned to their atoll in May 1954. In this report we provide a final dose assessment for current conditions at the atoll based on extensive data generated from samples collected in 1993 and 1994. The estimated population average maximum annual effective dose using a diet including imported foods is 0.037 mSv y{sup -1} (3.7 mrem y{sup -1}). The 95% confidence limits are within a factor of three of their population average value. The population average integrated effective dose over 30-, 50-, and 70-y is 0.84 mSv (84, mrem), 1.2 mSv (120 mrem), and 1.4 mSv (140 mrem), respectively. The 95% confidence limits on the population-average value post 1998, i.e., the 30-, 50-, and 70-y integral doses, are within a factor of two of the mean value and are independent of time, t, for t > 5 y. Cesium-137 ({sup 137}Cs) is the radionuclide that contributes most of this dose, mostly through the terrestrial food chain and secondarily from external gamma exposure. The dose from weapons-related radionuclides is very low and of no consequence to the health of the population. The annual background doses in the U. S. and Europe are 3.0 mSv (300 mrem), and 2.4 mSv (240 mrem), respectively. The annual background dose in the Marshall Islands is estimated to be 1.4 mSv (140 mrem). The total estimated combined Marshall Islands background dose plus the weapons-related dose is about 1.5 mSv y{sup -1} (150 mrem y{sup -1}) which can be directly compared to the annual background effective dose of 3.0 mSv y{sup -1} (300 mrem y{sup -1}) for the U. S. and 2.4 mSv y{sup -1} (240 mrem y{sup -1}) for Europe. Moreover, the doses listed in this report are based only on the radiological decay of {sup 137}Cs (30.1 y half-life) and other

  16. Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus.

    Science.gov (United States)

    Fan, Mingyue; Jin, Wei; Zhao, Haifeng; Xiao, Yining; Jia, Yanqiu; Yin, Yu; Jiang, Xin; Xu, Jing; Meng, Nan; Lv, Peiyuan

    2015-09-15

    Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.

  17. Method of dosing electrolyte in a sealed storage battery

    Energy Technology Data Exchange (ETDEWEB)

    Boldin, R.V.; Akbulatova, A.D.; Mel' nikova, T.A.; Perugina, T.P.

    1981-01-01

    A method is proposed for dosing electrolyte in a sealed storage battery by weighing the storage battery before pouring in the electrolyte, pouring in the electrolyte, forming, removing the surplus electrolyte, repeated weighing, calculation for the difference in the weight of the quantity of the remaining electrolyte and correction for the weight of the quantity of electrolyte according to theoretical calculations. In order to improve accuracy after repeated weighing, a measurement is made of the magnitude of free gas space of the storage battery and a volume of electrolyte is added until it reaches 90-95% of the degree of filling of the pores included in the volume of the gas space.

  18. 47 CFR 80.1179 - On-board repeater limitations.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false On-board repeater limitations. 80.1179 Section... On-board repeater limitations. When an on-board repeater is used, the following limitations must be met: (a) The on-board repeater antenna must be located no higher than 3 meters (10 feet) above...

  19. Assessment of internal doses

    CERN Document Server

    Rahola, T; Falk, R; Isaksson, M; Skuterud, L

    2002-01-01

    There is a definite need for training in dose calculation. Our first course was successful and was followed by a second, both courses were fully booked. An example of new tools for software products for bioassay analysis and internal dose assessment is the Integrated Modules for Bioassay Analysis (IMBA) were demonstrated at the second course. This suite of quality assured code modules have been adopted in the UK as the standard for regulatory assessment purposes. The intercomparison measurements are an important part of the Quality Assurance work. In what is known as the sup O utside workers ' directive it is stated that the internal dose measurements shall be included in the European Unions supervision system for radiation protection. The emergency preparedness regarding internal contamination was much improved by the training with and calibration of handheld instruments from participants' laboratories. More improvement will be gained with the handbook giving practical instructions on what to do in case of e...

  20. Effect of delayed anthrax vaccine dose on Bacillus anthracis protective antigen IgG response and lethal toxin neutralization activity.

    Science.gov (United States)

    Pittman, Phillip R; Fisher, Diana; Quinn, Xiaofei; Schmader, Trevor; Barrera-Oro, Julio G

    2013-10-17

    We describe the Bacillus anthracis protective antigen IgG antibody response and the B. anthracis lethal toxin neutralization activity to a delayed dose of anthrax vaccine adsorbed (AVA, BioThrax(®)) using validated assays. 373 individuals received 1, 2, or 3 priming doses, 18-24 months afterward, they received a delayed dose of AVA. Overall, 23.6% of subjects showed detectable anti-PA IgG before the boost, compared to 99.2% (P<0.0001) 28 days after the boost. Geometric mean anti-PA IgG concentration (GMC) was 1.66 μg/mL before and 887.82 μg/mL after the boost (P<0.0001). The proportion of individuals with four-fold increase in GMC following the boost ranged from 93.8% to 100%. Robust anti-PA IgG levels and B. anthracis lethal toxin neutralization activity are induced when an AVA dose is delayed as long as two years. These data support continuing with the vaccination schedule when a dose is delayed as long as two years rather than restarting the series.

  1. Dose Reduction Techniques

    Energy Technology Data Exchange (ETDEWEB)

    WAGGONER, L.O.

    2000-05-16

    As radiation safety specialists, one of the things we are required to do is evaluate tools, equipment, materials and work practices and decide whether the use of these products or work practices will reduce radiation dose or risk to the environment. There is a tendency for many workers that work with radioactive material to accomplish radiological work the same way they have always done it rather than look for new technology or change their work practices. New technology is being developed all the time that can make radiological work easier and result in less radiation dose to the worker or reduce the possibility that contamination will be spread to the environment. As we discuss the various tools and techniques that reduce radiation dose, keep in mind that the radiological controls should be reasonable. We can not always get the dose to zero, so we must try to accomplish the work efficiently and cost-effectively. There are times we may have to accept there is only so much you can do. The goal is to do the smart things that protect the worker but do not hinder him while the task is being accomplished. In addition, we should not demand that large amounts of money be spent for equipment that has marginal value in order to save a few millirem. We have broken the handout into sections that should simplify the presentation. Time, distance, shielding, and source reduction are methods used to reduce dose and are covered in Part I on work execution. We then look at operational considerations, radiological design parameters, and discuss the characteristics of personnel who deal with ALARA. This handout should give you an overview of what it takes to have an effective dose reduction program.

  2. Stability of dental waxes following repeated heatings.

    Science.gov (United States)

    Kotsiomiti, E; McCabe, J F

    1995-02-01

    The flow and strength properties of dental waxes were examined following excessive and repeated heatings of the materials. For one product, the flow at 40 +/- 0.5 degrees C was reduced by 25.3% following heating above 200 degrees C. A decrease of the elastic modulus at 20 +/- 1 degree C by approximately 66% was observed in some cases after the heating temperature had been increased to 300 degrees C. Property variations were related to compositional changes, which were investigated by infrared spectoscopy and thermal analysis. Exposure of dental waxes to temperatures higher than 200 degrees C, particularly if it is repeated, may affect the composition and properties, resulting in inferior materials.

  3. Learning with repeated-game strategies.

    Science.gov (United States)

    Ioannou, Christos A; Romero, Julian

    2014-01-01

    We use the self-tuning Experience Weighted Attraction model with repeated-game strategies as a computer testbed to examine the relative frequency, speed of convergence and progression of a set of repeated-game strategies in four symmetric 2 × 2 games: Prisoner's Dilemma, Battle of the Sexes, Stag-Hunt, and Chicken. In the Prisoner's Dilemma game, we find that the strategy with the most occurrences is the "Grim-Trigger." In the Battle of the Sexes game, a cooperative pair that alternates between the two pure-strategy Nash equilibria emerges as the one with the most occurrences. In the Stag-Hunt and Chicken games, the "Win-Stay, Lose-Shift" and "Grim-Trigger" strategies are the ones with the most occurrences. Overall, the pairs that converged quickly ended up at the cooperative outcomes, whereas the ones that were extremely slow to reach convergence ended up at non-cooperative outcomes.

  4. Learning With Repeated-Game Strategies

    Directory of Open Access Journals (Sweden)

    Christos A. Ioannou

    2014-07-01

    Full Text Available We use the self-tuning Experience Weighted Attraction model with repeated-game strategies as a computer testbed to examine the relative frequency, speed of convergence and progression of a set of repeated-game strategies in four symmetric 2x2 games: Prisoner's Dilemma, Battle of the Sexes, Stag-Hunt, and Chicken. In the Prisoner's Dilemma game, we fi□nd that the strategy with the most occurrences is the Grim-Trigger. In the Battle of the Sexes game, a cooperative pair that alternates between the two pure-strategy Nash equilibria emerges as the one with the most occurrences. In the Stag-Hunt and Chicken games, the Win-Stay, Lose-Shift and Grim-Trigger strategies are the ones with the most occurrences. Overall, the pairs that converged quickly ended up at the cooperative outcomes, whereas the ones that were extremely slow to reach convergence ended up at non-cooperative outcomes.

  5. Quantum repeaters with entangled coherent states

    CERN Document Server

    Sangouard, Nicolas; Gisin, Nicolas; Laurat, Julien; Tualle-Brouri, Rosa; Grangier, Philippe

    2009-01-01

    Entangled coherent states can be prepared remotely by subtracting non-locally a single photon from two quantum superpositions of coherent states, the so-called "Schroedinger's cat" state. Such entanglement can further be distributed over longer distances by successive entanglement swapping operations using linear optics and photon-number resolving detectors. The aim of this paper is to evaluate the performance of this approach to quantum repeaters for long distance quantum communications. Despite many attractive features at first sight, we show that, when using state-of-the-art photon counters and quantum memories, they do not achieve higher entanglement generation rates than repeaters based on single-photon entanglement. We discuss potential developments which may take better advantage of the richness of entanglement based on continuous variables, including in particular efficient parity measurements.

