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Sample records for preclinical efficacy studies

  1. The development of neural stimulators: a review of preclinical safety and efficacy studies.

    Science.gov (United States)

    Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

    2018-05-14

    Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to

  2. Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Ronald W Irwin

    /kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions.

  3. Chronic electrical stimulation with a suprachoroidal retinal prosthesis: a preclinical safety and efficacy study.

    Directory of Open Access Journals (Sweden)

    David A X Nayagam

    stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.

  4. Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study

    Science.gov (United States)

    Kode, Jyoti; Taur, Prasad; Gulia, Ashish; Jambhekar, Nirmala; Agarwal, Manish; Puri, Ajay

    2014-01-01

    Background & objectives: In current era of limb-salvage therapy, pasteurization of bone sarcomas is receiving growing attention as a potential extracorporeal treatment and cost-effective alternative to allografts and radiation before surgical reimplantation. Detailed in vitro and in vivo pre-clinical study to evaluate efficacy of pasteurization to eradicate malignant cells has not been reported yet. The present study was carried out to assess the efficacy of pasteurization to kill tumour cells both in vitro and in vivo. Methods: Surgically resected specimens of osteosarcomas (n=4) were cut into equal halves and one section was pasteurized by heating at 60°C to 65°C for 40 min. Paired samples before and after pasteurization were studied in vitro for DNA ploidy, evaluation of histological change and elimination of mitotic activity. These tissues were transplanted in immune-deficient NOD-SCID mice to evaluate effect on tumour-generating ability, presence of human nuclei, osteopontin and cytokine/chemokines released in tumour-transplanted mice. Results: Non-pasteurized tumour samples had viable tumour cells which exhibited significant growth in culture, increased proliferative ability and clonogenic potential while respective pasteurized tumour tissues did not grow in culture and did not exhibit clonogenicity. Flow cytometry revealed that propidium iodide positive dead cells increased significantly (Ppasteurization. Seven of 12 non-pasteurized tumour transplanted mice demonstrated tumour-forming ability as against 0 of 12 in pasteurized tumour transplanted mice. Solid tumour xenografts exhibited strong expression of anti-human nuclei and osteopontin by immunohistochemistry as well as secretary human interluekin-6 (IL-6) while pasteurized mice failed to express these markers. Interpretation & conclusions: This study has provided a basis to establish pasteurization as being efficacious in ensuring tumour eradication from resected bone tumour specimens. Pasteurized

  5. Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study.

    Science.gov (United States)

    Abedinpour, Parisa; Baron, Véronique T; Chrastina, Adrian; Rondeau, Gaelle; Pelayo, Jennifer; Welsh, John; Borgström, Per

    2017-12-01

    Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1 mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast, the combination of plumbagin with AR antagonists, such as bicalutamide and enzalutamide, showed no improvement over AR antagonists alone. Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice. © 2017 Wiley Periodicals, Inc.

  6. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

    Directory of Open Access Journals (Sweden)

    Valerie C Henderson

    Full Text Available The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external or programmatic research activity they primarily address.We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

  7. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

    Science.gov (United States)

    Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

    2013-01-01

    The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

  8. Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies.

    Science.gov (United States)

    Tan, Fenlai; Shen, Xiaoyan; Wang, Dechang; Xie, Guojian; Zhang, Xiaodong; Ding, Lieming; Hu, Yunyan; He, Wei; Wang, Yanping; Wang, Yinxiang

    2012-05-01

    Icotinib, one of the leading compounds selected from our compound library, was found to be a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an IC(50) of 5 nM. When profiled with 88 kinases, Icotinib only showed meaningful inhibitory activity to EGFR and its mutants. Icotinib blocked EGFR-mediated intracellular tyrosine phosphorylation (IC(50)=45 nM) in the human epidermoid carcinoma A431 cell line and inhibits tumor cell proliferation. In vivo studies demonstrated that Icotinib exhibited potent dose-dependent antitumor effects in nude mice carrying a variety of human tumor-derived xenografts. The drug was well tolerated at doses up to 120 mg/kg/day in mice without mortality or significant body weight loss during the treatment. A head to head randomized, double blind phase III trial using Gefitinib as an active control for patients with advanced non-small cell lung cancer (NSCLC) was finished recently (Trial registration ID: NCT01040780). The data shows that Icotinib was non-inferior to Gefitinib in terms of median progression free survival (PFS) and safety superior favor to Icotinib compared to Gefitinib. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. Preclinical efficacy and safety of herbal formulation for management ...

    African Journals Online (AJOL)

    Preclinical efficacy and safety of herbal formulation for management of wounds. ... The effects of the treatments on rate of wound closure, epithelialisation time ... inflammation and better tissue remodeling for rats treated with herbal product.

  10. Preclinical studies of dendrimer prodrugs.

    Science.gov (United States)

    Kojima, Chie

    2015-01-01

    Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

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

    Science.gov (United States)

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

    2015-02-15

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

  12. Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa.

    Directory of Open Access Journals (Sweden)

    Robert A Harrison

    2017-10-01

    Full Text Available Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa.We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a 'gold standard' comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom.None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro

  13. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming

    International Nuclear Information System (INIS)

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony

    2012-01-01

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab′ 2 based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of 99m Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab′ 2 product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab′ 2 based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ► Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ► Late injection of Nanobody restores hemodynamic parameters to baseline values. ► Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ► Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

  14. Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

    Science.gov (United States)

    Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

    2013-11-01

    Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

  15. Preclinical Studies for Cartilage Repair

    Science.gov (United States)

    Hurtig, Mark B.; Buschmann, Michael D.; Fortier, Lisa A.; Hoemann, Caroline D.; Hunziker, Ernst B.; Jurvelin, Jukka S.; Mainil-Varlet, Pierre; McIlwraith, C. Wayne; Sah, Robert L.; Whiteside, Robert A.

    2011-01-01

    Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral defects in immature laboratory species, particularly the rabbit, was considered adequate; however, if successful and timely translation from animal models to regulatory approval and clinical use is the goal, a step-wise development using laboratory animals for screening and early development work followed by larger species such as the goat, sheep and horse for late development and pivotal studies is recommended. Such animals must have fully organized and mature cartilage. Both acute and chronic chondral defects can be used but the later are more like the lesions found in patients and may be more predictive. Quantitative and qualitative outcome measures such as macroscopic appearance, histology, biochemistry, functional imaging, and biomechanical testing of cartilage, provide reliable data to support investment decisions and subsequent applications to regulatory bodies for clinical trials. No one model or species can be considered ideal for pivotal studies, but the larger animal species are recommended for pivotal studies. Larger species such as the horse, goat and pig also allow arthroscopic delivery, and press-fit or sutured implant fixation in thick cartilage as well as second look arthroscopies and biopsy procedures. PMID:26069576

  16. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming

    Energy Technology Data Exchange (ETDEWEB)

    Hmila, Issam [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Cosyns, Bernard [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Tounsi, Hayfa [Service d' Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Roosens, Bram; Caveliers, Vicky [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Abderrazek, Rahma Ben [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Boubaker, Samir [Service d' Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Muyldermans, Serge [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium); Department of Structural Biology, VIB, Brussels (Belgium); El Ayeb, Mohamed [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Bouhaouala-Zahar, Balkiss, E-mail: balkiss.bouhaouala@pasteur.rns.tn [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Faculté de Médecine de Tunis, Université de Tunis-El Manar (Tunisia); Lahoutte, Tony [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)

    2012-10-15

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab′{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab′{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab′{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ► Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ► Late injection of Nanobody restores hemodynamic parameters to baseline values. ► Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ► Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

  17. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    Science.gov (United States)

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

    2015-10-01

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

  18. USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

    Science.gov (United States)

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

    2014-01-01

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

  19. Melatonin and breast cancer: Evidences from preclinical and human studies.

    Science.gov (United States)

    Kubatka, Peter; Zubor, Pavol; Busselberg, Dietrich; Kwon, Taeg Kyu; Adamek, Mariusz; Petrovic, Daniel; Opatrilova, Radka; Gazdikova, Katarina; Caprnda, Martin; Rodrigo, Luis; Danko, Jan; Kruzliak, Peter

    2018-02-01

    The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2017-10-01

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

  1. Annular phased array transducer for preclinical testing of anti-cancer drug efficacy on small animals.

    Science.gov (United States)

    Kujawska, Tamara; Secomski, Wojciech; Byra, Michał; Postema, Michiel; Nowicki, Andrzej

    2017-04-01

    A technique using pulsed High Intensity Focused Ultrasound (HIFU) to destroy deep-seated solid tumors is a promising noninvasive therapeutic approach. A main purpose of this study was to design and test a HIFU transducer suitable for preclinical studies of efficacy of tested, anti-cancer drugs, activated by HIFU beams, in the treatment of a variety of solid tumors implanted to various organs of small animals at the depth of the order of 1-2cm under the skin. To allow focusing of the beam, generated by such transducer, within treated tissue at different depths, a spherical, 2-MHz, 29-mm diameter annular phased array transducer was designed and built. To prove its potential for preclinical studies on small animals, multiple thermal lesions were induced in a pork loin ex vivo by heating beams of the same: 6W, or 12W, or 18W acoustic power and 25mm, 30mm, and 35mm focal lengths. Time delay for each annulus was controlled electronically to provide beam focusing within tissue at the depths of 10mm, 15mm, and 20mm. The exposure time required to induce local necrosis was determined at different depths using thermocouples. Location and extent of thermal lesions determined from numerical simulations were compared with those measured using ultrasound and magnetic resonance imaging techniques and verified by a digital caliper after cutting the tested tissue samples. Quantitative analysis of the results showed that the location and extent of necrotic lesions on the magnetic resonance images are consistent with those predicted numerically and measured by caliper. The edges of lesions were clearly outlined although on ultrasound images they were fuzzy. This allows to conclude that the use of the transducer designed offers an effective noninvasive tool not only to induce local necrotic lesions within treated tissue without damaging the surrounding tissue structures but also to test various chemotherapeutics activated by the HIFU beams in preclinical studies on small animals

  2. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    Science.gov (United States)

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  3. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

    Science.gov (United States)

    Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

    2016-10-01

    Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under

  4. Gene therapy of Fanconi anemia: preclinical efficacy using lentiviral vectors.

    Science.gov (United States)

    Galimi, Francesco; Noll, Meenakshi; Kanazawa, Yoshiyuki; Lax, Timothy; Chen, Cindy; Grompe, Markus; Verma, Inder M

    2002-10-15

    Fanconi anemia (FA) is an inherited cancer susceptibility syndrome caused by mutations in a DNA repair pathway including at least 6 genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG). The clinical course of the disease is dominated by progressive, life-threatening bone marrow failure and high incidence of acute myelogenous leukemia and solid tumors. Allogeneic bone marrow transplantation (BMT) is a therapeutic option but requires HLA-matched donors. Gene therapy holds great promise for FA, but previous attempts to use retroviral vectors in humans have proven ineffective given the impaired proliferation potential of human FA hematopoietic progenitors (HPCs). In this work, we show that using lentiviral vectors efficient genetic correction can be achieved in quiescent hematopoietic progenitors from Fanca(-/-) and Fancc(-/-) mice. Long-term repopulating HPCs were transduced by a single exposure of unfractionated bone marrow mononuclear cells to lentivectors carrying the normal gene. Notably, no cell purification or cytokine prestimulation was necessary. Resistance to DNA- damaging agents was fully restored by lentiviral transduction, allowing for in vivo selection of the corrected cells with nonablative doses of cyclophosphamide. This study strongly supports the use of lentiviral vectors for FA gene therapy in humans.

  5. Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol.

    Science.gov (United States)

    Suen, Colin M; Zhai, Alex; Lalu, Manoj M; Welsh, Christopher; Levac, Brendan M; Fergusson, Dean; McIntyre, Lauralyn; Stewart, Duncan J

    2016-05-25

    Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies. We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and

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

    Science.gov (United States)

    Grill, Joshua D; Karlawish, Jason

    2017-12-06

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

  7. Ibrutinib brain distribution: a preclinical study.

    Science.gov (United States)

    Goldwirt, Lauriane; Beccaria, Kevin; Ple, Alain; Sauvageon, Hélène; Mourah, Samia

    2018-04-01

    Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model. Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method. Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC 0-t brain to AUC 0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area. The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL.

  8. Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies

    Science.gov (United States)

    Scarfe, Lauren; Brillant, Nathalie; Kumar, J. Dinesh; Ali, Noura; Alrumayh, Ahmed; Amali, Mohammed; Barbellion, Stephane; Jones, Vendula; Niemeijer, Marije; Potdevin, Sophie; Roussignol, Gautier; Vaganov, Anatoly; Barbaric, Ivana; Barrow, Michael; Burton, Neal C.; Connell, John; Dazzi, Francesco; Edsbagge, Josefina; French, Neil S.; Holder, Julie; Hutchinson, Claire; Jones, David R.; Kalber, Tammy; Lovatt, Cerys; Lythgoe, Mark F.; Patel, Sara; Patrick, P. Stephen; Piner, Jacqueline; Reinhardt, Jens; Ricci, Emanuelle; Sidaway, James; Stacey, Glyn N.; Starkey Lewis, Philip J.; Sullivan, Gareth; Taylor, Arthur; Wilm, Bettina; Poptani, Harish; Murray, Patricia; Goldring, Chris E. P.; Park, B. Kevin

    2017-10-01

    Regenerative medicine therapies hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. Most progress in this field to date has been achieved with cell-based regenerative medicine therapies, with over a thousand clinical trials performed up to 2015. However, lack of adequate safety and efficacy data is currently limiting wider uptake of these therapies. To facilitate clinical translation, non-invasive in vivo imaging technologies that enable careful evaluation and characterisation of the administered cells and their effects on host tissues are critically required to evaluate their safety and efficacy in relevant preclinical models. This article reviews the most common imaging technologies available and how they can be applied to regenerative medicine research. We cover details of how each technology works, which cell labels are most appropriate for different applications, and the value of multi-modal imaging approaches to gain a comprehensive understanding of the responses to cell therapy in vivo.

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

    Directory of Open Access Journals (Sweden)

    Helen B. Stone

    2016-02-01

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

  10. Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

    Science.gov (United States)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

    Versteegden, L.R.; Jonge, P. de; Hout, J. in't; Kuppevelt, T.H. van; Oosterwijk, E.; Feitz, W.F.J.; Vries, R.B.M. de; Daamen, W.F.

    2017-01-01

    CONTEXT: Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. OBJECTIVE: To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order

  12. Preclinical studies on gadolinium neutron capture therapy

    International Nuclear Information System (INIS)

    Akine, Yasuyuki

    1994-01-01

    Gadolinium neutron capture therapy is based on radiations (photons and electrons) produced in the tumor by a nuclear reaction between gadolinium and lower-energy neutrons. Studies with Chinese hamster cells have shown that the radiation effect resulting from gadolinium neutron capture reactions is mostly of low LET and that released electrons are the significant component in the over-all dose. Biological dosimetry revealed that the dose does not seem to increase in proportion to the gadolinium concentration, leading to a conclusion that there is a range of gadolinium concentrations most efficient for gadolinium neutron capture therapy. The in vivo studies with transplantable tumors in mice and rabbits have revealed that close contact between gadolinium and the cell is not necessarily required for cell inactivation and that gadolinium delivery selective to tumors is crucial. The results show that the potential of gadolinium neutron capture therapy as a therapeutic modality appears very promising. (author)

  13. Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies

    Directory of Open Access Journals (Sweden)

    A.G.M. Mostofa

    2017-06-01

    Full Text Available Thymoquinone (TQ, the main bioactive component of Nigella sativa, has been found to exhibit anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Moreover, TQ can specifically sensitize tumor cells toward conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy and simultaneously minimize therapy-associated toxic effects in normal cells. In this review, we summarized the adjuvant potential of TQ as observed in various in vitro and in vivo animal models and discussed the pharmacological properties of TQ to rationalize its supplementary role in potentiating the efficacy of standard therapeutic modalities namely surgery, radiotherapy, chemotherapy, and immunotherapy. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical levels to delineate its implied utility as a novel complementary adjuvant therapy for cancer treatment.

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

    Directory of Open Access Journals (Sweden)

    Kenneth S Plante

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

  15. Preliminary study for small animal preclinical hadrontherapy facility

    Energy Technology Data Exchange (ETDEWEB)

    Russo, G. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Pisciotta, P., E-mail: pietro.pisciotta@ibfm.cnr.it [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cirrone, G.A.P.; Romano, F. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Acquaviva, R. [University of Catania, Catania (Italy); Gilardi, M.C. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Cuttone, G. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy)

    2017-02-21

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  16. Preliminary study for small animal preclinical hadrontherapy facility

    Science.gov (United States)

    Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

    2017-02-01

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  17. Preliminary study for small animal preclinical hadrontherapy facility

    International Nuclear Information System (INIS)

    Russo, G.; Pisciotta, P.; Cirrone, G.A.P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M.C.; Cuttone, G.

    2017-01-01

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  18. Preclinical and clinical safety studies on DNA vaccines.

    NARCIS (Netherlands)

    Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

    2007-01-01

    DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and

  19. Resveratrol: A review of preclinical studies for human cancer prevention

    International Nuclear Information System (INIS)

    Athar, Mohammad; Back, Jung Ho; Tang Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

    2007-01-01

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations

  20. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Ilaria Naldi

    Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  1. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Science.gov (United States)

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  2. Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways

    International Nuclear Information System (INIS)

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Seth, Amlesh; Nafees, Sana; Rashid, Summya; Ali, Nemat; Sultana, Sarwat

    2011-01-01

    Graphical abstract: Diagrammatic presentation of the hypothesis of the article in a concise manner. It reveals the chemopreventive efficacy of GOH possibly through the modulation of multiple molecular targets. GOH inhibits ROS generation, NFκB and PCNA expression thereby abrogating inflammation and proliferation of tubular cells of kidney. Whereas, GOH induces effector caspase-3 expression both through mitochondrial signalling pathway and death receptor signalling pathway. Highlights: → Geraniol modulates renal carcinogenesis in Wistar rats. → It abrogates Fe-NTA induced oxidative stress, inflammation and hyperproliferation. → Promotes apoptosis via induction of both mitochondrial and death receptor pathway. → Thus, inhibits renal carcinogenesis by modulating multiple molecular targets. -- Abstract: In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200 mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NFκB, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein

  3. Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

    Science.gov (United States)

    Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D; Mitra, Ashim K

    2017-02-28

    Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Fish oil mitigates myosteatosis and improves chemotherapy efficacy in a preclinical model of colon cancer.