  6. Quantum repeaters based on heralded qubit amplifiers

    CERN Document Server

    Minář, Jiří; Sangouard, Nicolas

    2011-01-01

    We present a quantum repeater scheme based on the recently proposed qubit amplifier [N. Gisin, S. Pironio and N. Sangouard, Phys. Rev. Lett. 105, 070501 (2010)]. It relies on a on-demand entangled-photon pair source which uses on-demand single-photon sources, linear optical elements and atomic ensembles. Interestingly, the imperfections affecting the states created from this source, caused e.g. by detectors with non-unit efficiencies, are systematically purified from an entanglement swapping operation based on a two-photon detection. This allows the distribution of entanglement over very long distances with a high fidelity, i.e. without vacuum components and multiphoton errors. Therefore, the resulting quantum repeater architecture does not necessitate final postselections and thus achieves high entanglement distribution rates. This also provides unique opportunities for device-independent quantum key distribution over long distances with linear optics and atomic ensembles.

  7. Nonparametric additive regression for repeatedly measured data

    KAUST Repository

    Carroll, R. J.

    2009-05-20

    We develop an easily computed smooth backfitting algorithm for additive model fitting in repeated measures problems. Our methodology easily copes with various settings, such as when some covariates are the same over repeated response measurements. We allow for a working covariance matrix for the regression errors, showing that our method is most efficient when the correct covariance matrix is used. The component functions achieve the known asymptotic variance lower bound for the scalar argument case. Smooth backfitting also leads directly to design-independent biases in the local linear case. Simulations show our estimator has smaller variance than the usual kernel estimator. This is also illustrated by an example from nutritional epidemiology. © 2009 Biometrika Trust.

  8. Repeat-PPM Super-Symbol Synchronization

    Science.gov (United States)

    Connelly, J.

    2016-11-01

    To attain a wider range of data rates in pulse position modulation (PPM) schemes with constrained pulse durations, the sender can repeat a PPM symbol multiple times, forming a super-symbol. In addition to the slot and symbol synchronization typically required for PPM, the receiver must also properly align the noisy super-symbols. We present a low-complexity approximation of the maximum-likelihood method for performing super-symbol synchronization without use of synchronization sequences. We provide simulation results demonstrating performance advantage when PPM symbols are spread by a pseudo-noise sequence, as opposed to simply repeating. Additionally, the results suggest that this super-symbol synchronization technique requires signal levels below those required for reliable communication. This validates that the PPM spreading approach proposed to CCSDS can work properly as part of the overall scheme.

  9. High-bandwidth hybrid quantum repeater.

    Science.gov (United States)

    Munro, W J; Van Meter, R; Louis, Sebastien G R; Nemoto, Kae

    2008-07-25

    We present a physical- and link-level design for the creation of entangled pairs to be used in quantum repeater applications where one can control the noise level of the initially distributed pairs. The system can tune dynamically, trading initial fidelity for success probability, from high fidelity pairs (F=0.98 or above) to moderate fidelity pairs. The same physical resources that create the long-distance entanglement are used to implement the local gates required for entanglement purification and swapping, creating a homogeneous repeater architecture. Optimizing the noise properties of the initially distributed pairs significantly improves the rate of generating long-distance Bell pairs. Finally, we discuss the performance trade-off between spatial and temporal resources.

  10. Haematotoxic and reproductive toxicity of fixed dose combined anti-tuberculous agents: protective role of antioxidants in rats.

    Science.gov (United States)

    Awodele, O; Osunkalu, V O; Adejumo, I A; Odeyemi, A A; Ebuehi, O A T; Akintonwa, A

    2013-01-01

    Tuberculosis (TB) is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS. The major problem militating against the management of tuberculosis is the lack of compliance to medication by the infected patients as a result of multidrug needed to be taking daily leading to resistance. Occurrences of hepatic toxicity, teratogenicity, sperm quality damage, haematotoxicity and meningeal congestion of individual anti-tuberculous agents have been reported. The study is aimed to determine the reproductive and haematological toxicity of combined antituberculous agents and the modulatory role of antioxidants using animal model. Fifty rats (10 per group) were randomly allotted to five groups, consisting of the control, the fixed dose combined anti TB agents treated group, the fixed dose combined anti TB agents plus vitamin C treated group, the fixed dose combined anti TB agents plus vitamin E treated group and the fixed dose combined anti TB agents plus vitamin C plus vitamin E treated group. Therapeutic doses of the fixed dose combined anti TB agents (25 mg/kg/day), vitamin E (5 mg/kg) and vitamin C (8 mg/kg) were administered to the animals via oral gavage, daily over 28 days. After 28days, rats were sacrificed for internal macroscopic and histological examination of the organs, sperm analysis and haematological investigations were carried out. The results showed a significant increase (p < or = 0.05) in the levels of white blood cells (WBC), red blood cell (RBC) and haemoglobin (HB) of the combined anti-TB plus vitamins C or E treated groups compared with combined anti-TB treated group alone (56.34 +/- 0.11) that decreased the haematological parameters. A significant decrease (p < or = 0.05) in the sperm counts (22.26 +/- 0.02; 35.40 +/- 0.02) and motility (77.03 +/- 0.02; 94.50 +/- 0.01) of the combined anti-TB treated rats as compared with the control group were observed. The combined anti-TB plus

  11. Do Gamma-Ray Burst Sources Repeat?

    OpenAIRE

    Meegan, Charles A.; Hartmann, Dieter H.; Brainerd, J. J.; Briggs, Michael S.; Paciesas, William S.; Pendleton, Geoffrey; Kouveliotou, Chryssa; Fishman, Gerald; Blumenthal, George; Brock, Martin

    1995-01-01

    The demonstration of repeated gamma-ray bursts from an individual source would severely constrain burst source models. Recent reports (Quashnock and Lamb 1993; Wang and Lingenfelter 1993) of evidence for repetition in the first BATSE burst catalog have generated renewed interest in this issue. Here, we analyze the angular distribution of 585 bursts of the second BATSE catalog (Meegan et al. 1994). We search for evidence of burst recurrence using the nearest and farthest neighbor statistic and...

  12. 2D Metals by Repeated Size Reduction.

    Science.gov (United States)

    Liu, Hanwen; Tang, Hao; Fang, Minghao; Si, Wenjie; Zhang, Qinghua; Huang, Zhaohui; Gu, Lin; Pan, Wei; Yao, Jie; Nan, Cewen; Wu, Hui

    2016-10-01

    A general and convenient strategy for manufacturing freestanding metal nanolayers is developed on large scale. By the simple process of repeatedly folding and calendering stacked metal sheets followed by chemical etching, free-standing 2D metal (e.g., Ag, Au, Fe, Cu, and Ni) nanosheets are obtained with thicknesses as small as 1 nm and with sizes of the order of several micrometers.

  13. Repeatability and Workability Evaluation of SIGMOD 2011

    DEFF Research Database (Denmark)

    Bonnet, Philippe

    2011-01-01

    SIGMOD has offered, since 2008, to verify the experiments published in the papers accepted at the conference. This year, we have been in charge of reproducing the experiments provided by the authors (repeatability), and exploring changes to experiment parameters (workability). In this paper, we a...... find that most experiments are distributed as Linux packages accompanied by instructions on how to setup and run the experiments. We are still far from the vision of executable papers...

  14. Repeatability of Response to Asthma Medications

    Science.gov (United States)

    Wu, Ann; Tantisira, Kelan; Li, Lingling; Schuemann, Brooke; Weiss, Scott

    2010-01-01

    Background Pharmacogenetic studies of drug response in asthma assume that patients respond consistently to a treatment but that treatment response varies across patients, however, no formal studies have demonstrated this. Objective To determine the repeatability of commonly used outcomes for treatment response to asthma medications: bronchodilator response, forced expiratory volume in 1 second (FEV1), and provocative concentration of methacholine producing a 20% decline in FEV1 (PC20). Methods The Childhood Asthma Management Program (CAMP) was a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo. We determined the intraclass correlation coefficient (ICC) for each outcome over repeated visits over four years in CAMP using mixed effects regression models. We adjusted for the covariates: age, race/ethnicity, height, family income, parental education, and symptom score. We incorporated each outcome for each child as repeated outcome measurements and stratified by treatment group. Results The ICC for bronchodilator response was 0.31 in the budesonide group, 0.35 in the nedocromil group, and 0.40 in the placebo group, after adjusting for covariates. The ICC for FEV1 was 0.71 in the budesonide group, 0.60 in the nedocromil group, and 0.69 in the placebo group, after adjusting for covariates. The ICC for PC20 was 0.67 in the budesonide and placebo groups and 0.73 in the nedocromil group, after adjusting for covariates. Conclusion The within treatment group repeatability of FEV1 and PC20 are high; thus these phenotypes are heritable. FEV1 and PC20 may be better phenotypes than bronchodilator response for studies of treatment response in asthma. PMID:19064281

  15. Repeated extraction of DNA from FTA cards

    DEFF Research Database (Denmark)

    Stangegaard, Michael; Ferrero, Laura; Børsting, Claus

    2011-01-01

    Extraction of DNA using magnetic bead based techniques on automated DNA extraction instruments provides a fast, reliable and reproducible method for DNA extraction from various matrices. However, the yield of extracted DNA from FTA-cards is typically low. Here, we demonstrate that it is possible...... to repeatedly extract DNA from the processed FTA-disk. The method increases the yield from the nanogram range to the microgram range....

  16. Repeated extraction of DNA from FTA cards

    OpenAIRE

    Stangegaard, Michael; Ferrero, Laura; Børsting, Claus; Frank-Hansen, Rune; Hansen, Anders Johannes; Morling, Niels

    2011-01-01

    Extraction of DNA using magnetic bead based techniques on automated DNA extraction instruments provides a fast, reliable and reproducible method for DNA extraction from various matrices. However, the yield of extracted DNA from FTA-cards is typically low. Here, we demonstrate that it is possible to repeatedly extract DNA from the processed FTA-disk. The method increases the yield from the nanogram range to the microgram range.