    Directory of Open Access Journals (Sweden)

    Alaa A Almasud

    Full Text Available This study aimed to assess whether feeding a diet containing fish oil was efficacious in reducing tumor- and subsequent chemotherapy-associated myosteatosis, and improving tumor response to treatment.Female Fischer 344 rats were fed either a control diet for the entire study (control, or switched to a diet containing fish oil (2.0 g /100 g of diet one week prior to tumor implantation (long term fish oil or at the start of chemotherapy (adjuvant fish oil. Chemotherapy (irinotecan plus 5-fluorouracil was initiated 2 weeks after tumor implantation (cycle-1 and 1 week thereafter (cycle-2. Reference animals received no tumor or treatment and only consumed the control diet. All skeletal muscle measures were conducted in the gastrocnemius. To assess myosteatosis, lipids were assessed histologically by Oil Red O staining and total triglyceride content was quantified by gas chromatography. Expression of adipogenic transcription factors were assessed at the mRNA level by real-time RT-PCR.Feeding a diet containing fish oil significantly reduced tumor- and subsequent chemotherapy-associated increases in skeletal muscle neutral lipid (p<0.001 and total triglyceride content (p<0.03, and expression of adipogenic transcription factors (p<0.01 compared with control diet fed animals. The adjuvant fish oil diet was as effective as the long term fish oil diet in mitigating chemotherapy-associated skeletal muscle fat content, and in reducing tumor volume during chemotherapy compared with control fed animals (p<0.01.Long term and adjuvant fish oil diets are equally efficacious in reducing chemotherapy-associated myosteatosis that may be occurring by reducing expression of transcription factors involved in adipogenesis/lipogenesis, and improving tumor-response to chemotherapy in a neoplastic model.

  5. Novel technology to prepare oral formulations for preclinical safety studies.

    Science.gov (United States)

    Niwa, Toshiyuki; Hashimoto, Naofumi

    2008-02-28

    A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

  6. Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies.

    Science.gov (United States)

    Homberg, Judith R; Kyzar, Evan J; Stewart, Adam Michael; Nguyen, Michael; Poudel, Manoj K; Echevarria, David J; Collier, Adam D; Gaikwad, Siddharth; Klimenko, Viktor M; Norton, William; Pittman, Julian; Nakamura, Shun; Koshiba, Mamiko; Yamanouchi, Hideo; Apryatin, Sergey A; Scattoni, Maria Luisa; Diamond, David M; Ullmann, Jeremy F P; Parker, Matthew O; Brown, Richard E; Song, Cai; Kalueff, Allan V

    2016-01-01

    Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

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

    Science.gov (United States)

    Walker, Suellen M.; Yaksh, Tony L.

    2015-01-01

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

  8. A crowdsourcing model for creating preclinical medical education study tools.

    Science.gov (United States)

    Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

    2013-06-01

    During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning.

  9. Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles

    Science.gov (United States)

    Vilos, Cristian; Velasquez, Luis A.; Rodas, Paula I.; Zepeda, Katherine; Bong, Soung-Jae; Herrera, Natalia; Cantin, Mario; Simon, Felipe; Constandil, Luis

    2015-01-01

    Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5–2.2 μm, and a negative ζ potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry. PMID:25915043

  10. Preclinical studies for increasing radiation response of malignant brain tumours

    International Nuclear Information System (INIS)

    Kalia, Vijay K.; Kumari, Kalyani; Sai Shyam; George, Jennifer; Shobha, A.G.; Chandrasekhar Sagar, B.K.; Lal, Jagath

    2013-01-01

    Malignant gliomas are the most common among the CNS cancers. Standard treatment for these tumours - comprises of surgery, followed by Radiotherapy (RT). Combination of Temozolomide (TMZ) increases survival, but hematological toxicities are also increased as compared to RT alone. The median survival depends on grade and location of tumour, as well as the age of the patient. Grade IV gliomas (GSMs) are third leading cause of cancer induced death in the age group of 15 to 34 years. Therefore, it is important to carry out further preclinical studies to develop more effective treatment of malignant gliomas. The present studies were carried out on different established malignant glioma cell lines. (U373MG) as well as primary monolayer cultures derived from biopsies obtained from patients with malignant gliomas. Exponentially growing cells were exposed to TMZ, Lonidamine (LND) (in 0.1% DMSO), or 2-Deoxy-D-Glucose (2-DG, aqueous solution) - with or without 60 Co-Gamma-rays (1- 2 Gy). The drugs were removed 4 hours after irradiation and the cultures were processed further for different assays of damage. Short term (4 h) treatments with TMZ 20 μM, LND 100 μM or their combination; did not induce micronuclei formation in the unirradiated cultures of U373MG cells. However, radiation (2 Gy) induced micronuclei was significantly increased by drug treatments. In primary cultures from different tumours, TMZ (≤ 10 μM) or 2-DG (1 mM), or gamma-irradiation (1-2 Gy) induced micronuclei and/ or apoptosis. The effects, however, varied in different tumours. These data show that clinically achievable, very low concentrations of these drugs could induce cellular damage and death; and increase radiosensitivity of malignant gliomas. Therefore, adjuvants like Lonidamine and 2-DG, with non-overlapping toxicities, could optimize treatment of malignant gliomas, by reducing the side effects of radio-chemotherapy. (author)

  11. Preclinical Efficacy of [V4Q5]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer.

    Science.gov (United States)

    Garona, Juan; Sobol, Natasha T; Pifano, Marina; Segatori, Valeria I; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2018-06-01

    Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4Q5]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of AVPR2 present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained i.v. treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-FU resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

  12. Preclinical experimental stress studies: protocols, assessment and comparison.

    Science.gov (United States)

    Bali, Anjana; Jaggi, Amteshwar Singh

    2015-01-05

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

  13. Preclinical Efficacy of Clumping Factor A in Prevention of Staphylococcus aureus Infection

    OpenAIRE

    Li, Xue; Wang, Xiaogang; Thompson, Christopher D.; Park, Saeyoung; Park, Wan Beom; Lee, Jean C.

    2016-01-01

    ABSTRACT Treatment of Staphylococcus aureus infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent staphylococcal infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant staphylococcal infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel...

  14. Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison; Kass, David A; McNally, Elizabeth M; Metzger, Joseph M; Spurney, Christopher F; Kinnett, Kathi

    2016-02-01

    A recent working group meeting focused on contemporary cardiac issues in Duchenne muscular dystrophy (DMD) was hosted by the National Heart, Lung, and Blood Institute in collaboration with the Parent Project Muscular Dystrophy. An outcome of this meeting was to provide freely available detailed protocols for preclinical animal studies. The goal of these protocols is to improve the quality and reproducibility of cardiac preclinical studies aimed at developing new therapeutics for the prevention and treatment of DMD cardiomyopathy.

  15. Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

    Science.gov (United States)

    Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

    2016-01-01

    Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

  16. Preclinical efficacy and safety of an anti-IL-1β vaccine for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Gunther Spohn

    2014-01-01

    Full Text Available Neutralization of the inflammatory cytokine interleukin-1β (IL-1β is a promising new strategy to prevent the β-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1β consisting of a detoxified version of IL-1β chemically cross-linked to virus-like particles of the bacteriophage Qβ. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1β, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1β. Neutralization of IL-1β by vaccine-induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic β-cells. Hence, immunization with IL-1β conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes.

  17. Preclinical efficacy and safety of an anti-IL-1β vaccine for the treatment of type 2 diabetes

    Science.gov (United States)

    Spohn, Gunther; Schori, Christian; Keller, Iris; Sladko, Katja; Sina, Christina; Guler, Reto; Schwarz, Katrin; Johansen, Pål; Jennings, Gary T; Bachmann, Martin F

    2014-01-01

    Neutralization of the inflammatory cytokine interleukin-1β (IL-1β) is a promising new strategy to prevent the β-cell destruction, which leads to type 2 diabetes. Here, we describe the preclinical development of a therapeutic vaccine against IL-1β consisting of a detoxified version of IL-1β chemically cross-linked to virus-like particles of the bacteriophage Qβ. The vaccine was well tolerated and induced robust antibody responses in mice, which neutralized the biological activity of IL-1β, as shown both in cellular assays and in challenge experiments in vivo. Antibody titers were long lasting but reversible over time and not associated with the development of potentially harmful T cell responses against IL-1β. Neutralization of IL-1β by vaccine-induced antibodies had no influence on the immune responses of mice to Listeria monocytogenes and Mycobacterium tuberculosis. In a diet-induced model of type 2 diabetes, immunized mice showed improved glucose tolerance, which was mediated by improved insulin secretion by pancreatic β-cells. Hence, immunization with IL-1β conjugated to virus-like particles has the potential to become a safe, efficacious, and cost-effective therapy for the prevention and long-term treatment of type 2 diabetes. PMID:26015986

  18. Preclinical efficacy of the MDM2 inhibitor RG7112 in MDM2 amplified and TP53 wild-type glioblastomas

    Science.gov (United States)

    Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane; Pelton, Kristine; Haidar, Samer; Levasseur, Camille; Guehennec, Jeremy; Knoff, David; Labussiere, Marianne; Marie, Yannick; Ligon, Azra H.; Mokhtari, Karima; Hoang-Xuan, Khe; Sanson, Marc; Alexander, Brian M; Wen, Patrick Y.; Delattre, Jean-Yves; Ligon, Keith L.; Idbaih, Ahmed

    2016-01-01

    Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. PMID:26482041

  19. Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

    Science.gov (United States)

    Britton, Gabrielle B

    2012-02-01

    There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.

  20. Preclinical Efficacy of Clumping Factor A in Prevention of Staphylococcus aureus Infection

    Directory of Open Access Journals (Sweden)

    Xue Li

    2016-02-01

    Full Text Available Treatment of Staphylococcus aureus infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent staphylococcal infections remains a priority. To determine whether clumping factor A (ClfA is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant staphylococcal infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone. ClfA immunization induced the production of functional antibodies in rabbits and mice that blocked S. aureus binding to fibrinogen and were opsonic for S. aureus strains that produced little or no capsular polysaccharide. Mice immunized with ClfA showed a modest reduction in the bacterial burden recovered from subcutaneous abscesses provoked by S. aureus USA300 strain LAC. In addition, the ClfA vaccine reduced lethality in a sepsis model following challenge with strain Newman, but not ST80. Vaccination with ClfA did not protect against surgical wound infection, renal abscess formation, or bacteremia. Passive immunization with antibodies to ClfA did not protect against staphylococcal bacteremia in mice or catheter-induced endocarditis in rats. Some enhancement of bacteremia was observed by ClfA immunization or passive administration of ClfA antibodies when mice were challenged by the intraperitoneal route. Although rodent models of staphylococcal infection have their limitations, our data do not support the inclusion of ClfA in an S. aureus multivalent vaccine.

  1. Preclinical Efficacy of Clumping Factor A in Prevention of Staphylococcus aureus Infection

    Science.gov (United States)

    Li, Xue; Wang, Xiaogang; Thompson, Christopher D.; Park, Saeyoung; Park, Wan Beom

    2016-01-01

    ABSTRACT Treatment of Staphylococcus aureus infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent staphylococcal infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant staphylococcal infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone. ClfA immunization induced the production of functional antibodies in rabbits and mice that blocked S. aureus binding to fibrinogen and were opsonic for S. aureus strains that produced little or no capsular polysaccharide. Mice immunized with ClfA showed a modest reduction in the bacterial burden recovered from subcutaneous abscesses provoked by S. aureus USA300 strain LAC. In addition, the ClfA vaccine reduced lethality in a sepsis model following challenge with strain Newman, but not ST80. Vaccination with ClfA did not protect against surgical wound infection, renal abscess formation, or bacteremia. Passive immunization with antibodies to ClfA did not protect against staphylococcal bacteremia in mice or catheter-induced endocarditis in rats. Some enhancement of bacteremia was observed by ClfA immunization or passive administration of ClfA antibodies when mice were challenged by the intraperitoneal route. Although rodent models of staphylococcal infection have their limitations, our data do not support the inclusion of ClfA in an S. aureus multivalent vaccine. PMID:26838725

  2. Proteomics and antivenomics of Papuan black snake (Pseudechis papuanus) venom with analysis of its toxicological profile and the preclinical efficacy of Australian antivenoms.

    Science.gov (United States)

    Pla, Davinia; Bande, Benjamin W; Welton, Ronelle E; Paiva, Owen K; Sanz, Libia; Segura, Álvaro; Wright, Christine E; Calvete, Juan J; Gutiérrez, José María; Williams, David J

    2017-01-06

    The Papuan black snake (Pseudechis papuanus Serpentes: Elapidae) is endemic to Papua New Guinea, Indonesian Papua and Australia's Torres Strait Islands. We have investigated the biological activity and proteomic composition of its venom. The P. papuanus venom proteome is dominated by a variety (n≥18) of PLA 2 s, which together account for ~90% of the venom proteins, and a set of low relative abundance proteins, including a short-neurotoxic 3FTx (3.1%), 3-4 PIII-SVMPs (2.8%), 3 cysteine-rich secretory proteins (CRISP; 2.3%) 1-3 l-amino acid oxidase (LAAO) molecules (1.6%). Probing of a P. papuanus cDNA library with specific primers resulted in the elucidation of the full-length nucleotide sequences of six new toxins, including vespryn and NGF not found in the venom proteome, and a calglandulin protein involved in toxin expression with the venom glands. Intravenous injection of P. papuanus venom in mice induced lethality, intravascular haemolysis, pulmonary congestion and oedema, and anticoagulation after intravenous injection, and these effects are mainly due to the action of PLA 2 s. This study also evaluated the in vivo preclinical efficacy of Australian black snake and polyvalent Seqirus antivenoms. These antivenoms were effective in neutralising the lethal, PLA 2 and anticoagulant activities of P. papuanus venom in mice. On the other hand, all of the Seqirus antivenoms tested using an antivenomic approach exhibited strong immunorecognition of all the venom components. These preclinical results suggest that Australian Seqirus 1 antivenoms may provide paraspecific protection against P. papuanus venom in humans. The toxicological profile and proteomic composition of the venom of the Papuan black snake, Pseudechis papuanus, a large diurnal snake endemic to the southern coast of New Guinea and a handful of close offshore islands, were investigated. Intravenous injection of P. papuanus venom in mice induced intravascular hemolysis, pulmonary congestion and edema

  3. The effect of learning styles and study behavior on success of preclinical students in pharmacology.

    Science.gov (United States)

    Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

    2016-01-01

    To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

  4. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials.

    Science.gov (United States)

    Pardanani, A

    2008-01-01

    The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)-signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy has been demonstrated in mouse models of JAK2V617F-induced disease. In addition, ex vivo growth of progenitor cells from MPD patients harboring JAK2V617F or MPLW515L/K mutations is also potently inhibited. JAK2 inhibitors currently in clinical trials can be grouped into those designed to primarily target JAK2 kinase (JAK2-selective) and those originally developed for non-MPD indications, but that nevertheless have significant JAK2-inhibitory activity (non-JAK2 selective). This article discusses the rationale for using JAK2 inhibitors for the treatment of MPD, as well as relevant aspects of clinical trial development for these patients. For instance, which group of MPD patients is appropriate for initial Phase I studies? Should JAK2V617F-negative MPD patients be included in the initial studies? What are the likely consequences of 'off-target' JAK3 and wild-type JAK2 inhibition? How should treatment responses be monitored?

  5. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study.

    Directory of Open Access Journals (Sweden)

    Maha M Eissa

    Full Text Available Miltefosine (MFS is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD. This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%, good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs

  6. Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody.

    Science.gov (United States)

    Fu, Jie; Wang, Fang; Dong, Li-Hou; Zhang, Jing; Deng, Cheng-Lian; Wang, Xue-Li; Xie, Xin-Yao; Zhang, Jing; Deng, Ruo-Xian; Zhang, Li-Bo; Wu, Hai; Feng, Hui; Chen, Bo; Song, Hai-Feng

    2017-05-01

    JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC 50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC 50 of 3.0 and 3.1 nmol/L, respectively. Furthermore, JS-001 displayed distinct species cross-reactivity: it could bind to the PD-1 antigen on the peripheral blood mononuclear cells (PBMCs) of humans and cynomolgus monkeys, but not to those of mice and woodchucks; the K d values for the interaction between JS-001 and PD-1 antigens on CD8 + T cells of human and cynomolgus monkey were 2.1 nmol/L and 1.2 nmol/L, respectively. In vitro, treatment with JS-001 (0.01-10 μg/mL) dose-dependently stimulated human T cell proliferation, as well as IFN-γ and TNF-α secretion. In HBsAg-vaccinated cynomolgus monkeys, the expression of PD-1 + /CD4 + and PD-1 + /CD8 + was significantly elevated, intramuscular injection of JS-001 (1 and 10 mg/kg) resulted in dramatic decreases in PD-1 + /CD4 + and PD-1 + /CD8 + expression in a dose-dependent manner, which was supported by PD-1 receptor occupancy (RO) results. In the PK study, 18 cynomolgus monkeys treated with single, ascending doses of 1, 10, and 75 mg/kg, and another 6 cynomolgus monkeys received 10 mg/kg successive administration. The plasma clearance of JS-001 followed a linear PK profile with single administration in the 1 and 10 mg/kg groups and a non-linear PK profile in the 75 mg/kg group. In the successive 10 mg/kg administration group, no drug accumulation was observed. But the AUC from the last exposure was lower than that of the first

  7. Reproducibility of preclinical animal research improves with heterogeneity of study samples

    Science.gov (United States)

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

    2018-01-01

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

  8. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

    Directory of Open Access Journals (Sweden)

    Cristina Ferrari

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

  9. Modeling Acute Traumatic Hemorrhagic Shock Injury: Challenges and Guidelines for Preclinical Studies.

    Science.gov (United States)

    Tremoleda, Jordi L; Watts, Sarah A; Reynolds, Penny S; Thiemermann, Christoph; Brohi, Karim

    2017-12-01

    Trauma is responsible for a large proportion of the world's burden of disease, and is by far the biggest killer of young adults. Hemorrhage is the leading cause of preventable death and its effects are directly correlated with the incidence multi-organ failure in survivors. Trauma research is challenging due to patient heterogeneity, limited randomized controlled trials, and in vitro studies that fail to mimic the systemic injury response. Preclinical research remains essential for mechanistic and therapeutic discovery. Yet modeling the multifaceted nature of traumatic injury poses important experimental and welfare challenges associated with the onset of injury and prehospital and intra-operative care, the limited inter-species validation of coagulation profiles, the use of anesthesia/analgesia, and its impact on the systemic response to trauma; and the challenge of sustaining intensive care in recovery models. Proper model selection depends on the purpose of a given model and the criteria by which the experimental readouts will be clinically relevant. Such complexity warrants further refinement of experimental methodology and outcome measures to improve its clinical efficacy, while ensuring animal well-being. We review the experimental methodologies currently used for modeling traumatic hemorrhagic shock and addressing their impact on clinical translation. The aim of the review is to improve transparency and form a consensus when reporting methodology in trauma modeling.

  10. Pre-clinical efficacy assessment of Malva sylvestris on chronic skin inflammation.

    Science.gov (United States)

    Prudente, Arthur S; Sponchiado, Graziela; Mendes, Daniel A G B; Soley, Bruna S; Cabrini, Daniela A; Otuki, Michel F

    2017-09-01

    In the search for improved quality of life, the treatment of skin diseases like psoriasis (hyperproliferative disease) is valid, since it causes huge social discomfort to the patient. In this context, earlier studies showed that Malva sylvestris L. has anti-inflammatory activity demonstrated by acute animal models of skin inflammation, becoming a promising target for further studies. The present investigation aimed to verify the effect of hydroalcoholic extract of M. sylvestris (HEMS) on the chronic inflammatory and hyperproliferative response caused by multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on mouse ears. Topical application of HEMS reduced oedema, leukocyte migration (mono- and polymorphonuclear cells) and keratinocyte hyperproliferation, confirmed by histology and proliferating cell nuclear antigen (PCNA) immunostaining. It was found that the anti-inflammatory effects of the extract did not involve the glucocorticoid system, and its incubation with HaCaT keratinocytes caused low toxicity and reduced cell proliferation by apoptosis. Thus, HEMS proved to be effective as an anti-psoriatic therapy, with the ability to prevent keratinocyte hyperproliferation and with low toxicity by topical application. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Laurent Auboire

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

  12. Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

    Science.gov (United States)

    Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

    2017-01-01

    Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery

  13. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Kuo-Chen Wei

    Full Text Available The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI-monitored focused ultrasound (FUS-induced blood-brain barrier (BBB disruption to enhance Temozolomide (TMZ delivery for improving Glioblastoma Multiforme (GBM treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI, animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

  14. Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

    Directory of Open Access Journals (Sweden)

    Melissa Lo Monaco

    2018-01-01

    Full Text Available Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs or induced pluripotent stem cells (iPSCs have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

  15. Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures.

    Science.gov (United States)

    Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

    2018-01-01

    Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

  16. Investigating the Efficacy of Practical Skill Teaching: A Pilot-Study Comparing Three Educational Methods

    Science.gov (United States)

    Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

    2013-01-01

    Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a…

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

    International Nuclear Information System (INIS)

    Medin, Paul M.; Boike, Thomas P.

    2011-01-01

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

  18. Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies

    NARCIS (Netherlands)

    Homberg, J.R.; Kyzar, E.J.; Stewart, A.M.; Nguyen, M; Poudel, M.K.; Echevarria, D.J.; Collier, A.D.; Gaikwad, S.; Klimenko, V.M.; Norton, W.; Pittman, J.; Nakamura, S.; Koshiba, M.; Yamanouchi, H.; Apryatin, S.A.; Scattoni, M.L.; Diamond, D.M.; Ullmann, J.F.; Parker, M.O.; Brown, R.E.; Song, C.; Kalueff, A.V.

    2016-01-01

    INTRODUCTION: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. AREAS COVERED: Herein, the authors discuss the neurobiological mechanisms of

  19. Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium

    DEFF Research Database (Denmark)

    Knopp, K.L.; Stenfors, C.; Baastrup, Cathrine Søndergaard

    2015-01-01

    that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance...... and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome...... development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity...

  20. Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

    Directory of Open Access Journals (Sweden)

    Samarasekera Dharmabandu N

    2011-05-01

    Full Text Available Abstract Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA, strategic approach (SA and surface apathetic or superficial approach (SAA. The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST questionnaire. Results A total of 187 pre clinical (M: F = 96:91, 124 clinical (M: F = 61:63 and 53 post graduate trainees (M: F = 50:3 participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01, but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04 but females preferred a passive transmission of information (p Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed.

  1. Preclinical Studies of a Kidney Safe Iodinated Contrast Agent.

    Science.gov (United States)

    Rowe, Elizabeth S; Rowe, Vernon D; Biswas, Sangita; Mosher, Gerold; Insisienmay, Lovella; Ozias, Marlies K; Gralinski, Michael R; Hunter, John; Barnett, James S

    2016-09-01

    Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the use of iodinated contrast agents. This problem is particularly acute in interventional neurology and interventional cardiology, probably due to the intra-arterial route of injection, high contrast volumes, and preexisting risk factors of these patients. In an attempt to develop a contrast agent that is less damaging to the kidneys, we have studied the effects of adding a small amount of the substituted cyclodextrin, sulfobutyl-ether-β-cyclodextrin (SBECD), to iohexol in rodent models of renal toxicity. Renally compromised mice and rats were injected with iohexol and iohexol-SBECD via the tail vein. The renal pathology, creatinine clearance, and survival benefits of iohexol-SBECD were studied. The safety of direct intra-arterial injection of the iohexol-SBECD formulation was studied in a dog heart model system. Mechanism of action studies in cell culture model using a human kidney cell line was performed using flow cytometry. Nephrotoxicity was significantly reduced using iohexol-SBECD compared to iohexol alone, at mole ratios of iohexol:SBECD of 1:0.025. SBECD increased survival from 50% to 88% in a rat survival study. In the dog heart model, iohexol-SBECD was safe. Cell culture studies suggest that SBECD interferes with the early stages of contrast-induced apoptosis in a human renal cell line. We have shown that the addition of a small amount of SBECD (one molecule of SBECD per 40 iohexol molecules) significantly protects rodent kidneys from CI-AKI. Further development of this new formulation of iodinated contrast is warranted. © 2016 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.

  2. Reproducibility and replicability of rodent phenotyping in preclinical studies

    NARCIS (Netherlands)

    Kafkafi, Neri; Agassi, Joseph; Chesler, Elissa J.; Crabbe, John C.; Crusio, Wim E.; Eilam, David; Gerlai, Robert; Golani, Ilan; Gomez-Marin, Alex; Heller, Ruth; Iraqi, Fuad; Jaljuli, Iman; Karp, Natasha A.; Morgan, Hugh; Nicholson, George; Pfaff, Donald W.; Richter, S. Helene; Stark, Philip B.; Stiedl, Oliver; Stodden, Victoria; Tarantino, Lisa M.; Tucci, Valter; Valdar, William; Williams, Robert W.; Würbel, Hanno; Benjamini, Yoav

    The scientific community is increasingly concerned with the proportion of published “discoveries” that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex

  3. Intradermal Inactivated Poliovirus Vaccine: A Preclinical Dose-Finding Study

    OpenAIRE

    Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

    2014-01-01

    Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial...

  4. Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinoma.

    Science.gov (United States)

    Galal El-Shemi, A; Mohammed Ashshi, A; Oh, E; Jung, B-K; Basalamah, M; Alsaegh, A; Yun, C-O

    2018-01-01

    Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.

  5. Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Anastasia A. Ionkina

    2017-05-01

    Full Text Available PurposeTriple-negative breast cancer (TNBC is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076.Experimental designp53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance.ResultsSensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance.ConclusionENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored.

  6. Laparoscopic kidney orthotopic transplant: preclinical study in the pig model.

    Science.gov (United States)

    He, B; Musk, G C; Mou, L; Waneck, G L; Delriviere, L

    2013-06-01

    Laparoscopic surgery has rapidly expanded in clinical practice replacing conventional open surgery over the last three decades. Laparoscopic donor nephrectomy has been favored due to its multiple benefits. The aim of this study was to explore the safety and feasibility of kidney transplantation by a laparoscopic technique in a pig model. The study was approved by the university animal ethics committee. Eight female pigs (Sus Scrofra, weighing 45-50 kg) were divided into 2 groups: group I included 4 animals that underwent laparoscopic kidney orthotopic transplantation on the left side. The right kidney was remained functional in situ. The pigs recovered and were observed for 1 week. In the 4 hosts group II pigs underwent a laparoscopic kidney transplantation on the left side. With simultaneous clipping of the right ureter. After recovery, the pigs were observed for 4 weeks. A laparotomy for examination was performed prior to euthanasia. All 4 group I pigs survived for 1 week. The laparotomy showed normal graft perfusion with wall patent renal artery and vein as well as satisfactory urine output upon transection of ureter in 3 hosts. Renal artery stenosis occurred in one pig. In The Immediate kidney graft function was achieved in 3 group II pigs. The fourth died following extubation due to laryngospasm despite a functional graft. The average creatinine levels were 195.5 μmol/L on day 3; 224.5 μmol/L at week 1; 127 μmol/L at week 2; 182.7 umol/L at week 3; and 154.7 umol/L at week 4. Laparoscopic kidney transplantation was feasible and safe in a pig model with immediate graft function. This study will provide further evidence to support application of laparoscopic technique to human kidney transplant. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Association of taxanes and radiotherapy: preclinical and clinical studies

    International Nuclear Information System (INIS)

    Hennequin, C.

    2004-01-01

    Taxanes (paclitaxel and docetaxel) stabilized microtubules against depolymerization, and inhibit their function. Their radiosensitizing properties have been discovered more than 10 years ago; they synchronized tumor cells in G2/M phase, the most radiosensitive portion of the cell cycle. Other radiosensitizing mechanisms have been also discussed, as reoxygenation, promotion of radio-apoptosis and anti-angiogenic cooperation. Many phase I and II studies have been performed, essentially in bronchus and head and neck carcinomas. In lung cancer, paclitaxel was delivered weekly at a dose of 60 mg/m 2 . Many studies combined cisplatin or carbo-platin with paclitaxel, demonstrating that this combination is feasible and efficient. Only one phase III trial was reported; after two cycles of chemotherapy for inoperable lung cancers, radiotherapy was delivered, with or without paclitaxel radiosensitization: a benefit in disease-free survival was observed for the combination arm. In head and neck carcinomas, concomitant association of cisplatin, paclitaxel and radiation was feasible and showed promising results. Clinical trials with docetaxel are in progress. (author)

  8. Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

    Science.gov (United States)

    Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

    2015-05-01

    Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  9. Cocoa Diet and Antibody Immune Response in Preclinical Studies

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    Mariona Camps-Bossacoma

    2017-06-01

    Full Text Available The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system’s functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status.

  10. Recent Developments in Instrumentation for Pre-Clinical Imaging Studies

    International Nuclear Information System (INIS)

    Meikle, S.R.

    2002-01-01

    Full text: Recent advances in imaging instrumentation have led to a variety of tomograph designs for dedicated pre clinical imaging of laboratory animals. These advances make it possible to image and quantify the kinetics of radiolabelled pharmaceuticals in a wide range of animal models from rodents to non-human primates. Applications include evaluation of promising new radiopharmaceuticals, study of the molecular origins of human disease and evaluation of new forms of therapy. These applications and advances in instrumentation are equally applicable to positron emitters and single photon emitters. This paper provides an overview of recent advances which have led to the current state-of-the-art in pre clinical imaging. The common inorganic scintillators that have been used for SPECT and PET, including some of the promising materials recently studied. The current crystal of choice for SPECT imaging is NaI(Tl) because of its high light output and density which make it well suited to imaging photons in the 100-200 keV range. However, NaI(Tl) has the disadvantage that it must be hermetically sealed to prevent absorption of moisture from the environment. Therefore, investigators have explored a number of alternative inorganic crystals, including CsI(Tl) and cerium-doped yttrium aluminium perovskite (YAP), as well as solid state detectors such as cadmium zinc telluride (CZT). Many of the crystals used in SPECT have also been tried for PET, including NaI(Tl) and YAP. However these crystals have lower stopping power than BGO and NaI(Tl) is also relatively slow. A very promising scintillator for PET is cerium-doped lutetium oxyorthosilicate (LSO) (1) which has similar stopping power to BGO and relatively high light output and fast decay. The first PET scanner to use LSO was the UCLA animal scanner, microPET, which also makes use of a number of other new technologies and unique design features. Recently, improvements in multi-anode and crossed wire position sensitive

  11. Curcumin-Artemisinin Coamorphous Solid: Xenograft Model Preclinical Study

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    M. K. Chaitanya Mannava

    2018-01-01

    Full Text Available Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR, we evaluated Curcumin-Pyrogallol (CUR-PYR cocrystal and Curcumin-Artemisinin (CUR-ART coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose. Moreover, in simulated gastric and intestinal fluids (SGF and SIF, CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg. CUR-ART showed higher therapeutic effect and inhibited approximately 62% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg by i.v. administration.

  12. Reproducibility and replicability of rodent phenotyping in preclinical studies.

    Science.gov (United States)

    Kafkafi, Neri; Agassi, Joseph; Chesler, Elissa J; Crabbe, John C; Crusio, Wim E; Eilam, David; Gerlai, Robert; Golani, Ilan; Gomez-Marin, Alex; Heller, Ruth; Iraqi, Fuad; Jaljuli, Iman; Karp, Natasha A; Morgan, Hugh; Nicholson, George; Pfaff, Donald W; Richter, S Helene; Stark, Philip B; Stiedl, Oliver; Stodden, Victoria; Tarantino, Lisa M; Tucci, Valter; Valdar, William; Williams, Robert W; Würbel, Hanno; Benjamini, Yoav

    2018-04-01

    The scientific community is increasingly concerned with the proportion of published "discoveries" that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex interaction between genotype and environment; the definitions of behavioral constructs; and the use of laboratory mice and rats as model species for investigating human health and disease mechanisms. In January 2015, researchers from various disciplines gathered at Tel Aviv University to discuss these issues. The general consensus was that the issue is prevalent and of concern, and should be addressed at the statistical, methodological and policy levels, but is not so severe as to call into question the validity and the usefulness of model organisms as a whole. Well-organized community efforts, coupled with improved data and metadata sharing, have a key role in identifying specific problems and promoting effective solutions. Replicability is closely related to validity, may affect generalizability and translation of findings, and has important ethical implications. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

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    Maximilian Richter

    2016-01-01

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

  14. A study of preclinical myocardial damage in diabetes mellitus

    International Nuclear Information System (INIS)

    Mizuno, Sumio

    1986-01-01

    The scintigrams were evaluated by visual and circumferential profile analysis. In addition, mechanocardiography (MCG) and functional tests of the autonomic nerves were done. Coronary angiography and left ventriculography (LVG) were performed in 22 patients having cardiac symptoms. Of 61 patients, 20 (32, 8 %) showed perfusion defects in the scintigram (positive cases), consisting of 5 with stress-induced defect and 15 with fixed defect. The scintigrams in 41 patients showed normal perfusion of thallium (negative cases). The positive cases had more severe diabetic complications and longer duration of diabetes compared with the negative cases. The positive cases were incident to the treatment with insulin or oral drugs. Both systolic time intervals (STIs) in MCG and coefficients of variation of heart rate (CV) decreased in the diabetics, particularly in the positive cases. However, the decrement of STIs and CV was not significantly different in quantity between positive and negative cases; results therefore suggest that these two parameters may not correlate directly with the perfusion defects on Tl-201 scintigraphy. Twenty-two patients, 9 positive and 13 negative cases, had undergone cardiac catheterization, and showed normal coronary angiograms. On hemodynamic study, an ejection fraction decreased more in the positive cases than in the negative cases. The 13 negative cases showed normal wall motion in the LVG. Seven of the 9 positive cases, however, showed local hypokinetic wall motion. Abnormalities of the LVG corresponded to findings of the scintigram, i. e., perfusion defects or decrement of washout rate. On circumferential profile analysis, the mean washout rate of the whole heart decreased only in the positive cases. (J.P.N.)

  15. Learning style preferences: A study of pre-clinical medical students in Barbados

    OpenAIRE

    OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

    2017-01-01

    Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compar...

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  17. Exploratory study of factors related to educational scores of first preclinical year medical students.

    Science.gov (United States)

    Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

    2014-03-01

    The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P satisfaction.

  18. Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.

    Science.gov (United States)

    Xu, Chunxiao; Zhang, Yanping; Rolfe, P Alexander; Hernández, Vivian M; Guzman, Wilson; Kradjian, Giorgio; Marelli, Bo; Qin, Guozhong; Qi, Jin; Wang, Hong; Yu, Huakui; Tighe, Robert; Lo, Kin-Ming; English, Jessie M; Radvanyi, Laszlo; Lan, Yan

    2017-10-01

    Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies. Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt - mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8 + T cells was evaluated by ELISpot assay. Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8 + T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8 + T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy. Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

    Science.gov (United States)

    Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

    2018-02-01

    OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

  20. Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems

    International Nuclear Information System (INIS)

    Chang, Hae Ryung; Park, Hee Seo; Ahn, Young Zoo; Nam, Seungyoon; Jung, Hae Rim; Park, Sungjin; Lee, Sang Jin; Balch, Curt; Powis, Garth; Ku, Ja-Lok; Kim, Yon Hui

    2016-01-01

    “Biomarker-driven targeted therapy,” the practice of tailoring patients’ treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 – 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which

  1. Dementia, preclinical studies in neurodegeneration and its potential for translational medicine in SouthAmerica

    Directory of Open Access Journals (Sweden)

    Gloria Patricia Cardona Gomez

    2016-12-01

    Full Text Available Latin-American people with dementia will increase in a 368% in 2050, higher than USA and Europe. In addition, to sporadic dementia type Alzheimer and vascular dementia progression after Cerebrovascular disease, the statistics are increased in Colombia by specific populations affected with pure neurodegenerative and vascular dementias like autosomical dominant familial Alzheimer´s disease and CADASIL. In spite of the enormous human and economical effort and investment, neither sporadic nor genetic kinds of dementia progression have been prevented or blocked yet. Currently, exist several animal models that partially solve the understanding of the neurodegenerative etiopathogenesis and its treatment. However, when the potential therapies are translated to humans, those do not work or present a limited action. Main difficulties are the diverse comorbility associated to the cause and/or several affected brain regions, reducing the efficacy of some therapies which are limited to a tissue-specific action or modulating a kind of neurotransmission. Global investigation suggests that a general prevention could be achieved with the improvement in the quality of lifestyle, including healthy diet, physical and mental activity, and avoiding mechanical or chemical pro-inflammatory events in an early stage in the most of non-communicable diseases. In this review, we present some molecular targets and preclinical studies in animal models to propose strategies that could be useful in a future translation to prevent or block neurodegeneration: One is gene therapy silencing pathogenic genes in critical brain areas where excitotoxicity arise and spread. Another is to take advantage of the natural source and its wide biodiversity of natural products some of them identified by the blocking and prevention of neurodegeneration. On the other side, the casuistic of pure dementias in the Latin-American region give an exceptional opportunity to understand the pathogenesis

  2. Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

    Science.gov (United States)

    Sjögren, E; Halldin, M M; Stålberg, O; Sundgren-Andersson, A K

    2018-05-01

    The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (IC 50 ) determined was in the range of 3-32 nmol/L and 10-501 nmol/L using CHO-K1 and dorsal root ganglion cultures, respectively. In vivo, all compounds showed dose-dependent reduction in capsaicin-evoked pain-related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin in situ. This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as

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

    Science.gov (United States)

    Walker, Suellen M; Yaksh, Tony L

    2012-09-01

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

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

    OpenAIRE

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

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis act...