  17. Repeated extraction of DNA from FTA cards

    DEFF Research Database (Denmark)

    Stangegaard, Michael; Ferrero, Laura; Børsting, Claus

    2011-01-01

    Extraction of DNA using magnetic bead based techniques on automated DNA extraction instruments provides a fast, reliable and reproducible method for DNA extraction from various matrices. However, the yield of extracted DNA from FTA-cards is typically low. Here, we demonstrate that it is possible...... to repeatedly extract DNA from the processed FTA-disk. The method increases the yield from the nanogram range to the microgram range....

  18. A Central Limit Theorem for Repeating Patterns

    CERN Document Server

    Abrams, Aaron; Landau, Henry; Landau, Zeph; Pommersheim, James

    2012-01-01

    This note gives a central limit theorem for the length of the longest subsequence of a random permutation which follows some repeating pattern. This includes the case of any fixed pattern of ups and downs which has at least one of each, such as the alternating case considered by Stanley in [2] and Widom in [3]. In every case considered the convergence in the limit of long permutations is to normal with mean and variance linear in the length of the permutations.

  19. Repeatability and Workability Evaluation of SIGMOD 2011

    DEFF Research Database (Denmark)

    Bonnet, Philippe

    2011-01-01

    SIGMOD has offered, since 2008, to verify the experiments published in the papers accepted at the conference. This year, we have been in charge of reproducing the experiments provided by the authors (repeatability), and exploring changes to experiment parameters (workability). In this paper, we a...... find that most experiments are distributed as Linux packages accompanied by instructions on how to setup and run the experiments. We are still far from the vision of executable papers...

  20. Epigenetics and Triplet-Repeat Neurological Diseases

    OpenAIRE

    Nageshwaran, Sathiji; Festenstein, Richard

    2015-01-01

    The term “junk DNA” has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions f...

  1. Epigenetics and triplet repeat neurological diseases

    OpenAIRE

    Sathiji eNageshwaran; Richard eFestenstein

    2015-01-01

    The term ‘junk DNA’ has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterchromatinised resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions fr...

  2. Repeated-sprint ability and aerobic fitness.

    Science.gov (United States)

    Thébault, Nicolas; Léger, Luc A; Passelergue, Philippe

    2011-10-01

    The purpose of this study was to reinvestigate the relationship between aerobic fitness and fatigue indices of repeated-sprint ability (RSA), with special attention to methodological normalization. Soldiers were divided into low (n = 10) and high (n = 9) fitness groups according to a preset maximal aerobic speed (MAS) of 17 km·h(-1) (∼60 ml O2·kg(-1)·min) measured with the University of Montreal Track Test (UMTT). Subjects' assessment included the RSA test (3 sets of 5 40-m sprints with 1-minute rest between sprints and 1.5 minutes between sets), a 40-m sprint (criterion test used in the computation of fatigue indices for the RSA test), strength and power measurement of the lower limbs, and the 20-m shuttle run test (20-m SRT) and the UMTT, which are measures of maximal aerobic power. The highest correlation with the RSA fatigue indices was obtained with the 20-m SRT (r = 0.90, p = 0.0001, n = 19), a test with 180° direction changes and accelerations and decelerations. The lower correlation (r = 0.66, p repeated sprints and achieved better recovery between series. A MAS of at least 17 km·h(-1) favors constant and high speed level during repeated sprints. From a practical point of view, a high aerobic fitness is a precious asset in counteracting fatigue in sports with numerous sprint repetitions.

  3. Histone deacetylase complexes promote trinucleotide repeat expansions.

    Directory of Open Access Journals (Sweden)

    Kim Debacker

    2012-02-01

    Full Text Available Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor expansions. The inference is that expansions arise due to the presence of these promoting proteins, not their absence, and that interfering with these proteins can suppress expansions. The goal of this study was to identify novel factors that promote expansions. We discovered that specific histone deacetylase complexes (HDACs promote CTG•CAG repeat expansions in budding yeast and human cells. Mutation or inhibition of yeast Rpd3L or Hda1 suppressed up to 90% of expansions. In cultured human astrocytes, expansions were suppressed by 75% upon inhibition or knockdown of HDAC3, whereas siRNA against the histone acetyltransferases CBP/p300 stimulated expansions. Genetic and molecular analysis both indicated that HDACs act at a distance from the triplet repeat to promote expansions. Expansion assays with nuclease mutants indicated that Sae2 is one of the relevant factors regulated by Rpd3L and Hda1. The causal relationship between HDACs and expansions indicates that HDACs can promote mutagenesis at some DNA sequences. This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression.

  4. Landauer's Principle in Repeated Interaction Systems

    Science.gov (United States)

    Hanson, Eric P.; Joye, Alain; Pautrat, Yan; Raquépas, Renaud

    2017-01-01

    We study Landauer's Principle for Repeated Interaction Systems (RIS) consisting of a reference quantum system S in contact with a structured environment E made of a chain of independent quantum probes; S interacts with each probe, for a fixed duration, in sequence. We first adapt Landauer's lower bound, which relates the energy variation of the environment E to a decrease of entropy of the system S during the evolution, to the peculiar discrete time dynamics of RIS. Then we consider RIS with a structured environment E displaying small variations of order {T^{-1}} between the successive probes encountered by S, after {n ˜eq T} interactions, in keeping with adiabatic scaling. We establish a discrete time non-unitary adiabatic theorem to approximate the reduced dynamics of S in this regime, in order to tackle the adiabatic limit of Landauer's bound. We find that saturation of Landauer's bound is related to a detailed balance condition on the repeated interaction system, reflecting the non-equilibrium nature of the repeated interaction system dynamics. This is to be contrasted with the generic saturation of Landauer's bound known to hold for continuous time evolution of an open quantum system interacting with a single thermal reservoir in the adiabatic regime.

  5. A Unified Model for Repeating and Non-repeating Fast Radio Bursts

    Science.gov (United States)

    Bagchi, Manjari

    2017-04-01

    The model that fast radio bursts (FRBs) are caused by plunges of asteroids onto neutron stars can explain both repeating and non-repeating bursts. If a neutron star passes through an asteroid belt around another star, there would be a series of bursts caused by a series of asteroid impacts. Moreover, the neutron star would cross the same belt repetitively if it were in a binary with the star hosting the asteroid belt, leading to a repeated series of bursts. I explore the properties of neutron star binaries that could lead to the only known repeating FRB so far (FRB121102). In this model, the next two epochs of bursts are expected around 2017 February 27 and 2017 December 18. On the other hand, if the asteroid belt is located around the neutron star itself, then a chance fall of an asteroid from that belt onto the neutron star would lead to a non-repeating burst. Even a neutron star grazing an asteroid belt can lead to a non-repeating burst caused by just one asteroid plunge during the grazing. This is possible even when the neutron star is in a binary with the asteroid-hosting star, if the belt and the neutron star orbit are non-coplanar.

  6. Dose Reduction Techniques

    CERN Document Server

    Waggoner, L O

    2000-01-01

    As radiation safety specialists, one of the things we are required to do is evaluate tools, equipment, materials and work practices and decide whether the use of these products or work practices will reduce radiation dose or risk to the environment. There is a tendency for many workers that work with radioactive material to accomplish radiological work the same way they have always done it rather than look for new technology or change their work practices. New technology is being developed all the time that can make radiological work easier and result in less radiation dose to the worker or reduce the possibility that contamination will be spread to the environment. As we discuss the various tools and techniques that reduce radiation dose, keep in mind that the radiological controls should be reasonable. We can not always get the dose to zero, so we must try to accomplish the work efficiently and cost-effectively. There are times we may have to accept there is only so much you can do. The goal is to do the sm...

  7. T dose Vaccine Policy

    African Journals Online (AJOL)

    National Programme of Immunization (NPI), measles remains a disturbing cause ... or as a supplement is expected to offer a second opportunity to children who ... available in 1963, the world welcomed it with joy .... one dose of vaccine were not always protected from .... begins a long story Starting now is still early enough.

  8. Absorption, distribution, metabolism and excretion of selenium following oral administration of elemental selenium nanoparticles or selenite in rats

    DEFF Research Database (Denmark)

    Löschner, Katrin; Hadrup, Niels; Hansen, Marianne

    2014-01-01

    A suspension of nanoparticles of BSA-stabilized red amorphous elemental selenium (Se) or an aqueous solution of sodium selenite was repeatedly administered by oral gavage for 28 days at 0.05 mg/kg bw/day (low dose) or at 0.5 mg/kg bw/day (high dose) as Se to female rats. Prior to administration...

  9. Dose-dependent effects of a soluble dietary fibre (pectin on food intake, adiposity, gut hypertrophy and gut satiety hormone secretion in rats.

    Directory of Open Access Journals (Sweden)

    Clare L Adam

    Full Text Available Soluble fermentable dietary fibre elicits gut adaptations, increases satiety and potentially offers a natural sustainable means of body weight regulation. Here we aimed to quantify physiological responses to graded intakes of a specific dietary fibre (pectin in an animal model. Four isocaloric semi-purified diets containing 0, 3.3%, 6.7% or 10% w/w apple pectin were offered ad libitum for 8 or 28 days to young adult male rats (n = 8/group. Measurements were made of voluntary food intake, body weight, initial and final body composition by magnetic resonance imaging, final gut regional weights and histology, and final plasma satiety hormone concentrations. In both 8- and 28-day cohorts, dietary pectin inclusion rate was negatively correlated with food intake, body weight gain and the change in body fat mass, with no effect on lean mass gain. In both cohorts, pectin had no effect on stomach weight but pectin inclusion rate was positively correlated with weights and lengths of small intestine and caecum, jejunum villus height and crypt depth, ileum crypt depth, and plasma total glucagon-like peptide-1 (GLP-1 and peptide tyrosine tyrosine (PYY concentrations, and at 8 days was correlated with weight and length of colon and with caecal mucosal depth. Therefore, the gut's morphological and endocrine adaptations were dose-dependent, occurred within 8 days and were largely sustained for 28 days during continued dietary intervention. Increasing amounts of the soluble fermentable fibre pectin in the diet proportionately decreased food intake, body weight gain and body fat content, associated with proportionately increased satiety hormones GLP-1 and PYY and intestinal hypertrophy, supporting a role for soluble dietary fibre-induced satiety in healthy body weight regulation.