  5. Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

    Science.gov (United States)

    Sarris, Jerome; McIntyre, Erica; Camfield, David A

    2013-03-01

    Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase

  6. Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

    Directory of Open Access Journals (Sweden)

    Sam Illingworth

    2017-06-01

    Full Text Available Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

  7. Biological basis of sex differences in drug abuse: preclinical and clinical studies.

    Science.gov (United States)

    Lynch, Wendy J; Roth, Megan E; Carroll, Marilyn E

    2002-11-01

    The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

  8. Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome.

    Science.gov (United States)

    Bagley, Mark C; Davis, Terence; Dix, Matthew C; Fusillo, Vincenzo; Pigeaux, Morgane; Rokicki, Michal J; Kipling, David

    2010-09-01

    The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use. Microwave irradiation using a stop-flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C-S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield. This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.

  9. Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.

    Science.gov (United States)

    Wallace, Lindsay M; Saad, Nizar Y; Pyne, Nettie K; Fowler, Allison M; Eidahl, Jocelyn O; Domire, Jacqueline S; Griffin, Danielle A; Herman, Adam C; Sahenk, Zarife; Rodino-Klapac, Louise R; Harper, Scott Q

    2018-03-16

    RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.

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

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    Cheng eWang

    2012-10-01

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

  11. Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies.

    Science.gov (United States)

    Arenaza-Urquijo, Eider M; Vemuri, Prashanthi

    2018-04-10

    Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment. © 2018 American Academy of Neurology.

  12. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  13. Value of shared preclinical safety studies - The eTOX database.

    Science.gov (United States)

    Briggs, Katharine; Barber, Chris; Cases, Montserrat; Marc, Philippe; Steger-Hartmann, Thomas

    2015-01-01

    A first analysis of a database of shared preclinical safety data for 1214 small molecule drugs and drug candidates extracted from 3970 reports donated by thirteen pharmaceutical companies for the eTOX project (www.etoxproject.eu) is presented. Species, duration of exposure and administration route data were analysed to assess if large enough subsets of homogenous data are available for building in silico predictive models. Prevalence of treatment related effects for the different types of findings recorded were analysed. The eTOX ontology was used to determine the most common treatment-related clinical chemistry and histopathology findings reported in the database. The data were then mined to evaluate sensitivity of established in vivo biomarkers for liver toxicity risk assessment. The value of the database to inform other drug development projects during early drug development is illustrated by a case study.

  14. Preclinical Studies of Chemotherapy Using Histone Deacetylase Inhibitors in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Noriyuki Takai

    2010-01-01

    Full Text Available Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in endometrial cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating endometrial cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in a variety of endometrial cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human endometrial carcinoma cells. In xenograft models, some HDACIs have demonstrated antitumor activity with only few side effects. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating endometrial cancer, with a special focus on preclinical studies.

  15. Preparation and preclinical pharmacological study on a novel bone imaging agent 99mTc-EMIDP

    International Nuclear Information System (INIS)

    Lin Jianguo; Luo Shineng; Chen Chuanqing; Qiu Ling; Wang Yan; Cheng Wen; Ye Wanzhong; Xia Yongmei

    2010-01-01

    A novel zoledronic acid (ZL) derivative, 1-hydroxy-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid (EMIDP), was prepared and labeled with 99m Tc successfully in a high labeling yield and good stability in vitro. The preclinical pharmacological properties of 99m Tc-EMIDP were investigated and compared with 99m Tc-MDP and 99m Tc-ZL. The studies of biodistribution in mice and SPECT bone imaging of the rabbit suggest that 99m Tc-EMIDP has highly selective uptake in the skeletal system and rapid clearance in the soft tissues. The present findings indicate that 99m Tc-EMIDP holds great potential for bone scintigraphy.

  16. Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

    Science.gov (United States)

    Nam, I. F.; Zhuk, V. V.

    2015-04-01

    Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

  17. CCD-camera-based diffuse optical tomography to study ischemic stroke in preclinical rat models

    Science.gov (United States)

    Lin, Zi-Jing; Niu, Haijing; Liu, Yueming; Su, Jianzhong; Liu, Hanli

    2011-02-01

    Stroke, due to ischemia or hemorrhage, is the neurological deficit of cerebrovasculature and is the third leading cause of death in the United States. More than 80 percent of stroke patients are ischemic stroke due to blockage of artery in the brain by thrombosis or arterial embolism. Hence, development of an imaging technique to image or monitor the cerebral ischemia and effect of anti-stoke therapy is more than necessary. Near infrared (NIR) optical tomographic technique has a great potential to be utilized as a non-invasive image tool (due to its low cost and portability) to image the embedded abnormal tissue, such as a dysfunctional area caused by ischemia. Moreover, NIR tomographic techniques have been successively demonstrated in the studies of cerebro-vascular hemodynamics and brain injury. As compared to a fiberbased diffuse optical tomographic system, a CCD-camera-based system is more suitable for pre-clinical animal studies due to its simpler setup and lower cost. In this study, we have utilized the CCD-camera-based technique to image the embedded inclusions based on tissue-phantom experimental data. Then, we are able to obtain good reconstructed images by two recently developed algorithms: (1) depth compensation algorithm (DCA) and (2) globally convergent method (GCM). In this study, we will demonstrate the volumetric tomographic reconstructed results taken from tissuephantom; the latter has a great potential to determine and monitor the effect of anti-stroke therapies.

  18. Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

    Directory of Open Access Journals (Sweden)

    Paulo Henrique Rosado-de-Castro

    2016-01-01

    Full Text Available Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

  19. Learning style preferences: A study of pre-clinical medical students in Barbados

    Science.gov (United States)

    OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

    2017-01-01

    Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist

  20. Learning style preferences: A study of pre-clinical medical students in Barbados.

    Science.gov (United States)

    Ojeh, Nkemcho; Sobers-Grannum, Natasha; Gaur, Uma; Udupa, Alaya; Majumder, Md Anwarul Azim

    2017-10-01

    Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students' learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching

  1. Learning style preferences: A study of Pre-clinical Medical Students in Barbados

    Directory of Open Access Journals (Sweden)

    NKEMCHO OJEH

    2017-10-01

    Full Text Available Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V, aural (A, read/write (R and kinesthetic (K] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to preclinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5% and females (60.0%, with tetramodal being the most common. Read/write (33.8% followed by kinesthetic (32.5% were the most common learning style preferences. The sensory modality preference for females was read/write (34.2% and for males it was kinesthetic (40.5%. Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Yuan Feng

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

  4. Examination performances of German and international medical students in the preclinical studying-term--a descriptive study.

    Science.gov (United States)

    Huhn, D; Resch, F; Duelli, R; Möltner, A; Huber, J; Karimian Jazi, K; Amr, A; Eckart, W; Herzog, W; Nikendei, C

    2014-01-01

    Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all pstudents with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (pstudents completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations.

  5. Examination performances of German and international medical students in the preclinical studying-term – A descriptive study

    Science.gov (United States)

    Huhn, D.; Resch, F.; Duelli, R.; Möltner, A.; Huber, J.; Karimian Jazi, K.; Amr, A.; Eckart, W.; Herzog, W.; Nikendei, C.

    2014-01-01

    Introduction: Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. Method: A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). Results: German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all pstudents with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (pstudents completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations. PMID:25228931

  6. Preclinical studies on toxicity, antitumour activity and pharmacokinetics of cisplatin and three recently developed derivatives.

    Science.gov (United States)

    Lelieveld, P; Van der Vijgh, W J; Veldhuizen, R W; Van Velzen, D; Van Putten, L M; Atassi, G; Danguy, A

    1984-08-01

    Preclinical studies were performed in mice, rats and dogs of cis-diamminedichloroplatinum(II) (CDDP) and its derivatives cis-1,1-di(aminomethyl) cyclohexane platinum(II) sulphate (TNO-6), cis-diammine-1,1-cyclobutanedicarboxylate platinum(II) (CBDCA) and cis-dichloro, trans-dihydroxybis-isopropylamine platinum(IV) (CHIP). In mice toxicity and antitumour activity were determined. All three derivatives were at least as toxic as CDDP for haemopoietic stem cells and were less active than CDDP against the mouse tumours leukaemia L1210 and osteosarcoma C22LR. Toxicology studies in rats revealed no renal toxicity after a single dose of TNO-6. Fractionated doses of TNO-6 and CBDCA did cause renal toxicity but less than CDDP. CHIP produced little or no kidney damage. In dogs, TNO-6 (1.5 mg/kg) produced more severe kidney damage--although this was reversible--than CDDP (2 mg/kg). Half-lives of distribution were 4.0-5.1 min for TNO-6 and 9.7 min for CDDP, while half-lives of elimination were 3.6-6.6 days and 5.9 days respectively. Plasma levels, normalized for the dose, were at least two times higher after TNO-6 than after CDDP. Twelve weeks after drug administration, plasma levels were undetectable, while tissue concentrations could still be measured. The platinum concentration in kidney cortex was higher after CDDP than after TNO-6.

  7. Preclinical pharmacology, efficacy, and safety of varenicline in smoking cessation and clinical utility in high risk patients

    Directory of Open Access Journals (Sweden)

    Zheng-Xiong Xi

    2010-04-01

    Full Text Available Zheng-Xiong XiNational Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USAAbstract: Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain α4β2 nicotinic acetylcholine receptors (nAChRs. Varenicline is a novel α4β2 nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing postmarketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and psychosis as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles and heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline.Keywords: nicotine, varenicline, α4β2 nicotinic acetylcholine receptor, nAChRs, partial agonist, smoking cessation

  8. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

    Directory of Open Access Journals (Sweden)

    Jody E. Hooper

    2015-01-01

    Full Text Available Embryonal rhabdomyosarcoma (eRMS is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

  9. Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies

    Science.gov (United States)

    Hooijmans, Carlijn R.; de Vries, Rob B. M.; Ritskes-Hoitinga, Merel; Rovers, Maroeska M.; Leeflang, Mariska M.; IntHout, Joanna; Wever, Kimberley E.; Hooft, Lotty; de Beer, Hans; Kuijpers, Ton; Macleod, Malcolm R.; Sena, Emily S.; ter Riet, Gerben; Morgan, Rebecca L.; Thayer, Kristina A.; Rooney, Andrew A.; Guyatt, Gordon H.; Schünemann, Holger J.

    2018-01-01

    Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE’s indirectness domain as a tool to predict translation from animal models to humans. PMID:29324741

  10. Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies.

    Science.gov (United States)

    Hooijmans, Carlijn R; de Vries, Rob B M; Ritskes-Hoitinga, Merel; Rovers, Maroeska M; Leeflang, Mariska M; IntHout, Joanna; Wever, Kimberley E; Hooft, Lotty; de Beer, Hans; Kuijpers, Ton; Macleod, Malcolm R; Sena, Emily S; Ter Riet, Gerben; Morgan, Rebecca L; Thayer, Kristina A; Rooney, Andrew A; Guyatt, Gordon H; Schünemann, Holger J; Langendam, Miranda W

    2018-01-01

    Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

  11. Preclinical pharmacological studies of 99Tcm-TRODAT-1 as a dopamine transporter imaging agent

    International Nuclear Information System (INIS)

    Fang Ping; Wan Weixing; Liu Zhenguo; Wu Chunying; Chen Shengdi; Chen Zhengping; Zhou Xiang; Ji Shuren

    2001-01-01

    Objective: To develop a 99 Tc m labelled dopamine transporter (DAT) imaging agent, 99 Tc m -TRODAT-1 [TRODAT-1: 2β-([N,N'-bis(2-mercaptoethyl) ethylene diamino] methyl), 3β-(4-chlorophenyl) tropane], for evaluating the variation of DAT in patients with Parkinson's disease. Methods: 99 Tc m -TRODAT-1 was successfully prepared on a kit basis. Preclinical pharmacological studies were performed in rats, mice, rabbits, monkeys and a volunteer with diagnosed Parkinson disease (PD). Results: Radiochemical purity of 99 Tc m -TRODAT-1 was over 90%, and remained stable for 6 hours. The specific uptake in striatum was significantly diminished, from 3.45 to 0.12 at 2 h by pretreating rats with a dose of DAT competing ligand, β-CIT [1 mg/kg, 2β-carbomethoxy-3β-(4-iodophenyl) tropane]. Blood clearance kinetics was studied in rabbits, and the initial half-life was of 1.2 min, the elimination half-life was of 368 min. Images of normal monkey's brain exhibited an excellent accumulation in basal ganglia region, where dopamine neurons were concentrated. In hemi parkinsonism model monkeys, the ratio of normal ST/CB and lesioned ST/CB were 1.56 and 0.94, respectively. Brain imaging studies in volunteer indicated that uptake and retention in the basal ganglia, the ratio of normal striatal uptake to lesioned one's was 1.15 measured by SPECT imaging at 2 h. The result of imaging was conformable with his clinical symptoms. Conclusions: The stable, neutral and lipophilic complex, 99 Tc m -TRODAT-1, can be accumulated in the striatal area, where DAT is concentrated, high quality images can be obtained. It suggests that 99 Tc m -TRODAT-1 might be a safe and effective tracer for monitoring the variation in DAT which is associated with various neurodegenerative diseases

  12. Reconstitution of immunodeficient SCID/beige mice with human cells: Applications in preclinical studies

    International Nuclear Information System (INIS)

    Thomsen, Mogens; Galvani, Sylvain; Canivet, Cindy; Kamar, Nassim; Boehler, Torsten

    2008-01-01

    Experimental studies of the in vivo behaviour of human cells and tissues have become possible with the development of immunodeficient mice strains. Such mice accept readily allogeneic or xenogeneic grafts, including grafts of human cells or tissues, without rejection. In this review we describe different immunodeficient mouse strains that have been used for reconstitution by human immune cells. We subsequently go through the experience that we and others have had with reconstitution, and mention the adverse effects, in particular xenogeneic graft versus host reactions. The use of haematopoietic stem cells avoids such reactions but the immunological reconstitution may take several months. We then report the use of immunodeficient mice for the study of chronic vascular rejection of human mesenteric arteries due to cellular or humoral alloreaction. We have shown that SCID/beige mice grafted with a human artery at the place of the aorta developed a thickening of the intima of the human artery after 5-6 weeks, when they were reconstituted with spleen cells from another human donor. The thickening is mainly due to a proliferation of smooth muscle cells. The same type of lesion developed if they received injection of antibodies towards HLA class I antigens. The arteries of the mouse did not develop any lesion. The arterial lesions closely resembled those seen after clinical organ transplantation. Mice that received spleen cells from the same human donor developed little or no lesions. An important aspect of this experimental transplantation model is the possibility to test drugs that may be used in clinical transplantation. In recent experiments we have shown that novel immunosuppressive drugs can inhibit the hyperproliferation of smooth muscle cells in vitro. Preclinical testing in reconstituted SCID/beige mice grafted with human arteries will permit the evaluation of the potential use of these drugs to prevent chronic vascular rejection. The model also allows

  13. Developing a Measurement Tool for Assessing Physiotherapy Students' Self-Efficacy: A Pilot Study

    Science.gov (United States)

    Jones, Anne; Sheppard, Lorraine

    2012-01-01

    The aim of this research was to determine if self-efficacy can be correlated with prior academic achievement and whether self-efficacy can be an outcome measure of education. A self-efficacy instrument was developed and administered to physiotherapy students following completion of their pre-clinical theory experience. The questionnaire results…

  14. Characteristics of Effective Simulation (Preclinical) Teachers as Identified by Dental Students: A Qualitative Study.

    Science.gov (United States)

    McAndrew, Maureen; Mucciolo, Thomas W; Jahangiri, Leila

    2016-11-01

    The aim of this qualitative research study was to identify and categorize criteria for simulation teacher quality preferences as reported by dental students. Second-year dental students at New York University College of Dentistry in 2015 were given a two-question, open-ended survey asking what qualities they liked most and least in a simulation or preclinical teacher. Responses were collected until data saturation was reached. Key words in the responses were identified and coded based on similar relationships and then were grouped into defined categories. A total of 168 respondents out of the target group of 363 students (46.3%) provided 1,062 written comments. Three core themes-character, competence, and communication-emerged from 16 defined categories, which were validated using references from the educational literature. The theme of character encompassed eight of the defined categories (motivation, available, caring, patience, professionalism, empathy, fairness, and happiness) and accounted for 50% of the total student responses. The theme of competence comprised five categories (expertise, knowledgeable, efficient, skillful, and effective) and represented 34% of all responses. The communication theme covered the remaining three categories (feedback, approachable, and interpersonal communication) and contained 17% of the responses. Positive and negative comments in the category of motivation accounted for 11.2% of all student responses. Expertise was the next highest category with 9.3% of the responses, followed closely by 9.1% in the category of available. Among these students, the top five attributes of simulation teachers were motivation, expertise, available, caring, and feedback. While the study did not attempt to correlate these findings with improved student performance, the results can be used in the development of assessment tools for faculty and targeted faculty development programs.