  10. Ultraviolet radiation therapy and UVR dose models

    Energy Technology Data Exchange (ETDEWEB)

    Grimes, David Robert, E-mail: davidrobert.grimes@oncology.ox.ac.uk [School of Physical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland and Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratory, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ (United Kingdom)

    2015-01-15

    Ultraviolet radiation (UVR) has been an effective treatment for a number of chronic skin disorders, and its ability to alleviate these conditions has been well documented. Although nonionizing, exposure to ultraviolet (UV) radiation is still damaging to deoxyribonucleic acid integrity, and has a number of unpleasant side effects ranging from erythema (sunburn) to carcinogenesis. As the conditions treated with this therapy tend to be chronic, exposures are repeated and can be high, increasing the lifetime probability of an adverse event or mutagenic effect. Despite the potential detrimental effects, quantitative ultraviolet dosimetry for phototherapy is an underdeveloped area and better dosimetry would allow clinicians to maximize biological effect whilst minimizing the repercussions of overexposure. This review gives a history and insight into the current state of UVR phototherapy, including an overview of biological effects of UVR, a discussion of UVR production, illness treated by this modality, cabin design and the clinical implementation of phototherapy, as well as clinical dose estimation techniques. Several dose models for ultraviolet phototherapy are also examined, and the need for an accurate computational dose estimation method in ultraviolet phototherapy is discussed.

  11. Dose reduction in molecular breast imaging

    Science.gov (United States)

    Wagenaar, Douglas J.; Chowdhury, Samir; Hugg, James W.; Moats, Rex A.; Patt, Bradley E.

    2011-10-01

    Molecular Breast Imaging (MBI) is the imaging of radiolabeled drugs, cells, or nanoparticles for breast cancer detection, diagnosis, and treatment. Screening of broad populations of women for breast cancer with mammography has been augmented by the emergence of breast MRI in screening of women at high risk for breast cancer. Screening MBI may benefit the sub-population of women with dense breast tissue that obscures small tumors in mammography. Dedicated breast imaging equipment is necessary to enable detection of early-stage tumors less than 1 cm in size. Recent progress in the development of these instruments is reviewed. Pixellated CZT for single photon MBI imaging of 99mTc-sestamibi gives high detection sensitivity for early-stage tumors. The use of registered collimators in a near-field geometry gives significantly higher detection efficiency - a factor of 3.6-, which translates into an equivalent dose reduction factor given the same acquisition time. The radiation dose in the current MBI procedure has been reduced to the level of a four-view digital mammography study. In addition to screening of selected sub-populations, reduced MBI dose allows for dual-isotope, treatment planning, and repeated therapy assessment studies in the era of molecular medicine guided by quantitative molecular imaging.

  12. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    Science.gov (United States)

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-01-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans. PMID:1637802

  13. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    Science.gov (United States)

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-06-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans.

  14. Comparison of creatine monohydrate and carbohydrate supplementation on repeated jump height performance.

    Science.gov (United States)

    Koenig, Chad A; Benardot, Dan; Cody, Mildred; Thompson, Walter R

    2008-07-01

    Creatine monohydrate (CrMH) supplementation aids the ability to maintain performance during repeated bouts of high-intensity exercise, including jump performance. However, carbohydrate supplementation may also provide similar benefits and is less expensive. This study compared the effects of an energy-free placebo, 2 different caloric concentrations of carbohydrate drinks, and a CrMH supplement on repeated jump heights. Sixty active males (mean age, 22 +/- 3.2 years) performed 2 sets of countermovement static jump height tests (10 jumps over 60 seconds) separated by 5 days to determine the differential effects of the placebo, carbohydrate, and CrMH on jump height sustainability over 10 jumps. Subjects were randomly assigned to groups (15 subjects per group) to receive daily doses (x5 days) of carbohydrate drinks containing 100 or 250 kilocalories (kcal), a 25-g CrMH supplement, or an energy-free placebo. After 5 days, the CrMH group experienced a significant weight gain (+1.52; +/-0.89 kg, p energy-free placebo over the final 3-4 jumps. The 250-kcal carbohydrate-supplemented group experienced a level of benefit (p < 0.01) that was at least equal to that of the CrMH group (p < 0.05), suggesting that the higher dose of carbohydrate was as effective as CrMH in maintaining repeated bouts of high-intensity activity as measured by repeated static jumps. Given the equivalent performance improvement and the absence of weight gain, the carbohydrate supplementation could be considered the preferred option for weight-conscious power athletes involved in activities that require repeated- motion high-intensity activities.

  15. Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice.

    Science.gov (United States)

    Thelen, Connor; Sens, Jonathon; Mauch, Joseph; Pandit, Radhika; Pitychoutis, Pothitos M

    2016-10-01

    One of the most striking discoveries in the treatment of major depression was the finding that infusion of a single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant effects in treatment-resistant depressed patients. However, ketamine's antidepressant-like actions are transient and can only be sustained by repeated drug treatment. Despite the fact that women experience major depression at roughly twice the rate of men, research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Importantly, knowledge regarding the sex-differentiated effects, the frequency and the dose on which repeated ketamine administration stops being beneficial, is limited. In the current study, we investigated the behavioral, neurochemical and synaptic molecular effects of repeated ketamine treatment (10mg/kg; 21days) in male and female C57BL/6J mice. We report that ketamine induced beneficial antidepressant-like effects in male mice, but induced both anxiety-like (i.e., decreased time spent in the center of the open field arena) and depressive-like effects (i.e., enhanced immobility duration in the forced swim test; FST) in their female counterparts. Moreover, repeated ketamine treatment induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice. Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice, and thus, present data have far-reaching implications for the sex-oriented use of ketamine in both experimental and clinical research settings.

  16. Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ware, J.H.; Rusek, A.; Sanzari, J.; Avery, S.; Sayers, C.; Krigsfeld, G.; Nuth, M.; Wan, X.S.; Kennedy, A.R.

    2010-09-01

    The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

  17. Repeatability and Reproducibility of Virtual Subjective Refraction.

    Science.gov (United States)

    Perches, Sara; Collados, M Victoria; Ares, Jorge

    2016-10-01

    To establish the repeatability and reproducibility of a virtual refraction process using simulated retinal images. With simulation software, aberrated images corresponding with each step of the refraction process were calculated following the typical protocol of conventional subjective refraction. Fifty external examiners judged simulated retinal images until the best sphero-cylindrical refraction and the best visual acuity were achieved starting from the aberrometry data of three patients. Data analyses were performed to assess repeatability and reproducibility of the virtual refraction as a function of pupil size and aberrometric profile of different patients. SD values achieved in three components of refraction (M, J0, and J45) are lower than 0.25D in repeatability analysis. Regarding reproducibility, we found SD values lower than 0.25D in the most cases. When the results of virtual refraction with different pupil diameters (4 and 6 mm) were compared, the mean of differences (MoD) obtained were not clinically significant (less than 0.25D). Only one of the aberrometry profiles with high uncorrected astigmatism shows poor results for the M component in reproducibility and pupil size dependence analysis. In all cases, vision achieved was better than 0 logMAR. A comparison between the compensation obtained with virtual and conventional subjective refraction was made as an example of this application, showing good quality retinal images in both processes. The present study shows that virtual refraction has similar levels of precision as conventional subjective refraction. Moreover, virtual refraction has also shown that when high low order astigmatism is present, the refraction result is less precise and highly dependent on pupil size.

  18. Oxygen uptake during repeated-sprint exercise.

    Science.gov (United States)

    McGawley, Kerry; Bishop, David J

    2015-03-01

    Repeated-sprint ability appears to be influenced by oxidative metabolism, with reductions in fatigue and improved sprint times related to markers of aerobic fitness. The aim of the current study was to measure the oxygen uptake (VO₂) during the first and last sprints during two, 5 × 6-s repeated-sprint bouts. Cross-sectional study. Eight female soccer players performed two, consecutive, 5 × 6-s maximal sprint bouts (B1 and B2) on five separate occasions, in order to identify the minimum time (trec) required to recover total work done (Wtot) in B1. On a sixth occasion, expired air was collected during the first and last sprint of B1 and B2, which were separated by trec. The trec was 10.9 ± 1.1 min. The VO₂ during the first sprint was significantly less than the last sprint in each bout (psprint (measured in kJ) was significantly related to VO₂max in both B1 (r=0.81, p=0.015) and B2 (r=0.93, p=0.001). In addition, the VO₂ attained in the final sprint was not significantly different from VO₂max in B1 (p=0.284) or B2 (p=0.448). The current study shows that the VO₂ increases from the first to the last of 5 × 6-s sprints and that VO₂max may be a limiting factor to performance in latter sprints. Increasing V˙O₂max in team-sport athletes may enable increased aerobic energy delivery, and consequently work done, during a bout of repeated sprints. Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  19. Doses from radiation exposure

    CERN Document Server

    Menzel, H G

    2012-01-01

    Practical implementation of the International Commission on Radiological Protection's (ICRP) system of protection requires the availability of appropriate methods and data. The work of Committee 2 is concerned with the development of reference data and methods for the assessment of internal and external radiation exposure of workers and members of the public. This involves the development of reference biokinetic and dosimetric models, reference anatomical models of the human body, and reference anatomical and physiological data. Following ICRP's 2007 Recommendations, Committee 2 has focused on the provision of new reference dose coefficients for external and internal exposure. As well as specifying changes to the radiation and tissue weighting factors used in the calculation of protection quantities, the 2007 Recommendations introduced the use of reference anatomical phantoms based on medical imaging data, requiring explicit sex averaging of male and female organ-equivalent doses in the calculation of effecti...

  20. Entrance surface dose according to dose calculation: Head and wrist

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Ho Jin [Dept. Radiology, Chonnam National University Hospital, Gwangju (Korea, Republic of); Han, Jae Bok; Song, Jong Nam; Choi, Nam Gil [Dept. of Radiological Science, Dongshin University, Naju (Korea, Republic of)

    2016-09-15

    This study were compared with the direct measurement and indirect dose methods through various dose calculation in head and wrist. And, the modified equation was proposed considering equipment type, setting conditions, tube voltage, inherent filter, added filter and its accompanied back scatter factor. As a result, it decreased the error of the direct measurement than the existing dose calculation. Accordingly, diagnostic radiography patient dose comparison would become easier and radiographic exposure control and evaluation will become more efficient. The study findings are expected to be useful in patients' effective dose rate evaluation and dose reduction.

  1. Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Greiff Lennart

    2012-06-01

    Full Text Available Abstract Background Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective To evaluate the efficacy and safety of intranasal AZD8848. Methods In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779. In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003. Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. Conclusions Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. Trial registration NCT00688779 and NCT00770003 as indicated above.

  2. First dose in man

    DEFF Research Database (Denmark)

    2011-01-01

    Du er blevet ansat som læge i et lægemiddelfirma med ansvar for planlægning og sikkerhed i fase 1 forsøg. Firmaet har udviklet tre dopamin D2-receptor antagonister til behandling af skizofreni. Lægemidlerne har undergået et omfattende farmakologisk, toksikologisk og farmaceutisk afprøvningsprogra...... fase 1 forsøg alias »First dose in man«....

  3. Mechanical processes with repeated attenuated impacts

    CERN Document Server

    Nagaev, R F

    1999-01-01

    This book is devoted to considering in the general case - using typical concrete examples - the motion of machines and mechanisms of impact and vibro-impact action accompanied by a peculiar phenomenon called "impact collapse". This phenomenon is that after the initial collision, a sequence of repeated gradually quickening collisions of decreasing-to-zero intensity occurs, with the final establishment of protracted contact between the interacting bodies. The initiation conditions of the impact collapse are determined and calculation techniques for the quantitative characteristics of the corresp

  4. Source coding model for repeated snapshot imaging

    CERN Document Server

    Li, Junhui; Yang, Dongyue; wu, Guohua; Yin, Longfei; Guo, Hong

    2016-01-01

    Imaging based on successive repeated snapshot measurement is modeled as a source coding process in information theory. The necessary number of measurement to maintain a certain level of error rate is depicted as the rate-distortion function of the source coding. Quantitative formula of the error rate versus measurement number relation is derived, based on the information capacity of imaging system. Second order fluctuation correlation imaging (SFCI) experiment with pseudo-thermal light verifies this formula, which paves the way for introducing information theory into the study of ghost imaging (GI), both conventional and computational.

  5. REPEAT facility. Report for May, June, July

    Science.gov (United States)

    Winn, C. B.

    1981-08-01

    The construction of the REPEAT facility, a test facility for passive and hybrid solar heating systems is reported. The development of a simulation program for envelope type passive solar systems, constructing an envelope test cell, collecting data to validate the program, and application of the program to determine the best envelope type design are discussed. A low cost monitoring system using a dedicated microprocessor system, an inexpensive, high accuracy A/D converter, and minimum system hardware is developed. A method to determine the average temperature and the average daily temperature variation inside a passively heated solar building is presented.

  6. Cataractogenesis after Repeat Laser in situ Keratomileusis

    Directory of Open Access Journals (Sweden)

    Ahmad M. Mansour

    2012-08-01

    Full Text Available There has been the unsubstantiated clinical impression that laser refractive surgery accelerates cataract development along with solid experimental data about the cataractogenic effects of excimer laser treatment. We present the first documented case of significant cataract formation in a young myope after repeat excimer laser ablation necessitating phacoemulsification with a posterior chamber implant. Proposed explanations include focusing of the ablation wave on the posterior capsule (acoustic wave lens epithelial damage, photooxidative stress of the lens (ultraviolet and inflammatory oxidative stress, and corticosteroid-induced cataract (lens toxicity.

  7. Multiplicatively Repeated Non-Binary LDPC Codes

    CERN Document Server

    Kasai, Kenta; Poulliat, Charly; Sakaniwa, Kohichi

    2010-01-01

    We propose non-binary LDPC codes concatenated with multiplicative repetition codes. By multiplicatively repeating the (2,3)-regular non-binary LDPC mother code of rate 1/3, we construct rate-compatible codes of lower rates 1/6, 1/9, 1/12,... Surprisingly, such simple low-rate non-binary LDPC codes outperform the best low-rate binary LDPC codes so far. Moreover, we propose the decoding algorithm for the proposed codes, which can be decoded with almost the same computational complexity as that of the mother code.

  8. Improving repeated sprint ability in young elite soccer players: repeated shuttle sprints vs. explosive strength training.

    Science.gov (United States)

    Buchheit, Martin; Mendez-Villanueva, Alberto; Delhomel, Gregory; Brughelli, Matt; Ahmaidi, Said

    2010-10-01

    To compare the effects of explosive strength (ExpS) vs. repeated shuttle sprint (RS) training on repeated sprint ability (RSA) in young elite soccer players, 15 elite male adolescents (14.5 ± 0.5 years) performed, in addition to their soccer training program, RS (n = 7) or ExpS (n = 8) training once a week for a total of 10 weeks. RS training consisted of 2-3 sets of 5-6 × 15- to 20-m repeated shuttle sprints interspersed with 14 seconds of passive or 23 seconds of active recovery (≈2 m·s⁻¹); ExpS training consisted of 4-6 series of 4-6 exercises (e.g., maximal unilateral countermovement jumps (CMJs), calf and squat plyometric jumps, and short sprints). Before and after training, performance was assessed by 10 and 30 m (10 and 30 m) sprint times, best (RSAbest) and mean (RSAmean) times on a repeated shuttle sprint ability test, a CMJ, and a hopping (Hop) test. After training, except for 10 m (p = 0.22), all performances were significantly improved in both groups (all p's repeated shuttle sprint test were only observed after RS training, whereas CMJ height was only increased after ExpS. Because RS and ExpS were equally efficient at enhancing maximal sprinting speed, RS training-induced improvements in RSA were likely more related to progresses in the ability to change direction.

  9. Repeated vitrification/warming of human sperm gives better results than repeated slow programmable freezing

    Institute of Scientific and Technical Information of China (English)

    Teraporn Vutyavanich; Worashorn Lattiwongsakorn; Waraporn Piromlertamorn; Sudarat Samchimchom

    2012-01-01

    In this study,we compared the effects of repeated freezing/thawing of human sperm by our in-house method of rapid freezing with slow programmable freezing.Sperm samples from 11 normozoospermic subjects were processed through density gradients and divided into three aliquots:non-frozen,rapid freezing and slow programmable freezing.Sperm in the rapid freezing group had better motility and viability than those in the slow freezing group (P<O.01) after the first,second and third cycles of freezing/thawing,but there was no difference in morphology.In the second experiment,rapid freezing was repeated three times in 20 subjects.The samples from each thawing cycle were evaluated for DNA fragmentation using the alkaline comet assay.DNA fragmentation began to increase considerably after the second cycle of freezing/thawing,but to a level that was not clinically important.In the third experiment,rapid freezing was done repeatedly in 10 subjects,until no motile sperm were observed after thawing.The median number of repeated freezing/thawing that yielded no motile sperm was seven (range:5-8,mean:6.8).In conclusion,we demonstrated that repeated freezing/thawing of processed semen using our rapid freezing method gave better results than standard slow programmable freezing.This method can help maximize the usage of precious cryopreserved sperm samples in assisted reproduction technology.

  10. Estimation of the Dose and Dose Rate Effectiveness Factor

    Science.gov (United States)

    Chappell, L.; Cucinotta, F. A.

    2013-01-01

    Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

  11. Dose reduction in evacuation proctography

    Energy Technology Data Exchange (ETDEWEB)

    Hare, C.; Halligan, S.; Bartram, C.I.; Gupta, R.; Walker, A.E.; Renfrew, I. [Intestinal Imaging Centre, St. Mark' s Hospital, London (United Kingdom)

    2001-03-01

    The goal of this study was to reduce the patient radiation dose from evacuation proctography. Ninety-eight consecutive adult patients referred for proctography to investigate difficult rectal evacuation were studied using a digital imaging system with either a standard digital program for barium examinations, a reduced dose digital program (both with and without additional copper filtration), or Video fluoroscopy. Dose-area products were recorded for each examination and the groups were compared. All four protocols produced technically acceptable examinations. The low-dose program with copper filtration (median dose 382 cGy cm{sup 2}) and Video fluoroscopy (median dose 705 cGy cm{sup 2}) were associated with significantly less dose than other groups (p < 0.0001). Patient dose during evacuation proctography can be reduced significantly without compromising the diagnostic quality of the examination. A digital program with added copper filtration conveyed the lowest dose. (orig.)