  15. Osseointegration in osteoporotic-like condition: A systematic review of preclinical studies.

    Science.gov (United States)

    Dereka, X; Calciolari, E; Donos, N; Mardas, N

    2018-05-30

    Osteoporosis is one of the most common skeletal disorders affecting a significant percentage of people worldwide. Research data suggested that systemic diseases such as osteoporosis could act as risk factors for osseointegration, jeopardizing the healing process and thus the predictability of dental implant success on compromised patients. It is well accepted that preclinical studies in animal models reproducing the osteoporotic condition are one of the most important stages in the research of new biomaterials and therapeutic modalities. The aim of this systematic review was to investigate whether osteoporosis compromises dental implant osseointegration in experimental osteoporotic-like conditions. A 3-stage systematic literature research was conducted in MEDLINE via OVID and EMBASE up to and including March 2017. Experimental studies reporting on dental implant osseointegration on different osteoporotic animal models were assessed. The studies had to report on the percentage of bone-to-implant contact (%BIC) as the primary outcome. ARRIVE guidelines for reporting on animal research were applied to evaluate the methodological quality and risk of bias of the studies. Fifty-seven studies met the inclusion criteria and were assessed qualitatively. The most adopted animal model was the rat. A variability of %BIC values was observed, ranging from 30% to 99% and from 26% to 94% for the healthy and osteoporotic group, respectively. The great majority (47) of the included studies concluded that estrogen deficiency significantly affects BIC values, 9 studies stated that it was not possible to observe statistical differences in BIC between ovariectomized and healthy groups and 1 study did not provide a comparison between the healthy and osteoporotic group. Owing to the great heterogeneity in implant surface, study design, observation time-points, site of implant placement and reported outcomes, a meta-analysis could not be performed. An overall high risk of bias was observed

  16. Radioiodination of central nerves system dopamine D2 receptor imaging agent. IBZM preparation and preclinical study

    International Nuclear Information System (INIS)

    Lin Yansong; Lin Xiangtong; Hu Mingyang; Pan Shangren; Wang Bocheng

    1996-01-01

    To study preparation of central nerves system dopamine D2 imaging agent 131 I-IBZM and its preclinical investigation, peracetic acid was used as the oxidant for preparing radioiodinated 125 I-IBZM and 131 I-IBZM, D2 binding properties of IBZM were examined by in vitro binding saturation analysis, rat whole body and regional brain biodistribution, rat brain autoradiography and rabbit SPECT static imaging, etc. The results are: 1. The radiolabelling yields of 125 I-IBZM and 131 I-IBZM were 84.18% +- 3.06% and 78.50% +- 3.47%. The radiochemical purity were over 95% after being isolated by HPLC; and were over 90% after being isolated by organic extraction. 2. Scatchard plot of D2 receptor saturation binding analysis showed: K d = 0.53 +- 0.06 nmol/L, B max = 466.45 +- 45.88 fmol/mg protein. 3. The rat brain autoradiography and analysis showed that there was high 125 I-IBZM uptake in striatal area 2 hr after injection, the striatal/cerebellum ratio was 6.22 +- 0.48; the high 125 -IBZM uptake can be blocked by haloperidol--a special dopamine D2 receptor antagonist. 4. 131 I-IBZM rat biodistribution and rabbit SPECT planar imaging showed good initial brain uptake and retention, the initial uptake of rat brain was 1.893 +- 0.147% ID/g at 2 min and 1.044 +- 0.135% ID/g at 60 min. The results showed that the radioiodinated IBZM had high affinity, saturation and specificity to rat's and rabbit's central nerves system dopamine D2 receptors

  17. Radioiodination of central nerves system dopamine D2 receptor imaging agent. IBZM preparation and preclinical study

    Energy Technology Data Exchange (ETDEWEB)

    Yansong, Lin; Xiangtong, Lin; Mingyang, Hu; Shangren, Pan; Bocheng, Wang [Huashan Hospital of Shanghai Medical Univ., Shanghai (China)

    1996-11-01

    To study preparation of central nerves system dopamine D2 imaging agent {sup 131}I-IBZM and its preclinical investigation, peracetic acid was used as the oxidant for preparing radioiodinated {sup 125}I-IBZM and {sup 131}I-IBZM, D2 binding properties of IBZM were examined by in vitro binding saturation analysis, rat whole body and regional brain biodistribution, rat brain autoradiography and rabbit SPECT static imaging, etc. The results are: 1. The radiolabelling yields of {sup 125}I-IBZM and {sup 131}I-IBZM were 84.18% +- 3.06% and 78.50% +- 3.47%. The radiochemical purity were over 95% after being isolated by HPLC; and were over 90% after being isolated by organic extraction. 2. Scatchard plot of D2 receptor saturation binding analysis showed: K{sub d} = 0.53 +- 0.06 nmol/L, B{sub max} = 466.45 +- 45.88 fmol/mg protein. 3. The rat brain autoradiography and analysis showed that there was high {sup 125}I-IBZM uptake in striatal area 2 hr after injection, the striatal/cerebellum ratio was 6.22 +- 0.48; the high {sup 125}-IBZM uptake can be blocked by haloperidol--a special dopamine D2 receptor antagonist. 4. {sup 131}I-IBZM rat biodistribution and rabbit SPECT planar imaging showed good initial brain uptake and retention, the initial uptake of rat brain was 1.893 +- 0.147% ID/g at 2 min and 1.044 +- 0.135% ID/g at 60 min. The results showed that the radioiodinated IBZM had high affinity, saturation and specificity to rat`s and rabbit`s central nerves system dopamine D2 receptors.

  18. Clinical study on postoperative steroid hormon replacement for preclinical Cushing's syndrome

    International Nuclear Information System (INIS)

    Furuta, Nozomu; Koide, Haruhisa; Sasaki, Hiroshi; Miki, Jun; Kimura, Takahiro; Egawa, Shin

    2009-01-01

    Diagnostic criteria for preclinical Cushing's syndrome (PCS) were reported in 1996. However, requirement of postoperative steroid hormone replacement is still controversial issue. In this study, we observed recent surgical cases retrospectively and evaluate the use of postoperative steroid hormone replacement. Eighteen patients with PCS underwent surgery from 1997 to 2007 in Jikei University Hospital. Thirteen of them received postoperative steroid hormone replacement. We investigated preoperative hormone activity by 131 I-adosterol scintigraphy and suppression of adrenocorticotropic hormone (ACTH) and evaluated the requirement of postoperative steroid hormone replacement. Preoperative serum cortisol was normal range in all patients. Serum ACTH was suppressed in 10 of them (56%). In 131 I-adosterol scintigraphy, accumulation in ipsilateral side was observed in all patients. Accumulation in contralateral side was observed in 13 patients whose serum ACTH had tendency to be suppressed. Mean period of steroid hormone replacement was 19.8 weeks. Patients with lower preoperative ACTH tended to require longer period until withdrawal of steroid hormone replacement. In addition, patients received steroid hormone replacement with higher starting dose significantly required longer period. Three of them had complications during tapering of steroid hormone. Postoperative adrenal insufficiency is important issue as postoperative management of PCS patients whose function of contralateral adrenal or pituitary gland is suppressed. 131 I-adosterol scintigraphy and preoperative serum ACTH were important factors to evaluate the requirement of postoperative steroid hormone replacement. Especially, patients with low preoperative serum ACTH tended to require long duration of postoperative steroid hormone replacement. On the other hand, patients with accumulation of contralateral side in 131 I-adosterol scintigraphy and without suppression of serum ACTH may not require steroid hormone

  19. In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

    Directory of Open Access Journals (Sweden)

    Christiane Broichhausen

    2014-01-01

    Full Text Available A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

  20. Sex differences in the vulnerability to drug abuse: a review of preclinical studies.

    Science.gov (United States)

    Roth, Megan E; Cosgrove, Kelly P; Carroll, Marilyn E

    2004-10-01

    Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms of action underlying these sex differences. This review examines the preclinical literature on sex differences and ovarian hormonal influences on drug self-administration in animals. It summarizes the findings on the effects of these variables during different phases of drug addiction. Possible differences in the mechanisms of action of drugs of abuse due to interactions with sex differences or ovarian hormonal factors are considered. The animal literature on sex differences in drug abuse treatment effectiveness is also discussed.

  1. Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

    OpenAIRE

    Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

    2018-01-01

    Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain...

  2. Impact of diet restriction in the management of diabetes: evidences from preclinical studies.

    Science.gov (United States)

    Krishan, Pawan; Bedi, Onkar; Rani, Monika

    2018-03-01

    The inappropriate dietary habits lead to the onset of age-related pathologies which include diabetes and cardiovascular ailments. Dietary restriction and nutritional therapy play an important role in the prevention of these chronic ailments. Preclinical research provides a basis for the therapeutic exploration of new dietary interventions for the clinical trials to potentiate the scientific management of diabetes and its related complications which further help in translating these nutritional improvements from bench to bedside. Within the same context, numerous therapeutically proved preclinical dietary interventions like high-fiber diet, caloric restriction, soy isoflavone-containing diets, etc., have shown the promising results for the management of diabetes and the associated complications. The focus of the present review is to highlight the various preclinical evidences of diet restriction for the management of diabetes and which will be helpful for enlightening the new ideas of nutritional therapy for future research exploration. In addition, some potential approaches are also discussed which are associated with various nutritional interventions to combat progressive diabetes and the associated disorders. Graphical abstract ᅟ.

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

    Science.gov (United States)

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

    2017-08-01

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

  4. The preclinical pharmacological study of dopamine transporter imaging agnet (99mTc)trodat-1

    International Nuclear Information System (INIS)

    Fang, P.; Wan, W.; Wu, C.; Liu, Z.; Wang, T.; Chen, S.; Chen, Z.; Zhou, X.

    2000-01-01

    To develop 99m Tc labeled dopamine transporter (DAT) imaging agent 99m Tc-TRODAT-1 (TRODAT-1:2 β-[[N,N'-bis(2-mercaptoethyl)ethylenediamino]methl], 3 β-(4-chlorophenyl)tropane], used in SPECT, for evaluating changes of DAT in patients with Parkinson's disease(PD). Using Stannous as reducing agent, and the present of Na-glucoheptonate, 99m Tc-TRODAT-1 was successfully prepared. Preclinical pharmacological studies have been performed in rats. C57BL mice, normal and PD model monkeys and volunteers. Radiochemical purity of 99m Tc-TRODAT-1 was over 90%, and stable for 6 hours. The specific uptake in striatum was significantly diminished from 3.45 to 0.12 at 3 h by pretreated rats with a dose of competing DAT ligand β-CIT (1 mg/kg). Autoradiographic images in C57BL mice shows that the specific uptake has a good linear relationship with the quantity of neural-toxin (MPTP) which was given to the animals (r=0.9792). Images of normal monkey's brain exhibited excellent localization in basal ganglia region, where dopamine neurons were concentrated, and the ratios of ST/CB were 1.56-2.0. In hemiparkinsonian model monkeys, the ratio of normal ST/CB and lesioned ST/CB were 1.56 and 0.94, respectively. Brain image studies in volunteers indicated that uptake and retention in the basal ganglia, the ratio of normal striatal to lesioned one was 1.15 measured by SPECT imaging at 2 h. The result of images was consistent with the clinical symptoms. Above-mentioned results showed that 99m Tc-TRODAT-1 can be accumulated in the striatal area, where DAT are concentrated, high quality images were obtained. It is suggested that 99m Tc-TRODAT-1 might turn to be a safe and effective tracer for monitoring the change in DAT associated with various neurodegenerative diseases

  5. Challenges for Preclinical Investigations of Human Biofield Modalities

    Science.gov (United States)

    Gronowicz, Gloria; Bengston, William

    2015-01-01

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

  6. Evaluation of preclinical single and multiple dose toxicity and efficacy of 213 Bi-labeled plasminogen activator inhibitor 2 for breast and prostate cancer

    International Nuclear Information System (INIS)

    Rizvi, S.; Li, Y.; Allen, B.; Littlejohn, T.; Ranson, M.; Links, M.; Irving, D.; Andrews, J.

    2003-01-01

    The aim of the study was to evaluate the single and multiple dose toxicity (maximum tolerated dose or MTD) regimes for 213 Bi-labeled PAI2. Dose range of 2-8 mCi/kg was used for the single dose toxicity studies. It was found that end point (20% weight loss and/or distressed behaviour) was not reached for the highest dose either with single or multiple dose injections. For multiple dose toxicity studies, the dose levels ranged between 0.4 - 2 mCi/kg, and were administered daily for 5 days. The highest level tested (2mCi/kg/day x 5) was the maximum tolerated dose as 3/6 mice succumbed to the endpoints. However, histological examination of major organs showed no adverse morphological changes. From these toxicity studies, we concluded that either a dose of 1.6mCi/kg of 213 Bi-PAI2 per day for 5 days or a single injection of 8 mCi/kg can be administered without reaching the endpoints. These dose levels were used for efficacy trials. The efficacy studies were conducted to examine if the 1.6mCi/kgday x 5 multiple dose schedule (sub-maximum tolerated dose) showed efficacy against established and early stage human breast and prostate tumours in mice. Statistical analyses of the data indicate a significant tumour growth rate delay and increased time to reach tumour size endpoint for alpha-PAI2 treatment compared to control tumours, in both pre-tumour stage and established tumour models

  7. Pig Models of Neurodegenerative Disorders: Utilization in Cell Replacement-Based Preclinical Safety and Efficacy Studies

    Czech Academy of Sciences Publication Activity Database

    Doležalová, D.; Hruška-Plocháň, M.; Bjarkam, C. R.; Sorensen, J. C. H.; Cunningham, M.; Weingarten, D.; Ciacci, J. D.; Juhás, Štefan; Juhásová, Jana; Motlík, Jan; Hefferan, M. P.; Hazel, T.; Johe, K.; Carromeu, C.; Muotri, A.; Bui, J. D.; Strnádel, J.; Marsala, M.

    2014-01-01

    Roč. 522, č. 12 (2014), s. 2784-2801 ISSN 0021-9967 R&D Projects: GA TA ČR(CZ) TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : pig * neurodegenerative models * stem cells Subject RIV: FH - Neurology Impact factor: 3.225, year: 2014

  8. Demonstrating Efficacy in Preclinical Studies of Cellular Therapies for Spinal Cord Injury - How Much is Enough?

    Czech Academy of Sciences Publication Activity Database

    Kwon, B. K.; Soril, L. J. J.; Bacon, M.; Beattie, M. S.; Blesch, A.; Bresnahan, J. C.; Bunge, M. B.; Dunlop, S. A.; Fehlings, M. G.; Ferguson, A. R.; Hill, C. E.; Karimi-Abdolrezaee, S.; Lu, P.; McDonald, J. W.; Müller, H. W.; Oudega, M.; Rosenzweig, E. S.; Reier, P. J.; Silver, J.; Syková, Eva; Xu, X. M.; Guest, J. D.; Tetzlaff, W.

    2013-01-01

    Roč. 248, Oct (2013), s. 30-44 ISSN 0014-4886 R&D Projects: GA ČR GA13-00939S; GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:68378041 Keywords : spinal cord injury * cell transplantation therapies * clinical trial Subject RIV: FH - Neurology Impact factor: 4.617, year: 2013

  9. Preclinical studies of lymphographic applilcation of 99mTc-dextrans of different molecular weight

    International Nuclear Information System (INIS)

    Lamka, J.; Kvetina, J.; Kafka, P.

    1986-01-01

    In a preclinical investigation on rabbits the distribution was tested of dextrans of two molecular weights (40,000 and 70,000) with regard to their use as a carrier in indirect lymphography. The tests showed that both 99m Tc-dextrans achieve high ratios of lymph/blood levels. It is suggested that for clinical work it is better to use dextran with a molecular weight of 70,000 than that with a molecular weight of 40,000. (author)

  10. Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression

    Directory of Open Access Journals (Sweden)

    Karishma Rahman

    2018-05-01

    Full Text Available Atherosclerosis, the underlying cause of coronary artery (CAD and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed “residual inflammatory risk” of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.

  11. Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

    OpenAIRE

    Rivulgo, Virginia Margarita; Sparo, Mónica; Ceci, Mónica; Fumuso, Elida; Confalonieri, Alejandra; Delpech, Gastón; Sanchez Bruni, Sergio Fabian

    2016-01-01

    Azithromycin(AZM)therapeutic failure and relapses of patients treated with generic -35 formulations have been observed in clinical practice.The main goal of this research was 36 to compare in a pre-clinical study the serum exposure and lung tissue concentrationof 37 two commercial formulations AZM-based in murine model. The current study involved 38 264 healthy Balb-C.Mice were divided in two groups (n=44): Animals of Group A 39 (Reference Formulation ?R-) were orally treated with AZM suspens...

  12. Systematic Approach to Remediation in Basic Science Knowledge for Preclinical Students: A case study

    Science.gov (United States)

    Amara, Francis

    Remediation of pre-clerkship students for deficits in basic science knowledge should help them overcome their learning deficiencies prior to clerkship. However, very little is known about remediation in basic science knowledge during pre-clerkship. This study utilized the program theory framework to collect and organize mixed methods data of the remediation plan for pre-clerkship students who failed their basic science cognitive examinations in a Canadian medical school. This plan was analyzed using a logic model narrative approach and compared to literature on the learning theories. The analysis showed a remediation plan that was strong on governance and verification of scores, but lacked: clarity and transparency of communication, qualified remedial tutors, individualized diagnosis of learner's deficits, and student centered learning. Participants admitted uncertainty about the efficacy of the remediation process. A remediation framework is proposed that includes student-centered participation, individualized learning plan and activities, deliberate practice, feedback, reflection, and rigorous reassessment.

  13. A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design.

    Science.gov (United States)

    Selimkhanov, J; Thompson, W C; Guo, J; Hall, K D; Musante, C J

    2017-08-01

    The design of well-powered in vivo preclinical studies is a key element in building the knowledge of disease physiology for the purpose of identifying and effectively testing potential antiobesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic end points such as food intake and body composition. This, combined with limitations inherent in the measurement of certain end points, presents challenges to study design that can have significant consequences for an antiobesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of the key metabolic end points. To demonstrate how conclusions can change as a function of study size, we show that a simulated preclinical study properly powered for one end point may lead to false conclusions based on secondary end points. We then propose the guidelines for end point selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design.

  14. Preclinical and phase I studies of monoclonal antibodies in melanoma: Application to boron neutron capture therapy of melanoma

    International Nuclear Information System (INIS)

    Hersey, P.