  12. Comparative genomics and molecular dynamics of DNA repeats in eukaryotes.

    Science.gov (United States)

    Richard, Guy-Franck; Kerrest, Alix; Dujon, Bernard

    2008-12-01

    Repeated elements can be widely abundant in eukaryotic genomes, composing more than 50% of the human genome, for example. It is possible to classify repeated sequences into two large families, "tandem repeats" and "dispersed repeats." Each of these two families can be itself divided into subfamilies. Dispersed repeats contain transposons, tRNA genes, and gene paralogues, whereas tandem repeats contain gene tandems, ribosomal DNA repeat arrays, and satellite DNA, itself subdivided into satellites, minisatellites, and microsatellites. Remarkably, the molecular mechanisms that create and propagate dispersed and tandem repeats are specific to each class and usually do not overlap. In the present review, we have chosen in the first section to describe the nature and distribution of dispersed and tandem repeats in eukaryotic genomes in the light of complete (or nearly complete) available genome sequences. In the second part, we focus on the molecular mechanisms responsible for the fast evolution of two specific classes of tandem repeats: minisatellites and microsatellites. Given that a growing number of human neurological disorders involve the expansion of a particular class of microsatellites, called trinucleotide repeats, a large part of the recent experimental work on microsatellites has focused on these particular repeats, and thus we also review the current knowledge in this area. Finally, we propose a unified definition for mini- and microsatellites that takes into account their biological properties and try to point out new directions that should be explored in a near future on our road to understanding the genetics of repeated sequences.

  13. Repeat Whole Brain Radiation Therapy with a Simultaneous Infield Boost: A Novel Technique for Reirradiation

    Directory of Open Access Journals (Sweden)

    William A. Hall

    2014-01-01

    Full Text Available The treatment of patients who experience intracranial progression after whole brain radiation therapy (WBRT is a clinical challenge. Novel radiation therapy delivery technologies are being applied with the objective of improving tumor and symptom control in these patients. The purpose of this study is to describe the clinical outcomes of the application of a novel technology to deliver repeat WBRT with volume modulated arc therapy (VMAT and a simultaneous infield boost (WB-SIB to gross disease. A total of 16 patients were initially treated with WBRT between 2000 and 2008 and then experienced intracranial progression, were treated using repeat WB-SIB, and were analyzed. The median dose for the first course of WBRT was 35 Gy (range: 30–50.4 Gy. Median time between the initial course of WBRT and repeat WB-SIB was 11.3 months. The median dose at reirradiation was 20 Gy to the whole brain with a median boost dose of 30 Gy to gross disease. A total of 2 patients demonstrated radiographic disease progression after treatment. The median overall survival (OS time from initial diagnosis of brain metastases was 18.9 months (range: 7.1–66.6 (95% CI: 0.8–36.9. The median OS time after initiation of reirradiation for all patients was 2.7 months (range: 0.46–14.46 (95% CI: 1.3–8.7. Only 3 patients experienced CTCAE grade 3 fatigue. No other patients experienced any ≥ CTCAE grade 3 toxicity. This analysis reports the result of a novel RT delivery technique for the treatment of patients with recurrent brain metastases. Side effects were manageable and comparable to other conventional repeat WBRT series. Repeat WB-SIB using the VMAT RT delivery technology is feasible and appears to have acceptable short-term acute toxicity. These results may provide a foundation for further exploration of the WB-SIB technique for repeat WBRT in future prospective clinical trials.

  14. Calcium kinetics with microgram stable isotope doses and saliva sampling

    Science.gov (United States)

    Smith, S. M.; Wastney, M. E.; Nyquist, L. E.; Shih, C. Y.; Wiesmann, H.; Nillen, J. L.; Lane, H. W.

    1996-01-01

    Studies of calcium kinetics require administration of tracer doses of calcium and subsequent repeated sampling of biological fluids. This study was designed to develop techniques that would allow estimation of calcium kinetics by using small (micrograms) doses of isotopes instead of the more common large (mg) doses to minimize tracer perturbation of the system and reduce cost, and to explore the use of saliva sampling as an alternative to blood sampling. Subjects received an oral dose (133 micrograms) of 43Ca and an i.v. dose (7.7 micrograms) of 46Ca. Isotopic enrichment in blood, urine, saliva and feces was well above thermal ionization mass spectrometry measurement precision up to 170 h after dosing. Fractional calcium absorptions determined from isotopic ratios in blood, urine and saliva were similar. Compartmental modeling revealed that kinetic parameters determined from serum or saliva data were similar, decreasing the necessity for blood samples. It is concluded from these results that calcium kinetics can be assessed with micrograms doses of stable isotopes, thereby reducing tracer costs and with saliva samples, thereby reducing the amount of blood needed.

  15. Extending Teach and Repeat to Pivoting Wheelchairs

    Directory of Open Access Journals (Sweden)

    Guillermo Del Castillo

    2003-02-01

    Full Text Available The paper extends the teach-and-repeat paradigm that has been successful for the control of holonomic robots to nonholonomic wheelchairs which may undergo pivoting action over the course of their taught movement. Due to the nonholonomic nature of the vehicle kinematics, estimation is required -- in the example given herein, based upon video detection of wall-mounted cues -- both in the teaching and the tracking events. In order to accommodate motion that approaches pivoting action as well as motion that approaches straight-line action, the estimation equations of the Extended Kalman Filter and the control equations are formulated using two different definitions of a nontemporal independent variable. The paper motivates the need for pivoting action in real-life settings by reporting extensively on the abilities and limitations of estimation-based teach-and-repeat action where pivoting and near-pivoting action is disallowed. Following formulation of the equations in the near-pivot mode, the paper reports upon experiments where taught trajectories which entail a seamless mix of near-straight and near-pivot action are tracked.

  16. The Perpetual Repeater: an Educative Musical Experience.

    Directory of Open Access Journals (Sweden)

    Svetlana Skriagina

    2014-05-01

    Full Text Available To commemorate the 40th anniversary of the Music Undergraduate Program of the Universidad Pedagógica Nacional (National Pedagogic University, two musical events were planned: an original work written for choir, soloists and symphonic band, and an opera for children. As a result, the cantata ‘The Perpetual Repeater” has been created as an adaptation of a work named “50 Milions de Segons” (50 Millions of Seconds, staged by the CATANIA project of the Barcelona Servei Educatiu de L’Auditori. This work tells the story of those school teachers who, paradoxically enough repeat the same course year after year. After visiting L’Auditori of Barcelona to participate in the pedagogic musical work carried out with school children, we considered the possibility of developing an analogous project, in a similar sociocultural and educational environment, within our Music Undergraduate Program. So, this article deals with two fundamental moments which are essential to understand the educational work implemented with the ISPA students of sixth degree, as well as with a group of the program’s students: The Purpose, which describes in detail the planning of the musical work for children, and The Experience, in which the way the process of The Perpetual Repeater Cantatawas carried out is described.

  17. Airborne Radar Interferometric Repeat-Pass Processing

    Science.gov (United States)

    Hensley, Scott; Michel, Thierry R.; Jones, Cathleen E.; Muellerschoen, Ronald J.; Chapman, Bruce D.; Fore, Alexander; Simard, Marc; Zebker, Howard A.

    2011-01-01

    Earth science research often requires crustal deformation measurements at a variety of time scales, from seconds to decades. Although satellites have been used for repeat-track interferometric (RTI) synthetic-aperture-radar (SAR) mapping for close to 20 years, RTI is much more difficult to implement from an airborne platform owing to the irregular trajectory of the aircraft compared with microwave imaging radar wavelengths. Two basic requirements for robust airborne repeat-pass radar interferometry include the ability to fly the platform to a desired trajectory within a narrow tube and the ability to have the radar beam pointed in a desired direction to a fraction of a beam width. Uninhabited Aerial Vehicle Synthetic Aperture Radar (UAVSAR) is equipped with a precision auto pilot developed by NASA Dryden that allows the platform, a Gulfstream III, to nominally fly within a 5 m diameter tube and with an electronically scanned antenna to position the radar beam to a fraction of a beam width based on INU (inertial navigation unit) attitude angle measurements.

  18. Aggregating quantum repeaters for the quantum internet

    Science.gov (United States)

    Azuma, Koji; Kato, Go

    2017-09-01

    The quantum internet holds promise for accomplishing quantum teleportation and unconditionally secure communication freely between arbitrary clients all over the globe, as well as the simulation of quantum many-body systems. For such a quantum internet protocol, a general fundamental upper bound on the obtainable entanglement or secret key has been derived [K. Azuma, A. Mizutani, and H.-K. Lo, Nat. Commun. 7, 13523 (2016), 10.1038/ncomms13523]. Here we consider its converse problem. In particular, we present a universal protocol constructible from any given quantum network, which is based on running quantum repeater schemes in parallel over the network. For arbitrary lossy optical channel networks, our protocol has no scaling gap with the upper bound, even based on existing quantum repeater schemes. In an asymptotic limit, our protocol works as an optimal entanglement or secret-key distribution over any quantum network composed of practical channels such as erasure channels, dephasing channels, bosonic quantum amplifier channels, and lossy optical channels.

  19. Automated Planning in Repeated Adversarial Games

    CERN Document Server

    de Cote, Enrique Munoz; Sykulski, Adam M; Jennings, Nicholas R

    2012-01-01

    Game theory's prescriptive power typically relies on full rationality and/or self-play interactions. In contrast, this work sets aside these fundamental premises and focuses instead on heterogeneous autonomous interactions between two or more agents. Specifically, we introduce a new and concise representation for repeated adversarial (constant-sum) games that highlight the necessary features that enable an automated planing agent to reason about how to score above the game's Nash equilibrium, when facing heterogeneous adversaries. To this end, we present TeamUP, a model-based RL algorithm designed for learning and planning such an abstraction. In essence, it is somewhat similar to R-max with a cleverly engineered reward shaping that treats exploration as an adversarial optimization problem. In practice, it attempts to find an ally with which to tacitly collude (in more than two-player games) and then collaborates on a joint plan of actions that can consistently score a high utility in adversarial repeated gam...

  20. Chromosome-specific DNA Repeat Probes

    Energy Technology Data Exchange (ETDEWEB)

    Baumgartner, Adolf; Weier, Jingly Fung; Weier, Heinz-Ulrich G.

    2006-03-16

    In research as well as in clinical applications, fluorescence in situ hybridization (FISH) has gained increasing popularity as a highly sensitive technique to study cytogenetic changes. Today, hundreds of commercially available DNA probes serve the basic needs of the biomedical research community. Widespread applications, however, are often limited by the lack of appropriately labeled, specific nucleic acid probes. We describe two approaches for an expeditious preparation of chromosome-specific DNAs and the subsequent probe labeling with reporter molecules of choice. The described techniques allow the preparation of highly specific DNA repeat probes suitable for enumeration of chromosomes in interphase cell nuclei or tissue sections. In addition, there is no need for chromosome enrichment by flow cytometry and sorting or molecular cloning. Our PCR-based method uses either bacterial artificial chromosomes or human genomic DNA as templates with {alpha}-satellite-specific primers. Here we demonstrate the production of fluorochrome-labeled DNA repeat probes specific for human chromosomes 17 and 18 in just a few days without the need for highly specialized equipment and without the limitation to only a few fluorochrome labels.

  1. Repeat-induced gene silencing in mammals.

    Science.gov (United States)

    Garrick, D; Fiering, S; Martin, D I; Whitelaw, E

    1998-01-01

    In both plants and Drosophila melanogaster, expression from a transgenic locus may be silenced when repeated transgene copies are arranged as a concatameric array. This repeat-induced gene silencing is frequently manifested as a decrease in the proportion of cells that express the transgene, resulting in a variegated pattern of expression. There is also some indication that, in transgenic mammals, the number of transgene copies within an array can exert a repressive influence on expression, with several mouse studies reporting a decrease in the level of expression per copy as copy number increases. However, because these studies compare different sites of transgene integration as well as arrays with different numbers of copies, the expression levels observed may be subject to varying position effects as well as the influence of the multicopy array. Here we describe use of the lox/Cre system of site-specific recombination to generate transgenic mouse lines in which different numbers of a transgene are present at the same chromosomal location, thereby eliminating the contribution of position effects and allowing analysis of the effect of copy number alone on transgene silencing. Reduction in copy number results in a marked increase in expression of the transgene and is accompanied by decreased chromatin compaction and decreased methylation at the transgene locus. These findings establish that the presence of multiple homologous copies of a transgene within a concatameric array can have a repressive effect upon gene expression in mammalian systems.

  2. Repeated administration of histamine improves memory retrieval of inhibitory avoidance by lithium in mice.

    Science.gov (United States)

    Zarrindast, Mohammad Reza; Parsaei, Leila; Ahmadi, Shamseddin

    2008-01-01

    The influence of repeated administration of histamine on lithium-induced state dependency has been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg), immediately after training (post-training), impaired inhibitory avoidance memory on the test day. Pre-test administration of lithium reversed amnesia induced by the drug given after training, with the maximum response at a dose of 10 mg/kg. Repeated intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) for 3 consecutive days followed by 5 days of no drug treatment improved memory retrieval of inhibitory avoidance by a pre-test lower dose (5 mg/kg i.p.) of lithium. In contrast, 3 days of i.c.v. injections of both the histamine H1 receptor antagonist pyrilamine (40 microg/mouse) and the histamine H2 receptor antagonist ranitidine (6.25 and 12.5 microg/mouse) prevented the improving effect of pre-test lithium (10 mg/kg i.p.) on memory retrieval. The results suggest that the repeated administration of histaminergic agents may induce a sensitization which affects the memory impairment induced by lithium.

  3. Receptionist input to quality and safety in repeat prescribing in UK general practice: ethnographic case study.

    Science.gov (United States)

    Swinglehurst, Deborah; Greenhalgh, Trisha; Russell, Jill; Myall, Michelle

    2011-11-03

    To describe, explore, and compare organisational routines for repeat prescribing in general practice to identify contributors and barriers to safety and quality. Ethnographic case study. Four urban UK general practices with diverse organisational characteristics using electronic patient records that supported semi-automation of repeat prescribing. 395 hours of ethnographic observation of staff (25 doctors, 16 nurses, 4 healthcare assistants, 6 managers, and 56 reception or administrative staff), and 28 documents and other artefacts relating to repeat prescribing locally and nationally. Potential threats to patient safety and characteristics of good practice. Observation of how doctors, receptionists, and other administrative staff contributed to, and collaborated on, the repeat prescribing routine. Analysis included mapping prescribing routines, building a rich description of organisational practices, and drawing these together through narrative synthesis. This was informed by a sociological model of how organisational routines shape and are shaped by information and communications technologies. Results Repeat prescribing was a complex, technology-supported social practice requiring collaboration between clinical and administrative staff, with important implications for patient safety. More than half of requests for repeat prescriptions were classed as "exceptions" by receptionists (most commonly because the drug, dose, or timing differed from what was on the electronic repeat list). They managed these exceptions by making situated judgments that enabled them (sometimes but not always) to bridge the gap between the idealised assumptions about tasks, roles, and interactions that were built into the electronic patient record and formal protocols, and the actual repeat prescribing routine as it played out in practice. This work was creative and demanded both explicit and tacit knowledge. Clinicians were often unaware of this input and it did not feature in policy

  4. Discrepancies in reporting the CAG repeat lengths for Huntington's disease

    DEFF Research Database (Denmark)

    Quarrell, Oliver W; Handley, Olivia; O'Donovan, Kirsty

    2011-01-01

    Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original...

  5. Micro dose acquisition in Leg length Discrepancy using the EOS imaging system

    DEFF Research Database (Denmark)

    Jensen, Janni; Mussmann, Bo; Pedersen, Niels Wisbech

    to the acquisition of diagnostic images a scout image is acquired at extremely low dose for planning purposes, i.e. approximately 1% of the dose required for diagnostic images. Dose reduction is important because children and adolescents are more sensitive to radiation than adults and they may undergo several LLD......Objectives Leg Length Discrepancy (LLD) is often diagnosed in young patients who undergo repeated x-ray examinations quantifying the length discrepancy and monitoring progression. In our department LLD images are currently acquired using a low dose bi-plane system named EOS. Prior...

  6. Effect of different 1-methylcyclopropene doses on the postharvest period of pitahaya fruits (Selenicereus megalanthus Haw.

    Directory of Open Access Journals (Sweden)

    Javier Giovanni Álvarez-Herrera

    2016-07-01

    application of 1-methylcyclopropene (1-MCP on the preservation and quality of dragon fruit, given that it has been effective in the conservation and postharvest quality of many agricultural species allowing longer life, using a completely randomized experiment design with three treatments: 0, 300 and 600 mg L-1 of 1-MCP, with four replications. The 600 mg L-1 of 1-MCP dose was able to maintain the quality of the dragon fruit longer (28 days after harvest (dah because it managed to reduce the respiratory rate. The application of 1-MCP did not affect the firmness, loss of mass, total soluble solids, total titratable acidity, or total carotenoids in the fruits. The application of 1-MCP slowed the loss of fruit quality in terms of color because the 600 mg L-1 dose maintained the lightness of the fruits longer, reduced the color changes as expressed in a* and b* values and decreased the chlorophyll degradation.

  7. 47 CFR 90.247 - Mobile repeater stations.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Mobile repeater stations. 90.247 Section 90.247... MOBILE RADIO SERVICES Non-Voice and Other Specialized Operations § 90.247 Mobile repeater stations. A... repeater to extend the communications range of hand-carried units subject to the following: (a)...

  8. Polymorphic GGC repeat differentially regulates human reelin gene expression levels.

    Science.gov (United States)

    Persico, A M; Levitt, P; Pimenta, A F

    2006-10-01

    The human gene encoding Reelin (RELN), a pivotal protein in neurodevelopment, includes a polymorphic GGC repeat in its 5' untranslated region (UTR). CHO cells transfected with constructs encompassing the RELN 5'UTR with 4-to-13 GGC repeats upstream of the luciferase reporter gene show declining luciferase activity with increasing GGC repeat number (P autism.

  9. CGG repeat in the FMR1 gene: Size matters

    NARCIS (Netherlands)

    R.A. Willemsen (Ralph); G.J. Levenga (Josien); B.A. Oostra (Ben)

    2011-01-01

    textabstractThe FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs (full

  10. SimDoseCT: dose reporting software based on Monte Carlo simulation for a 320 detector-row cone-beam CT scanner and ICRP computational adult phantoms

    Science.gov (United States)

    Cros, Maria; Joemai, Raoul M. S.; Geleijns, Jacob; Molina, Diego; Salvadó, Marçal

    2017-08-01

    This study aims to develop and test software for assessing and reporting doses for standard patients undergoing computed tomography (CT) examinations in a 320 detector-row cone-beam scanner. The software, called SimDoseCT, is based on the Monte Carlo (MC) simulation code, which was developed to calculate organ doses and effective doses in ICRP anthropomorphic adult reference computational phantoms for acquisitions with the Aquilion ONE CT scanner (Toshiba). MC simulation was validated by comparing CTDI measurements within standard CT dose phantoms with results from simulation under the same conditions. SimDoseCT consists of a graphical user interface connected to a MySQL database, which contains the look-up-tables that were generated with MC simulations for volumetric acquisitions at different scan positions along the phantom using any tube voltage, bow tie filter, focal spot and nine different beam widths. Two different methods were developed to estimate organ doses and effective doses from acquisitions using other available beam widths in the scanner. A correction factor was used to estimate doses in helical acquisitions. Hence, the user can select any available protocol in the Aquilion ONE scanner for a standard adult male or female and obtain the dose results through the software interface. Agreement within 9% between CTDI measurements and simulations allowed the validation of the MC program. Additionally, the algorithm for dose reporting in SimDoseCT was validated by comparing dose results from this tool with those obtained from MC simulations for three volumetric acquisitions (head, thorax and abdomen). The comparison was repeated using eight different collimations and also for another collimation in a helical abdomen examination. The results showed differences of 0.1 mSv or less for absolute dose in most organs and also in the effective dose calculation. The software provides a suitable tool for dose assessment in standard adult patients undergoing CT

  11. Dose distributions around selectron applicators

    Energy Technology Data Exchange (ETDEWEB)

    Pla, C.; Evans, M.D.; Podgorsak, E.B.