    1989-01-01

    Monoclonal antibodies (MAbs) provide an attractive method of selectively localizing sufficient boron atoms around tumour cells to capture neutrons. Assuming that 10(8)-10(10) 10B atoms are needed for one capture event and that 10(3)-10(4) atoms can be coupled to each antibody molecule, then 10(5)-10(6) antibody molecules gathered on an individual cell will destroy that cell. Binding to normal tissues, on the other hand, would need to be at least 20-fold less than that to tumour tissues to avoid toxic effects of neutrons on surrounding tissues. Preclinical studies in animals show that several MAbs may bind to melanoma cells in sufficient quantities in vitro to localize the required amount of boron per cell. Whether this will occur in vivo, however, may depend not only on antigen density but a variety of other properties of the tumour cells and MAbs. These include the Ig class and affinity of the antibody and whether the antibody is internalized into the tumour cell. The ratio of uptake between tumour and normal tissue is governed by such factors as the percentage of tumour cells within a tumour expressing the antigen and whether the MAb react with normal tissues. Use of Fab or F(ab)2 preparations of the MAb may increase the uptake ratio by preventing uptake of MAb by cells with Fc receptors. In contrast to preclinical animal studies, tumour/normal tissue uptake ratios in phase I studies in humans have been disappointingly low.80 references

  15. A method for comparing intra-tumoural radioactivity uptake heterogeneity in preclinical positron emission tomography studies

    International Nuclear Information System (INIS)

    Grafström, Jonas; Ahlzén, Hanna-Stina; Stone-Elander, Sharon

    2015-01-01

    Non-uniformity influences the interpretation of nuclear medicine based images and consequently their use in treatment planning and monitoring. However, no standardised method for evaluating and ranking heterogeneity exists. Here, we have developed a general algorithm that provides a ranking and a visualisation of the heterogeneity in small animal positron emission tomography (PET) images. The code of the algorithm was written using the Matrix Laboratory software (MATLAB). Parameters known to influence the heterogeneity (distances between deviating peaks, gradients and size compensations) were incorporated into the algorithm. All data matrices were mathematically constructed in the same format with the aim of maintaining overview and control. Histograms visualising the spread and frequency of contributions to the heterogeneity were also generated. The construction of the algorithm was tested using mathematically generated matrices and by varying post-processing parameters. It was subsequently applied in comparisons of radiotracer uptake in preclinical images in human head and neck carcinoma and endothelial and ovarian carcinoma xenografts. Using the developed algorithm, entire tissue volumes could be assessed and gradients could be handled in an indirect manner. Similar-sized volumes could be compared without modifying the algorithm. Analyses of the distribution of different tracers gave results that were generally in accordance with single plane preclinical images, indicating that it could appropriately handle comparisons of targeting vs. non-targeting tracers and also for different target levels. Altering the reconstruction algorithm, pixel size, tumour ROI volumes and lower cut-off limits affected the calculated heterogeneity factors in expected directions but did not reverse conclusions about which tumour was more or less heterogeneous. The algorithm constructed is an objective and potentially user-friendly tool for one-to-one comparisons of heterogeneity in

  16. A method for comparing intra-tumoural radioactivity uptake heterogeneity in preclinical positron emission tomography studies

    Energy Technology Data Exchange (ETDEWEB)

    Grafström, Jonas; Ahlzén, Hanna-Stina [Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm (Sweden); Stone-Elander, Sharon [Department of Clinical Neuroscience, Karolinska Institutet, SE-17176 Stockholm (Sweden); PET Radiochemistry, Neuroradiology Department, Karolinska University Hospital, SE-17176 Stockholm (Sweden)

    2015-09-08

    Non-uniformity influences the interpretation of nuclear medicine based images and consequently their use in treatment planning and monitoring. However, no standardised method for evaluating and ranking heterogeneity exists. Here, we have developed a general algorithm that provides a ranking and a visualisation of the heterogeneity in small animal positron emission tomography (PET) images. The code of the algorithm was written using the Matrix Laboratory software (MATLAB). Parameters known to influence the heterogeneity (distances between deviating peaks, gradients and size compensations) were incorporated into the algorithm. All data matrices were mathematically constructed in the same format with the aim of maintaining overview and control. Histograms visualising the spread and frequency of contributions to the heterogeneity were also generated. The construction of the algorithm was tested using mathematically generated matrices and by varying post-processing parameters. It was subsequently applied in comparisons of radiotracer uptake in preclinical images in human head and neck carcinoma and endothelial and ovarian carcinoma xenografts. Using the developed algorithm, entire tissue volumes could be assessed and gradients could be handled in an indirect manner. Similar-sized volumes could be compared without modifying the algorithm. Analyses of the distribution of different tracers gave results that were generally in accordance with single plane preclinical images, indicating that it could appropriately handle comparisons of targeting vs. non-targeting tracers and also for different target levels. Altering the reconstruction algorithm, pixel size, tumour ROI volumes and lower cut-off limits affected the calculated heterogeneity factors in expected directions but did not reverse conclusions about which tumour was more or less heterogeneous. The algorithm constructed is an objective and potentially user-friendly tool for one-to-one comparisons of heterogeneity in

  17. Impact of a Differential Learning Approach on Practical Exam Performance: A Controlled Study in a Preclinical Dental Course.

    Science.gov (United States)

    Pabel, Sven-Olav; Pabel, Anne-Kathrin; Schmickler, Jan; Schulz, Xenia; Wiegand, Annette

    2017-09-01

    The aim of this study was to evaluate if differential learning in a preclinical dental course impacted the performance of dental students in a practical exam (preparation of a gold partial crown) immediately after the training session and 20 weeks later compared to conventional learning. This controlled study was performed in a preclinical course in operative dentistry at a dental school in Germany. Third-year students were trained in preparing gold partial crowns by using either the conventional learning (n=41) or the differential learning approach (n=32). The differential learning approach consisted of 20 movement exercises with a continuous change of movement execution during the learning session, while the conventional learning approach was mainly based on repetition, a methodological series of exercises, and correction of preparations during the training phase. Practical exams were performed immediately after the training session (T1) and 20 weeks later (T2, retention test). Preparations were rated by four independent and blinded examiners. At T1, no significant difference between the performance (exam passed) of the two groups was detected (conventional learning: 54.3%, differential learning: 68.0%). At T2, significantly more students passed the exam when trained by the differential learning approach (68.8%) than by the conventional learning approach (18.9%). Interrater reliability was moderate (Kappa: 0.57, T1) or substantial (Kappa: 0.67, T2), respectively. These results suggest that a differential learning approach can increase the manual skills of dental students.

  18. Formulation, stability study, and pre-clinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis.

    Science.gov (United States)

    de Souza Fernandes, Lígia; Amorim, Yuri Martins; Silva, Elton Libério da; Silva, Samuel Calixto; Santos, Alécia Junia Aparecida; Peixoto, Franciele Natália; Pires, Luara Moniele Neves; Sakamoto, Raquel Yumi; Pinto, Flávia do Carmo Horta; Scarpa, Maria Virgínia Costa; Gonzaga de Freitas Araújo, Marcelo

    2018-03-08

    Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis METHODS: Curcumin was incorporated in a vaginal cream in three concentrations (0.01, 0.1 and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC RESULTS: The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After six days of pre-clinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction of the inflammatory infiltrate was observed in the group treated with 1.0% cream CONCLUSION: Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Contribution of micro-scanner in the preclinical study of hepatic and pancreatic cancer treatments in rat

    International Nuclear Information System (INIS)

    Youssef Azer Akladios, Cherif

    2010-01-01

    Animal experimentation is an unavoidable step in preclinical studies and relies on small animals. In vivo imaging constitutes a precious tool giving information on anatomy, biochemistry, physiology, genetic, pharmacology, while saving cell and tissue integrities of investigated animals. It opens wide the scientific perspective in the field of biological development, physiopathology of diseases, as well as in oncology, from early diagnosis to cancer treatment. This thesis had demonstrated the relevance of micro-scanner in the longitudinal follow up and the management of ortho-topic models of hepatic and pancreatic carcinoma in the rat. For both of these cancers, known to be very poorly or even non curable, there is an urgent need of research on the bases of their onco-genesis as of investigation of the resulting new therapeutic routes. The results of our thesis suggest a role for micro-CT in the preclinical evaluation of their emerging therapies. As far as animal experiment is concerned, in vivo micro-scanner imaging permits, beside a reduction in the number of experimental animals, to establish new (imaging) end-points allowing experiment ending before any sign of animal suffering. It fulfils the main requirements of animal experiment. (author) [fr

  20. Teachers’ work ability: a study of relationships between collective efficacy and self-efficacy beliefs

    Directory of Open Access Journals (Sweden)

    Guidetti G

    2018-05-01

    Full Text Available Gloria Guidetti,1 Sara Viotti,1 Andreina Bruno,2 Daniela Converso1 1Department of Psychology, University of Turin, Turin, Italy; 2Department of Education Science, University of Genoa, Genoa, Italy Introduction: Work ability constitutes one of the most studied well-being indicators related to work. Past research highlighted the relationship with work-related resources and demands, and personal resources. However, no studies highlight the role of collective and self-efficacy beliefs in sustaining work ability. Purpose: The purpose of this study was to examine whether and by which mechanism work ability is linked with individual and collective efficacies in a sample of primary and middle school teachers. Materials and methods: Using a dataset consisting of 415 primary and middle school Italian teachers, the analysis tested for the mediating role of self-efficacy between collective efficacy and work ability. Results: Mediational analysis highlights that teachers’ self-efficacy totally mediates the relationship between collective efficacy and perceived work ability. Conclusion: Results of this study enhance the theoretical knowledge and empirical evidence regarding the link between teachers’ collective efficacy and self-efficacy, giving further emphasis to the concept of collective efficacy in school contexts. Moreover, the results contribute to the study of well-being in the teaching profession, highlighting a process that sustains and promotes levels of work ability through both collective and personal resources. Keywords: collective efficacy, mediation, self-efficacy, teachers, work ability

  1. Preclinical studies and clinical trial of targeted alpha therapy for cancer

    International Nuclear Information System (INIS)

    Allen, B.J.

    2002-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukemia, colorectal, breast and prostate cancers. Materials and Methods: The alpha-emitting radioisotope is Bi-213, which is produced by the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (eg plasmmogen activator inhibitor PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukemia (WM60 mab), colorectal (C30.6 mab), breast (PAI2) and prostate (PAI2, J591 mab) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Results: In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than nonspecific ACs, specific beta emitting conjugates or free isotope. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can also completely regress advanced sc melanomas but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Conclusions: These results point to the application of local and systemic TAT in the management of secondary cancer. A phase 1 and 2 clinical trial of TAT of subcutaneous, secondary melanoma has commenced at St George Hospital, and 10/30 subjects have been treated by intralesional injection

  2. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

    Science.gov (United States)

    Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

    2012-06-01

    Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

  3. Effect of the dedicated education unit on nursing student self-efficacy: A quasi-experimental research study.

    Science.gov (United States)

    George, Lynn E; Locasto, Lisa W; Pyo, Katrina A; W Cline, Thomas

    2017-03-01

    Although the Dedicated Education Unit (DEU) has shown initial promise related to satisfaction with the teaching/learning environment, few studies have examined student outcomes related to the use of the DEU as a clinical education model beyond student satisfaction. The purpose of this quantitative, quasi-experimental study was to compare student outcomes from the traditional clinical education (TCE) model with those from the DEU model. Participants were students enrolled in a four-year baccalaureate program in nursing (n = 193) who had clinical education activities in one of three clinical agencies. Participants were assigned to either the DEU or a TCE model. Pre-clinical and post-clinical self-efficacy scores were measured for each group using an adapted Generalized Self-Efficacy Scale (Schwarzer and Jerusalem, 1995). Both groups experienced a significant increase in self-efficacy scores post clinical education. The increase in self-efficacy for the DEU students was significantly greater than the increase in self-efficacy for the traditional students. Self-efficacy is considered an important outcome of nursing education because high self-efficacy has been linked to making an easier transition from student to nursing professional. This study supports the quality of the DEU as a clinical education model by examining student self-efficacy outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Cartilage Repair With Autologous Bone Marrow Mesenchymal Stem Cell Transplantation: Review of Preclinical and Clinical Studies.

    Science.gov (United States)

    Yamasaki, Shinya; Mera, Hisashi; Itokazu, Maki; Hashimoto, Yusuke; Wakitani, Shigeyuki

    2014-10-01

    Clinical trials of various procedures, including bone marrow stimulation, mosaicplasty, and autologous chondrocyte implantation, have been explored to treat articular cartilage defects. However, all of them have some demerits. We focused on autologous culture-expanded bone marrow mesenchymal stem cells (BMSC), which can proliferate without losing their capacity for differentiation. First, we transplanted BMSC into the defective articular cartilage of rabbit and succeeded in regenerating osteochondral tissue. We then applied this transplantation in humans. Our previous reports showed that treatment with BMSC relieves the clinical symptoms of chondral defects in the knee and elbow joint. We investigated the efficacy of BMSC for osteoarthritic knee treated with high tibial osteotomy, by comparing 12 BMSC-transplanted patients with 12 cell-free patients. At 16-month follow-up, although the difference in clinical improvement between both groups was not significant, the arthroscopic and histological grading score was better in the cell-transplanted group. At the over 10-year follow-up, Hospital for Special Surgery knee scores improved to 76 and 73 in the BMSC-transplanted and cell-free groups, respectively, which were better than preoperative scores. Additionally, neither tumors nor infections were observed in all patients, and in the clinical study, we have never observed hypertrophy of repaired tissue, thereby guaranteeing the clinical safety of this therapy. Although we have never observed calcification above the tidemark in rabbit model and human histologically, the repair cartilage was not completely hyaline cartilage. To elucidate the optimum conditions for cell therapy, other stem cells, culture conditions, growth factors, and gene transfection methods should be explored.

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

    NARCIS (Netherlands)

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

    2006-01-01

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

  6. Effect of Previous Irradiation on Vascular Thrombosis of Microsurgical Anastomosis: A Preclinical Study in Rats

    Science.gov (United States)

    Gallardo-Calero, Irene; López-Fernández, Alba; Romagosa, Cleofe; Vergés, Ramona; Aguirre-Canyadell, Marius; Soldado, Francisco; Velez, Roberto

    2016-01-01

    Background: The objective of the present investigation was to compare the effect of neoadjuvant irradiation on the microvascular anastomosis in cervical bundle using an experimental model in rats. Methods: One hundred forty male Sprague–Dawley rats were allocated into 4 groups: group I, control, arterial microanastomosis; group II, control, venous microanastomosis; group III, arterial microanastomosis with previous irradiation (20 Gy); and group IV, venous microanastomosis with previous irradiation (20 Gy). Clinical parameters, technical values of anastomosis, patency, and histopathological parameters were evaluated. Results: Irradiated groups (III and IV) and vein anastomosis groups (II and IV) showed significantly increased technical difficulties. Group IV showed significantly reduced patency rates (7/35) when compared with the control group (0/35). Radiotherapy significantly decreased the patency rates of the vein (7/35) when compared with the artery (1/35). Groups III and IV showed significantly reduced number of endothelial cells and also showed the presence of intimal thickening and adventitial fibrosis as compared with the control group. Conclusion: Neoadjuvant radiotherapy reduces the viability of the venous anastomosis in a preclinical rat model with a significant increase in the incidence of vein thrombosis. PMID:27975009

  7. Preclinical studies on [{sup 11}C]MPDX for mapping adenosine A{sub 1} receptors by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ishiwata, Kiichi; Kimura, Yuichi; Oda, Keiichi; Kawamura, Kazunori; Ishii, Kenji; Senda, Michio [Tokyo Metropolitan Inst. of Gerontology (Japan). Positron Medical Center; Nariai, Tadashi; Wakabayashi, Shinichi [Tokyo Medical and Dental Univ. (Japan). School of Medicine; Shimada, Junichi [Kyowa Hakko Kogyo Co. Ltd., Tokyo (Japan). Pharmaceutical Research Inst.

    2002-09-01

    In previous in vivo studies with mice, rats and cats, we have demonstrated that [{sup 11}C]MPDX ([1-methyl-{sup 11}C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A{sub 1} receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [{sup 11}C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [{sup 11}C]MPDX. We have concluded that [{sup 11}C]MPDX is suitable for mapping adenosine A{sub 1} receptors in the human brain by PET. (author)

  8. A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

    Science.gov (United States)

    Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

    2016-01-01

    Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

  9. [Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

    Science.gov (United States)

    Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

    1998-01-01

    The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

  10. [Preclinical study of immunocorrection action of the sum of active substances of Coluria geoides (Pall.) Ledeb. (Rosaceae)].

    Science.gov (United States)

    Dutova, S V; Karpova, M R; Myadelets, M A; Myasnaya, N V; Sherstoboev, E Yu

    2015-01-01

    A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties.

  11. Therapeutic efficacy and toxicity of {sup 225}Ac-labelled vs. {sup 213}Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

    Energy Technology Data Exchange (ETDEWEB)

    Essler, Markus; Gaertner, Florian C.; Blechert, Birgit; Senekowitsch-Schmidtke, Reingard; Seidl, Christof [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Neff, Frauke [Helmholtz Zentrum Muenchen, Institute of Pathology, Neuherberg (Germany); Bruchertseifer, Frank; Morgenstern, Alfred [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany)

    2012-04-15

    Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with {sup 225}Ac and {sup 213}Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of {sup 225}Ac-DOTA-F3 in comparison with that of {sup 213}Bi-DTPA-F3. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 x 10{sup 7} MDA-MB-435 cells. Therapy with 6 x 1.85 kBq of {sup 225}Ac-DOTA-F3 or 6 x 1.85 MBq of {sup 213}Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived {sup 213}Bi (t{sub 1/2} 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of {sup 225}Ac-DOTA-F3 (t{sub 1/2} 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with {sup 225}Ac-DOTA-F3 (43%) and with {sup 213}Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with {sup 225}Ac-DOTA-F3 or {sup 213}Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both {sup 225}Ac-DOTA-F3 and {sup 213}Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both

  12. Analysis of machine perfusion benefits in kidney grafts: a preclinical study

    Directory of Open Access Journals (Sweden)

    Eugene Michel

    2011-01-01

    Full Text Available Abstract Background Machine perfusion (MP has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD. However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. Methods We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation. Endpoints were: function recovery, quality of function during follow up (3 month, inflammation, fibrosis, animal survival. Results ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and β-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. Conclusions With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits.