    1987-11-01

    Measured and calculated dose distributions around selectron applicators, loaded with /sup 60/Co high dose rate pellets, are presented. The effect of the stopping screw, spacers, pellets themselves and the applicator wall on the dose distribution is discussed. The measured dose distribution is in almost perfect agreement with the calculated distribution in planes perpendicular to the applicator axis and containing a source. On the applicator axis directly below the applicator the measured dose amounts to about 75% of the calculated value, when only the stopping screw attenuates the beam from a pellet. When the beam is attenuated by spacers in addition to the stopping screw, the discrepancy between the calculated and measured dose may exceed 50%. Clinically relevant source geometries are also discussed. It is shown that for most regions around the applicator the method of a simple addition of dose contributions from individual point sources is an acceptable approximation for the calculation of dose distributions around the selectron applicators.

  12. Ceftriaxone attenuates locomotor activity induced by acute and repeated cocaine exposure in mice.

    Science.gov (United States)

    Tallarida, Christopher S; Corley, Gladys; Kovalevich, Jane; Yen, William; Langford, Dianne; Rawls, Scott M

    2013-11-27

    Ceftriaxone (CTX) decreases locomotor activation produced by initial cocaine exposure and attenuates development of behavioral sensitization produced by repeated cocaine exposure. An important question that has not yet been answered is whether or not CTX reduces behavioral sensitization to cocaine in cases in which the antibiotic is administered only during the period of cocaine absence that follows repeated cocaine exposure and precedes reintroduction to cocaine. We investigated this question using C57BL/6 mice. Mice pretreated with cocaine (15mg/kg×14 days) and then challenged with cocaine (15mg/kg) after 30 days of cocaine absence displayed sensitization of locomotor activity. For combination experiments, CTX injected during the 30 days of cocaine absence attenuated behavioral sensitization produced by cocaine challenge. In the case in which CTX was injected together with cocaine for 14 days, development of behavioral sensitization to cocaine challenge was also reduced. CTX attenuated the increase in locomotor activity produced by acute cocaine exposure; however, its efficacy was dependent on the dose of cocaine as inhibition was detected against 30mg/kg, but not 15mg/kg, of cocaine. These results from mice indicate that CTX attenuates locomotor activity produced by acute and repeated cocaine exposure and counters cocaine's locomotor activating properties in a paradigm in which the antibiotic is injected during the period of forced cocaine absence that follows repeated cocaine exposure.

  13. Repeated Challenge with Virulent Newcastle Disease Virus Does Not Decrease the Efficacy of Vaccines.

    Science.gov (United States)

    Taylor, Tonya L; Miller, Patti J; Olivier, Timothy L; Montiel, Enrique; Cardenas Garcia, Stivalis; Dimitrov, Kiril M; Williams-Coplin, Dawn; Afonso, Claudio L

    2017-06-01

    Globally, poultry producers report that birds well-vaccinated for Newcastle disease (ND) often present clinical disease and mortality after infection with virulent strains of Newcastle disease (vNDV), which is contrary to what is observed in experimental settings. One hypothesis for this discrepancy is that the birds in the field may be exposed to multiple successive challenges with vNDV, rather than one challenge dose, and that the repeated infection may overwhelm the immune system and neutralizing antibodies available to prevent clinical disease. In this study, we evaluated this hypothesis under highly controlled conditions. We challenged well-vaccinated chickens with high doses of vNDV daily for 10 days, and looked for signs of clinical disease, changes in antibody titers, and mortality. All sham-vaccinated birds died by the fourth day postchallenge. No morbidity or mortality was observed in any of the NDV-vaccinated birds up to 14 days postchallenge; repeated high-dose challenges of vNDV was not sufficient to overcome vaccine immunity.

  14. Repeat Testing Effects on Credentialing Exams: Are Repeaters Misinformed or Uninformed?

    Science.gov (United States)

    Feinberg, Richard A.; Raymond, Mark R.; Haist, Steven A.

    2015-01-01

    To mitigate security concerns and unfair score gains, credentialing programs routinely administer new test material to examinees retesting after an initial failing attempt. Counterintuitively, a small but growing body of recent research suggests that repeating the identical form does not create an unfair advantage. This study builds upon and…

  15. Who Repeats Algebra, and How Does Initial Performance Relate to Improvement When the Course Is Repeated?

    Science.gov (United States)

    Fong, Anthony; Jaquet, Karina; Finkelstein, Neal

    2016-01-01

    The information provided in this report shows how students perform when they repeat algebra I and how the level of improvement varies depending on initial course performance and the academic measure (course grades or CST scores). This information can help inform decisions and policies regarding whether and under what circumstances students should…

  16. Hanford Environmental Dose Reconstruction Project

    Energy Technology Data Exchange (ETDEWEB)

    Finch, S.M.; McMakin, A.H. (comps.)

    1992-02-01

    The objective of the Hanford Environmental Dose Reconstruction Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed, from release to impact on humans (dose estimates): source terms; environmental transport; environmental monitoring data; demography, food consumption, and agriculture; environmental pathways and dose estimates.

  17. Sustained Antibody Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent Human Papillomavirus (HPV) Vaccine in Adolescent Fijian Girls, and Subsequent Responses to a Single Dose of Bivalent HPV Vaccine: A Prospective Cohort Study.

    Science.gov (United States)

    Toh, Zheng Quan; Russell, Fiona M; Reyburn, Rita; Fong, James; Tuivaga, Evelyn; Ratu, Tupou; Nguyen, Cattram D; Devi, Rachel; Kama, Mike; Matanitobua, Silivia; Tabrizi, Sepehr N; Garland, Suzanne M; Sinha, Rohit; Frazer, Ian; Tikoduadua, Lisi; Kado, Joseph; Rafai, Eric; Mulholland, Edward K; Licciardi, Paul V

    2017-04-01

    The duration of antibody response following reduced human papillomavirus (HPV) vaccine doses has not been determined. We compared the antibody responses in girls previously vaccinated with zero, 1, 2, or 3 doses of quadrivalent HPV vaccine (4vHPV; Gardasil, Merck) 6 years previously. A prospective cohort study was undertaken in 200 Fijian girls 15-19 years of age. Approximately equal numbers of girls from 2 main ethnic groups (Fijians of Indian descent [FID] and Indigenous Fijians [iTaukei]) in Fiji were recruited for each dosage groups. Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine (2vHPV; Cervarix, GlaxoSmithKline). We measured neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 using the pseudovirion-based neutralization assay. After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695-2896]; 2D: 1476 [95% CI, 1019-2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396-5783]; 2D: 2951 [95% CI, 1984-4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511-4530]; 2D: 3275 [95% CI, 2452-4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445-888]; 2D: 606 [95% CI, 462-862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously. Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years, although the clinical significance is unknown. A single dose of 4vHPV elicits antibodies that persisted for at least 6 years, and induced immune memory, suggesting possible protection against HPV vaccine types after a single dose of 4vHPV.

  18. Hybrid quantum repeater using bright coherent light.

    Science.gov (United States)

    van Loock, P; Ladd, T D; Sanaka, K; Yamaguchi, F; Nemoto, Kae; Munro, W J; Yamamoto, Y

    2006-06-23

    We describe a quantum repeater protocol for long-distance quantum communication. In this scheme, entanglement is created between qubits at intermediate stations of the channel by using a weak dispersive light-matter interaction and distributing the outgoing bright coherent-light pulses among the stations. Noisy entangled pairs of electronic spin are then prepared with high success probability via homodyne detection and postselection. The local gates for entanglement purification and swapping are deterministic and measurement-free, based upon the same coherent-light resources and weak interactions as for the initial entanglement distribution. Finally, the entanglement is stored in a nuclear-spin-based quantum memory. With our system, qubit-communication rates approaching 100 Hz over 1280 km with fidelities near 99% are possible for reasonable local gate errors.

  19. Potential of repeated polymer well treatments

    Energy Technology Data Exchange (ETDEWEB)

    Lakatos, I.; Lakatos-Szabo, J. (Hungarian Academy of Sciences, Budapest (Hungary)); Munkacsi, I.; Troemboeczki, S.

    1993-11-01

    This paper analyzes field results obtained by routine application of a polymer/silicate well treatment technique at the Algyo-2 field in Hungary. First, the reservoir is described briefly; then, the basic concept of the method is outlined. Reference is made to the multifunctioning chemical mechanism of gelation and the favorable rheological properties of the treating fluids that jointly result in a highly selective placement and an efficient permeability reduction in the target reservoir space. Application of the method 17 times in 16 producing wells yielded more than 90,000 Mg of incremental oil production. Typical well behaviors also are illustrated. Finally, the potential of repeated treatments is discussed, taking laboratory and field results into account.

  20. Quantum repeaters using continuous-variable teleportation

    Science.gov (United States)

    Dias, Josephine; Ralph, T. C.

    2017-02-01

    Quantum optical states are fragile and can become corrupted when passed through a lossy communication channel. Unlike for classical signals, optical amplifiers cannot be used to recover quantum signals. Quantum repeaters have been proposed as a way of reducing errors and hence increasing the range of quantum communications. Current protocols target specific discrete encodings, for example quantum bits encoded on the polarization of single photons. We introduce a more general approach that can reduce the effect of loss on any quantum optical encoding, including those based on continuous variables such as the field amplitudes. We show that in principle the protocol incurs a resource cost that scales polynomially with distance. We analyze the simplest implementation and find that while its range is limited it can still achieve useful improvements in the distance over which quantum entanglement of field amplitudes can be distributed.