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

    Science.gov (United States)

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

    2018-02-01

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

  14. Feature tracking CMR reveals abnormal strain in preclinical arrhythmogenic right ventricular dysplasia/ cardiomyopathy: a multisoftware feasibility and clinical implementation study.

    Science.gov (United States)

    Bourfiss, Mimount; Vigneault, Davis M; Aliyari Ghasebeh, Mounes; Murray, Brittney; James, Cynthia A; Tichnell, Crystal; Mohamed Hoesein, Firdaus A; Zimmerman, Stefan L; Kamel, Ihab R; Calkins, Hugh; Tandri, Harikrishna; Velthuis, Birgitta K; Bluemke, David A; Te Riele, Anneline S J M

    2017-09-01

    Regional right ventricular (RV) dysfunction is the hallmark of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), but is currently only qualitatively evaluated in the clinical setting. Feature Tracking Cardiovascular Magnetic Resonance (FT-CMR) is a novel quantitative method that uses cine CMR to calculate strain values. However, most prior FT-CMR studies in ARVD/C have focused on global RV strain using different software methods, complicating implementation of FT-CMR in clinical practice. We aimed to assess the clinical value of global and regional strain using FT-CMR in ARVD/C and to determine differences between commercially available FT-CMR software packages. We analyzed cine CMR images of 110 subjects (39 overt ARVD/C [mutation+/phenotype+], 40 preclinical ARVD/C [mutation+/phenotype-] and 31 control) for global and regional (subtricuspid, anterior, apical) RV strain in the horizontal longitudinal axis using four FT-CMR software methods (Multimodality Tissue Tracking, TomTec, Medis and Circle Cardiovascular Imaging). Intersoftware agreement was assessed using Bland Altman plots. For global strain, all methods showed reduced strain in overt ARVD/C patients compared to control subjects (p  0.275). For regional strain, overt ARVD/C patients showed reduced strain compared to control subjects in all segments which reached statistical significance in the subtricuspid region for all software methods (p < 0.037), in the anterior wall for two methods (p < 0.005) and in the apex for one method (p = 0.012). Preclinical subjects showed abnormal subtricuspid strain compared to control subjects using one of the software methods (p = 0.009). Agreement between software methods for absolute strain values was low (Intraclass Correlation Coefficient = 0.373). Despite large intersoftware variability of FT-CMR derived strain values, all four software methods distinguished overt ARVD/C patients from control subjects by both global and subtricuspid

  15. Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents

    Directory of Open Access Journals (Sweden)

    Katherine M. Weh

    2016-08-01

    Full Text Available Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered.

  16. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    International Nuclear Information System (INIS)

    Schiff, Rachel; Chamness, Gary C; Brown, Powel H

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

  17. A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies.

    Science.gov (United States)

    Navarro-Fontestad, Carmen; González-Álvarez, Isabel; Fernández-Teruel, Carlos; Bermejo, Marival; Casabó, Vicente Germán

    2012-01-01

    The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable. Copyright © 2011 John Wiley & Sons, Ltd.

  18. Translational reciprocity: bridging the gap between preclinical studies and clinical treatment of stress effects on the adolescent brain.

    Science.gov (United States)

    Neigh, G N; Ritschel, L A; Kilpela, L S; Harrell, C S; Bourke, C H

    2013-09-26

    The genetic, biological, and environmental backgrounds of an organism fundamentally influence the balance between risk and resilience to stress. Sex, age, and environment transact with responses to trauma in ways that can mitigate or exacerbate the likelihood that post-traumatic stress disorder will develop. Translational approaches to modeling affective disorders in animals will ultimately provide novel treatments and a better understanding of the neurobiological underpinnings behind these debilitating disorders. The extant literature on trauma/stress has focused predominately on limbic and cortical structures that innervate the hypothalamic-pituitary-adrenal axis and influence glucocorticoid-mediated negative feedback. It is through these neuroendocrine pathways that a self-perpetuating fear memory can propagate the long-term effects of early life trauma. Recent work incorporating translational approaches has provided novel pathways that can be influenced by early life stress, such as the glucocorticoid receptor chaperones, including FKBP51. Animal models of stress have differing effects on behavior and endocrine pathways; however, complete models replicating clinical characteristics of risk and resilience have not been rigorously studied. This review discusses a four-factor model that considers the importance of studying both risk and resilience in understanding the developmental response to trauma/stress. Consideration of the multifactorial nature of clinical populations in the design of preclinical models and the application of preclinical findings to clinical treatment approaches comprise the core of translational reciprocity, which is discussed in the context of the four-factor model. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

    Science.gov (United States)

    Martin, Frederic D C; Benjamin, Amanda; MacLean, Ruth; Hollinshead, David M; Landqvist, Claire

    2017-12-01

    In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

    Energy Technology Data Exchange (ETDEWEB)

    Kudalkar, Shalley N.; Beloor, Jagadish; Chan, Albert H.; Lee, Won-Gil; Jorgensen, William L.; Kumar, Priti; Anderson, Karen S.

    2017-02-06

    The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 µg/ml for compound I and 82.9 µg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (Cmax) of 4000- to 15,000-fold higher than their therapeutic/effective concentrations. These Cmax values were 4- to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0–last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.

  1. Two-Dimensional High Definition Versus Three-Dimensional Endoscopy in Endonasal Skull Base Surgery: A Comparative Preclinical Study.

    Science.gov (United States)

    Rampinelli, Vittorio; Doglietto, Francesco; Mattavelli, Davide; Qiu, Jimmy; Raffetti, Elena; Schreiber, Alberto; Villaret, Andrea Bolzoni; Kucharczyk, Walter; Donato, Francesco; Fontanella, Marco Maria; Nicolai, Piero

    2017-09-01

    Three-dimensional (3D) endoscopy has been recently introduced in endonasal skull base surgery. Only a relatively limited number of studies have compared it to 2-dimensional, high definition technology. The objective was to compare, in a preclinical setting for endonasal endoscopic surgery, the surgical maneuverability of 2-dimensional, high definition and 3D endoscopy. A group of 68 volunteers, novice and experienced surgeons, were asked to perform 2 tasks, namely simulating grasping and dissection surgical maneuvers, in a model of the nasal cavities. Time to complete the tasks was recorded. A questionnaire to investigate subjective feelings during tasks was filled by each participant. In 25 subjects, the surgeons' movements were continuously tracked by a magnetic-based neuronavigator coupled with dedicated software (ApproachViewer, part of GTx-UHN) and the recorded trajectories were analyzed by comparing jitter, sum of square differences, and funnel index. Total execution time was significantly lower with 3D technology (P < 0.05) in beginners and experts. Questionnaires showed that beginners preferred 3D endoscopy more frequently than experts. A minority (14%) of beginners experienced discomfort with 3D endoscopy. Analysis of jitter showed a trend toward increased effectiveness of surgical maneuvers with 3D endoscopy. Sum of square differences and funnel index analyses documented better values with 3D endoscopy in experts. In a preclinical setting for endonasal skull base surgery, 3D technology appears to confer an advantage in terms of time of execution and precision of surgical maneuvers. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Is lecture dead? A preliminary study of medical students' evaluation of teaching methods in the preclinical curriculum.

    Science.gov (United States)

    Zinski, Anne; Blackwell, Kristina T C Panizzi Woodley; Belue, F Mike; Brooks, William S

    2017-09-22

    To investigate medical students' perceptions of lecture and non-lecture-based instructional methods and compare preferences for use and quantity of each during preclinical training. We administered a survey to first- and second-year undergraduate medical students at the University of Alabama School of Medicine in Birmingham, Alabama, USA aimed to evaluate preferred instructional methods.  Using a cross-sectional study design, Likert scale ratings and student rankings were used to determine preferences among lecture, laboratory, team-based learning, simulation, small group case-based learning, large group case-based learning, patient presentation, and peer teaching. We calculated mean ratings for each instructional method and used chi-square tests to compare proportions of first- and second-year cohorts who ranked each in their top 5 preferred methods. Among participating students, lecture (M=3.6, SD=1.0), team based learning (M=4.2, SD=1.0), simulation (M=4.0, SD=1.0), small group case-based learning (M=3.8, SD=1.0), laboratory (M=3.6, SD=1.0), and patient presentation (M=3.8, SD=0.9) received higher scores than other instructional methods. Overall, second-year students ranked lecture lower (χ 2 (1, N=120) =16.33, p<0.0001) and patient presentation higher (χ 2 (1, N=120) =3.75, p=0.05) than first-year students. While clinically-oriented teaching methods were preferred by second-year medical students, lecture-based instruction was popular among first-year students. Results warrant further investigation to determine the ideal balance of didactic methods in undergraduate medical education, specifically curricula that employ patient-oriented instruction during the second preclinical year.

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

    Directory of Open Access Journals (Sweden)

    Jawad Fares

    2016-09-01

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

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

    Science.gov (United States)

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

    2016-09-01

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

  5. [Does the transition to clinical training change students' perception of career choice, physician's character and preclinical studies?].

    Science.gov (United States)

    Lotan, Eyal; Kimhi, Oded; Lishner, Michael; Notzer, Netta

    2010-04-01

    In Israel, the transition to clinical training in hospitals is the first direct encounter of the medical student with the reality of the profession. This is a significant socialization step for his upcoming professional decisions. This study aimed to identify how this encounter influences students' perceptions of career choice, physician's character and preclinical studies. Fourth year Israeli medical students at the Tel Aviv University voluntarily completed a questionnaire before and after their first clinical clerkship. The questionnaire was comprised of 30 5-point Likert scale statements and 3 multiple choice questions with the possibility to add remarks. The random response rate was 90% (81/90) before the clerkship and 82% (90/110) at its end. Results indicate that the students are satisfied with their medical studies at both junctures. However, after the clerkship, 23% of the students consider alternatives to clinical medicine compared with only 6% before, and 16% would rethink studying medicine. Physicians are perceived as professional, compassionate, respectful to colleagues and actively participating in students' education. Physicians' levels of workload and bitterness are evaluated as high and moderate, respectively, while their levels of reward and satisfaction with medicine are evaluated as low and moderate, respectively. Their evaluation of the contribution of preclinical studies as preparation for clinical studies had not changed after the clerkship and was moderate, and earlier exposure to patients and clinical relevancy of the learned subjects were preferred. The students enter the medical world highly satisfied, and this feeling shall be maintained until the stage of being independent physicians and choosing their specialties. The picture that evolved, in which a high proportion of the students consider alternatives to clinical medicine, is disappointing. Educators should be aware of their role model function not only in knowledge and skills, but

  6. A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies : important issues and lessons relevant to the design of future clinical research

    NARCIS (Netherlands)

    Disma, Nicola; Mondardini, Maria C.; Terrando, Niccolo; Absalom, Anthony R.; Bilotta, Federico

    Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents

  7. Study of Doxicycline Efficacy in Broilers’ Colibacilosis

    Directory of Open Access Journals (Sweden)

    Romeo Teodor Cristina

    2010-05-01

    Full Text Available The aim of study is a therapeutic assessment of doxicycline’s hyclate efficacy, a wide spectrum antibiotic (efficient in majority of bacterial Gram-positive and Gram-negative infections and mycoplasmas, frequently isolated in poultry in a colisepticemia outbreak in a 3,000 chicken farm. Disease started at the broiler’s age of 20 days and mortality rate reached 32.5%. The behaviour to antibiotics of isolated bacterial strains was tested and antibiogram (Sanofi was used, doxicycline revealing a very good antibiotic activity. The treatments (with the dose of 10 mg x kg.b.w.-1 were done individually for five days, clinical evolution being observed until day ten of the experiment. Analyzing evolutions after treatments it was observed that the mortality diminished progressively from 14.2% in the first day, to 8.3% - 5.9% - 2.5% - 1.7% and respectively 0.8% in the sixth treatments day, in days seven, eight, nine, and ten of the study not being registered any mortality cases. In our opinion the favorable clinical evolution was recorded after the third treatment day, at the end of experiment from 120 remaining live 80 chickens (representing 66.7% proving the fact that doxicycline was efficient, confirmed also by the average daily weight gain for the remaining live chickens.

  8. Preclinical cadaveric study of transanal endoscopic da Vinci® surgery.

    Science.gov (United States)

    Hompes, R; Rauh, S M; Hagen, M E; Mortensen, N J

    2012-08-01

    Single-port platforms are increasingly being used for transanal surgery and may be associated with a shorter learning curve than transanal endoscopic microsurgery. However, these procedures remain technically challenging, and robotic technology could overcome some of the limitations and increase intraluminal manoeuvrability. An initial experimental experience with transanal endoscopic da Vinci(®) surgery (TEdS) using a glove port on human cadavers is reported. After initial dry laboratory experiments, the feasibility of TEdS and ideal set-up were further evaluated in human cadavers. For transanal access a glove port was constructed on-table by using a circular anal dilator, a standard wound retractor and a surgical glove. A da Vinci(®) Si HD system was used in combination with the glove port for transanal endoscopic resections. It was possible to perform all necessary tasks to complete a full-thickness excision and closure of the rectal wall, with cadavers in both prone and supine positions. The stable magnified view, combined with the EndoWrist(®) technology of the robotic instruments, made every task straightforward. Intraluminal manoeuvrability could be improved further by intersecting the robotic instruments. The glove port proved to be very reliable and the inherent flexibility of the glove facilitated docking of the robotic arms in a narrow confined space. Using a reliable and universally available glove port, TEdS was feasible and a preferred set-up was determined. Further clinical trials will be necessary to assess the safety and efficacy of this technique. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

  9. An observational study investigating the impact of simulated patients in teaching communication skills in preclinical dietetic students.

    Science.gov (United States)

    Gibson, S J; Davidson, Z E

    2016-08-01

    Simulated patients (SPs) are often used in dietetics for the teaching and assessment of communication skills. The present study aimed to determine the impact of a SP encounter on communication skills in undergraduate preclinical dietetic students in the context of the resources required for delivering this educational strategy. This observational study collected assessment data from four cohorts of third-year dietetic students to examine the effect of participation in SP-embedded Objective Structured Clinical Exams. Students completed two SP interviews, 2 weeks apart, and communication skills were measured on both occasions. A subgroup of students received a video of their SP encounter. Differences between the two SP interview scores were compared to assess the impact of the SP encounter on communication skills. The required staff and resources were described. Data were collected involving 215 students. Out of 30 marks, there was a modest mean (SD) improvement in communication skills from the first to the second SP interview of 2.5 (4.2) (P skills, with failing students demonstrating the greatest improvement between SP encounters. There were no observed benefits for the subset of students who received videos. Providing repeat SP interview opportunities results in only modest improvement in communication skills for most students. The use of SPs needs to be considered in context of the substantial costs and resources involved and tailored to student ability. © 2015 The British Dietetic Association Ltd.

  10. Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies

    International Nuclear Information System (INIS)

    Amacher, David E.

    2011-01-01

    Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the 'two hit' theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R and D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.

  11. Common handling procedures conducted in preclinical safety studies result in minimal hepatic gene expression changes in Sprague-Dawley rats.

    Directory of Open Access Journals (Sweden)

    Yudong D He

    Full Text Available Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance.

  12. Study Skills Course Impact on Academic Self-Efficacy

    Science.gov (United States)

    Wernersbach, Brenna M.; Crowley, Susan L.; Bates, Scott C.; Rosenthal, Carol

    2014-01-01

    Although study skills courses improve student retention, the impact of study skills courses on students' academic self-efficacy has not been investigated. The present study examined pre- and posttest levels of academic self-efficacy in college students enrolled in a study skills course (n = 126) compared to students enrolled in a general education…

  13. A review of treatment planning for precision image-guided photon beam pre-clinical animal radiation studies

    International Nuclear Information System (INIS)

    Verhaegen, Frank; Hoof, Stefan van; Granton, Patrick V.; Trani, Daniela

    2014-01-01

    Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly.

  14. Preventing Electromagnetic Pulse Irradiation Damage on Testis Using Selenium-rich Cordyceps Fungi. A Preclinical Study in Young Male Mice.

    Science.gov (United States)

    Miao, Xia; Wang, Yafeng; Lang, Haiyang; Lin, Yanyun; Guo, Qiyan; Yang, Mingjuan; Guo, Juan; Zhang, Yanjun; Zhang, Jie; Liu, Junye; Liu, Yaning; Zeng, Lihua; Guo, Guozhen

    2017-02-01

    Networked 21st century society, globalization, and communications technologies are paralleled by the rise of electromagnetic energy intensity in our environments and the growing pressure of the environtome on human biology and health. The latter is the entire complement of environmental factors, including the electromagnetic energy and the technologies that generate them, enacting on the digital citizen in the new century. Electromagnetic pulse (EMP) irradiation might have serious damaging effects not only on electronic equipment but also in the whole organism and reproductive health, through nonthermal effects and oxidative stress. We sought to determine whether EMP exposure (1) induces biological damage on reproductive health and (2) the extent to which selenium-rich Cordyceps fungi (daily coadministration) offer protection on the testicles and spermatozoa. In a preclinical randomized study, 3-week-old male BALB/c mice were repeatedly exposed to EMP (peak intensity 200 kV/m, pulse edge 3.5 ns, pulse width 15 ns, 0.1 Hz, and 400 pulses/day) 5 days per week for four consecutive weeks, with or without coadministration of daily selenium-rich Cordyceps fungi (100 mg/kg). Testicular index and spermatozoa formation were measured at baseline and 1, 7, 14, 28, and 60 day time points after EMP exposure. The group without Cordyceps cotreatment displayed decreased spermatozoa formation, shrunk seminiferous tubule diameters, and diminished antioxidative capacity at 28 and 60 days after exposure (p digital citizenship.

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

    Science.gov (United States)

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

    2018-05-10

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

  16. CCR 20th anniversary commentary: Preclinical study of proteasome inhibitor bortezomib in head and neck cancer.

    Science.gov (United States)

    Allen, Clint T; Conley, Barbara; Sunwoo, John B; Van Waes, Carter

    2015-03-01

    In a study published in the May 1, 2001, issue of Clinical Cancer Research, Sunwoo and colleagues provided evidence for proteasome inhibition of NF-κB and tumorigenesis, supporting early-phase clinical trials in solid malignancies of the upper aerodigestive tract. Subsequent clinical studies uncovered a dichotomy of responses in patients with hematopoietic and solid malignancies, and the mechanisms of resistance. ©2015 American Association for Cancer Research.

  17. Safety Evaluation of Sclerotium from a Medicinal Mushroom, Lignosus cameronensis (Cultivar: Preclinical Toxicology Studies

    Directory of Open Access Journals (Sweden)

    Sook-Shien Lee

    2017-09-01

    Full Text Available Twenty-eight days subacute toxicity studies performed in rats using sclerotial powder of Lignosus cameronensis cultivar was conducted to assess its safety for consumption prior to other scientific investigations on its medicinal benefits, nutraceutical or pharmaceutical application of the mushroom. The study was conducted at 250, 500, and 1000 mg/kg sclerotial powder of L. cameronensis cultivar (n = 5 for each respective dose, on both male and female groups while control groups received only distilled water. At the end of the study (29th day, the animals were sacrificed followed by blood and organs collection for analysis. Subacute toxicity studies done shows that sclerotial powder of L. cameronensis cultivar at 250, 500, and 1000 mg/kg did not induce treatment related changes on behavioral patterns, gross physical appearance, growth pattern, body weight gain, values of hematological and clinical biochemical panels as well as histopathological findings on kidney, spleen, heart, lung and liver of the experimental rats. The no-observed-adverse-effect level dose for sclerotial powder of L. cameronensis cultivar in 28-days sub-acute toxicity study is determined to be 1000 mg/kg.

  18. Preclinical safety and efficacy of an anti–HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor

    Directory of Open Access Journals (Sweden)

    Orit Wolstein

    2014-01-01

    Full Text Available Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4+ T lymphocytes, and CD34+ hematopoietic stem/progenitor cells (HSPC. CCR5-targeted shRNA (sh5 and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.

  19. Wound-Healing Potential of Cultured Epidermal Sheets Is Unaltered after Lyophilization: A Preclinical Study in Comparison to Cryopreserved CES

    Directory of Open Access Journals (Sweden)

    H. Jang

    2013-01-01

    Full Text Available Lyophilized Cultured Epidermal Sheets (L-CES have been reported to be as effective as the cryopreserved CES (F-CES in treating skin ulcers. However, unlike F-CES, no preclinical study assessing wound-healing effects has been conducted for L-CES. The present study was set out to investigate the microstructure, cytokine profile, and wound-healing effects of L-CES in comparison to those of F-CES. Keratinocytes were cultured to prepare CES, followed by cryopreservation at −70°C and lyophilization. Under microscopic observation, intact cells with apparent intracellular junctions were observed in L-CES. The L-CES, like fresh CES, consisted of three to four well-maintained epidermal layers, as shown by the expression of keratins, involucrin, and p63. There were no differences in the epidermal layer or protein expression between L-CES and F-CES, and both CES were comparable to fresh CES. TGF-α, EGF, VEGF, IL-1α, and MMPs were detected in L-CES at levels similar to those in F-CES. In a mouse study, wounds treated with L-CES or F-CES completely healed at least 4 days faster than untreated wounds. CES-treated wounds completely healed by day 10, while the untreated wounds did not heal by day 14. Masson’s trichrome staining showed that collagen deposition in the CES-treated wounds was highly increased in the dermis of the wound center compared to that in the control wounds. Thus, this study demonstrates that L-CES is as clinically effective as F-CES for wound treatment.

  20. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    Science.gov (United States)

    Mi, Xue-Song; Yuan, Ti-Fei; Ding, Yong; Zhong, Jing-Xiang; So, Kwok-Fai

    2014-01-01

    Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. PMID:25429204

  1. A gender study investigating physics self-efficacy

    Science.gov (United States)

    Sawtelle, Vashti

    The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively the influence of self-efficacy in predicting success and then to qualitatively explore the development of self-efficacy. In the initial quantitative studies, I explore the utility of self-efficacy in predicting the success of introductory physics students, both women and men. Results indicate that self-efficacy is a significant predictor of success for all students. I then disaggregate the data to examine how self-efficacy develops differently for women and men in the introductory physics course. Results show women rely on different sources of self-efficacy than do men, and that a particular instructional environment, Modeling Instruction, has a positive impact on these sources of self-efficacy. In the qualitative phase of the project, this dissertation focuses on the development of self-efficacy. Using the qualitative tool of microanalysis, I introduce a methodology for understanding how self-efficacy develops moment-by-moment using the lens of self-efficacy opportunities. I then use the characterizations of self-efficacy opportunities to focus on a particular course environment and to identify and describe a mechanism by which Modeling Instruction impacts student self-efficacy. Results indicate that the emphasizing the development and deployment of models affords opportunities to impact self-efficacy. The findings of this dissertation indicate that introducing key elements into the classroom, such as cooperative group work, model development and deployment, and interaction with the instructor, create a mechanism by which instructors can impact the self-efficacy of their students. Results from this study indicate that

  2. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    Directory of Open Access Journals (Sweden)

    Mi XS

    2014-11-01

    Full Text Available Xue-Song Mi,1,2 Ti-Fei Yuan,3,4 Yong Ding,1 Jing-Xiang Zhong,1 Kwok-Fai So4,5 1Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 3School of Psychology, Nanjing Normal University, Nanjing, People’s Republic of China; 4Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; 5Guangdong-Hongkong-Macau Institute of Central Nervous System, Jinan University, Guangzhou, People’s Republic of China Abstract: Diabetic retinopathy (DR is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. Keywords: animal model, in vitro culture, ex vivo culture, neurovascular dysfunction

  3. Validation of the Filovirus Plaque Assay for Use in Preclinical Studies

    Directory of Open Access Journals (Sweden)

    Amy C. Shurtleff

    2016-04-01

    Full Text Available A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4 studies. After standardization studies were completed, Good Laboratory Practices (GLP-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV variant and Ebola Virus Kikwit (EBOV variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID. The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay’s precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies.

  4. Perfluorochemical emulsions as adjuncts to radiation therapy: a review of preclinical studies

    International Nuclear Information System (INIS)

    Rockwell, S.

    1989-01-01

    Oxygen is a potent radiosensitizer. As virtually complete radiosensitization is observed at 0 2 levels similar to those in venous blood, most healthy normal tissues exhibit an aerobic radiosensitivity. In contrast, solid tumors contain avascular areas and blood vessels which are subject to transient and persistent interruptions in blood flow; as a result, tumors contain viable cells existing under acute and chronic hypoxia. These hypoxic cells are resistant to radiation and to many drugs used in cancer therapy, and can limit the curability of tumors by conventional therapeutic regimens. Many laboratory and clinical studies are examining ways to circumvent the problem of hypoxic cells in cancer therapy. Studies reviewed here examine the effects of infusion of perfluorochemical emulsions (PFC-E) combined with the administration of 0 2 at ambient or hyperbaric pressures on the radiation responses of solid tumors and of the normal tissues which limit the intensity of therapy. Appropriate regimens of treatment with a PFC-E and oxygen-enriched atmospheres increase the radiation response of solid tumors, without causing severe host toxicities and without producing equivalent increases in radiation injury to normal tissues. These studies show that PFC-E's have significant potential as adjuncts to radiotherapy and provide a basis for the design and initiation of clinical trials testing these agents [fr

  5. SU-F-R-01: Preclinical Radioimmunogenomics Study to Design Personalized Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Abdollahi, H [Iran University of Medical Sciences, Tehran, Iran, Tehran, Tehran (Iran, Islamic Republic of)

    2016-06-15

    Purpose: Radiogenomics is an active area of research to find clinical correlation between genomics and radiotherapy outcomes. In this era, many different biological issues should be taken into account. In this study we aimed to introduce “Radioimmunogenomics” as a new approach to study immunogetics issue regard to radiotherapy induced clinical manifestations. Methods: We studied different immunological pathways and signaling molecules which underling radiation response of normal and malignant tissues. In the other hand, we found many genes and proteins are responsible to radiation effects on biological tissues. We defined a theoretical framework to correlate these genes with radiotherapy outcomes as TCP and NTCP biological dose tools. Results: Our theoretical results showed, high-throughput immunogenomics biomarkers can be correlated with radiotherapy outcomes. Genes regarding to inflammation, apoptosis, repair molecules and many other immunological markers can be defined as radioimmune markers to predict radiotherapy response. Conclusion: Radioimmunogenomics can be used as a new personalized radiotherapy research area to enhance treatment outcome as well as quality of life.

  6. Radiosynthesis, evaluation and preclinical studies of a new 5HT2A radioligand

    International Nuclear Information System (INIS)

    Mertens, J.; Terriere, D.; Baeken, C.; D'Haenan, H.; Flamen, P.; Bossuyt, A.; Leysen, J.

    1998-01-01

    123 I-5-I-R91150, a radioiodinated analogue of R91150 (a ligand (antagonist) of Janssen Research Foundation), showing high affinity and selectivity for 5HT 2A receptors, was developed as a potential in vivo 5HT 2A receptor tracer for SPECT. The applied radiochemistry, whereby the radioiodine was substituted on the 5 - position of the benzamide ring, allowed to obtain the tracer with high specific activity and high purity. In vitro and in vivo rat studies revealed that the new tracer bound reversibly with the required high affinity (Kd=0.1 nM) and high selectivity (a factor ranging from 10000 to at least 50 vis a vis other receptors) to 5HT 2A receptors. In young normal subjects the major part of the 123 I-5-I-R91150 radioactivity in the brain is present in cortical areas. Cortical area to cerebellum activity ratio reaches an equilibrium value of about 1.8 around 90 min. till 4 hours p.i.. This binding was specific and reversible. The cortical activity reflects a distribution in the brain similar to that of the mapping of 5HT 2A receptors from post mortem studies. These findings suggested that 123 I-5-I-R91150 allows imaging and quantitative estimation with SPECT and could be used for further clinical studies. The radiobromine analogue was synthetised as a potential PET tracer. (author)

  7. Influence of Teaching Strategies and its Order of Exposure on Pre-Clinical Teeth Arrangement - A Pilot Study.

    Science.gov (United States)

    Jeyapalan, Karthigeyan; Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar

    2016-10-01

    Teeth arrangement is a vital skill for the undergraduate dental student. The attainment of skills depends largely on the methodology of teaching. In a dental curriculum, the students are exposed to a wide variety of inputs and teaching methodologies from different sources. The educational unit in dental school must identify the sequence of teaching methods that enhance the learning and practising ability of students. The aim of this study was to evaluate the effectiveness of three different teaching methodologies for teeth arrangement and compare the differences between the orders of exposure to each teaching methodology on the development of teeth arrangement skills. The first year B.D.S students were study participants and were divided into three groups A, B, C. They were exposed to three teaching patterns namely live demonstration with video assisted teaching, group discussion with hand-outs and lectures with power point presentation. After each teaching methodology, their skill was assessed. The groups were exposed to three methodologies in different order for three arrangements. The scores obtained were analysed using Kruskal Wallis rank sum test and Dunn test for statistical significance. Significantly higher scores in the teeth arrangement procedure were obtained by the Group A students who were exposed initially to live demonstration with video-assisted teaching. Difference in the scores was noted among and within the groups. The difference between Group A and Group C was statistically significant after both first and third teeth arrangement (p=0.0031, p=0.0057). The study suggests each pre-clinical practice should begin with a live demonstration to enhance immediate learning absorption followed by lectures with power point presentation and group discussion for retention of knowledge and memory retrieval.

  8. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    Science.gov (United States)

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-11-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction.

  9. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    Directory of Open Access Journals (Sweden)

    Julián Ernesto Nicolás Gulin

    2015-11-01

    Full Text Available Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%. Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction.

  10. Curcumin nanoformulations : A review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment

    NARCIS (Netherlands)

    Naksuriya, Ornchuma; Okonogi, Siriporn; Schiffelers, Raymond M.|info:eu-repo/dai/nl/212909509; Hennink, Wim E.|info:eu-repo/dai/nl/070880409

    2014-01-01

    Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Curcuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical

  11. Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

    Science.gov (United States)

    Papageorgiou, A; Lialiaris, Th; Stergiou, E; Stergiou, I; Tsigris, C; Kourti, A; Geromichalos, G; Stravoravdi, P; Trafalis, D; Athanassiou, A E; Pitsas, A; Camoutsis, Ch

    2008-01-01

    In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

  12. Optimal Solution Volume for Luminal Preservation: A Preclinical Study in Porcine Intestinal Preservation.

    Science.gov (United States)

    Oltean, M; Papurica, M; Jiga, L; Hoinoiu, B; Glameanu, C; Bresler, A; Patrut, G; Grigorie, R; Ionac, M; Hellström, M

    2016-03-01

    Rodent studies suggest that luminal solutions alleviate the mucosal injury and prolong intestinal preservation but concerns exist that excessive volumes of luminal fluid may promote tissue edema. Differences in size, structure, and metabolism between rats and humans require studies in large animals before clinical use. Intestinal procurement was performed in 7 pigs. After perfusion with histidine-tryptophan-ketoglutarate (HTK), 40-cm-long segments were cut and filled with 13.5% polyethylene glycol (PEG) 3350 solution as follows: V0 (controls, none), V1 (0.5 mL/cm), V2 (1 mL/cm), V3 (1.5 mL/cm), and V4 (2 mL/cm). Tissue and luminal solutions were sampled after 8, 14, and 24 hours of cold storage (CS). Preservation injury (Chiu score), the apical membrane (ZO-1, brush-border maltase activity), and the electrolyte content in the luminal solution were studied. In control intestines, 8-hour CS in HTK solution resulted in minimal mucosal changes (grade 1) that progressed to significant subepithelial edema (grade 3) by 24 hours. During this time, a gradual loss in ZO-1 was recorded, whereas maltase activity remained unaltered. Moreover, variable degrees of submucosal edema were observed. Luminal introduction of high volumes (2 mL/mL) of PEG solution accelerated the development of the subepithelial edema and submucosal edema, leading to worse histology. However, ZO-1 was preserved better over time than in control intestines (no luminal solution). Maltase activity was reduced in intestines receiving luminal preservation. Luminal sodium content decreased in time and did not differ between groups. This PEG solution protects the apical membrane and the tight-junction proteins but may favor water absorption and tissue (submucosal) edema, and luminal volumes >2 mL/cm may result in worse intestinal morphology. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Alveolar Ridge Augmentation with Three-Dimensional Printed Hydroxyapatite Devices: A Preclinical Study.

    Science.gov (United States)

    Fiorellini, Joseph P; Norton, Michael R; Luan, Kevin WanXin; Kim, David Minjoon; Wada, Kei; Sarmiento, Hector L

    2018-02-14

    The objective of this study was to evaluate the effectiveness of precise three-dimensional hydroxyapatite printed micro- and macrochannel devices for alveolar ridge augmentation in a canine model. All grafts induced minimal inflammatory and fibrotic reactions. Examination of undecalcified sections revealed that both types of grafts demonstrated bone ingrowth. The majority of the bone growth into the block graft was into the channels, though a portion grew directly into the construct in the form of small bony spicules. In conclusion, bone ingrowth was readily demonstrated in the middle of the implanted printed devices.

  14. Modulation of radiation-induced oral mucositis by pentoxifylline: Preclinical studies

    International Nuclear Information System (INIS)

    Gruber, Sylvia; Bozsaky, Eva; Schmidt, Margret; Doerr, Wolfgang

    2015-01-01

    Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model. Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), followed by graded local top-up doses (day 7/14), in order to generate complete dose-effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint. With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day - 5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation. PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies. (orig.) [de

  15. Precision medicine for hepatocelluar carcinoma using molecular pattern diagnostics: results from a preclinical pilot study.

    Science.gov (United States)

    Agarwal, Rahul; Cao, Yuan; Hoffmeier, Klaus; Krezdorn, Nicolas; Jost, Lukas; Meisel, Alejandro Rodriguez; Jüngling, Ruth; Dituri, Francesco; Mancarella, Serena; Rotter, Björn; Winter, Peter; Giannelli, Gianluigi

    2017-06-08

    The aim of this study was to design a road map for personalizing cancer therapy in hepatocellular carcinoma (HCC) by using molecular pattern diagnostics. As an exploratory study, we investigated molecular patterns of tissues of two tumors from individual HCC patients, which in previous experiments had shown contrasting reactions to the phase 2 transforming growth factor beta receptor 1 inhibitor galunisertib. Cancer-driving molecular patterns encompass - inter alias - altered transcription profiles and somatic mutations in coding regions differentiating tumors from their respective peritumoral tissues and from each other. Massive analysis of cDNA ends and all-exome sequencing demonstrate a highly divergent transcriptional and mutational landscape, respectively, for the two tumors, that offers potential explanations for the tumors contrasting responses to galunisertib. Molecular pattern diagnostics (MPDs) suggest alternative, individual-tumor-specific therapies, which in both cases deviate from the standard sorafenib treatment and from each other. Suggested personalized therapies use kinase inhibitors and immune-focused drugs as well as low-toxicity natural compounds identified using an advanced bioinformatics routine included in the MPD protocol. The MPD pipeline we describe here for the prediction of suitable drugs for treatment of two contrasting HCCs may serve as a blueprint for the design of therapies for various types of cancer.

  16. Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies.

    Science.gov (United States)

    Dos Santos, Rafael G; Hallak, Jaime E C

    2017-01-01

    Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.

  17. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration.

    Science.gov (United States)

    Filardo, G; Kon, E; Roffi, A; Di Matteo, B; Merli, M L; Marcacci, M

    2015-09-01

    The aim of this review was to analyze the available evidence on the clinical application of this biological approach for the injective treatment of cartilage lesions and joint degeneration, together with preclinical studies to support the rationale for the use of platelet concentrates, to shed some light and give indications on what to treat and what to expect from intra-articular injections of platelet-rich plasma (PRP). All in vitro, in vivo preclinical and clinical studies on PRP injective treatment in the English language concerning the effect of PRP on cartilage, synovial tissue, menisci, and mesenchymal stem cells were considered. A systematic review on the PubMed database was performed using the following words: (platelet-rich plasma or PRP or platelet concentrate or platelet lysate or platelet supernatant) and (cartilage or chondrocytes or synoviocytes or menisci or mesenchymal stem cells). Fifty-nine articles met the inclusion criteria: 26 were in vitro, 9 were in vivo, 2 were both in vivo and in vitro, and 22 were clinical studies. The analysis showed an increasing number of published studies over time. Preclinical evidence supports the use of PRP injections that might promote a favourable environment for joint tissues healing. Only a few high-quality clinical trials have been published, which showed a clinical improvement limited over time and mainly documented in younger patients not affected by advanced knee degeneration. Besides the limits and sometimes controversial findings, the preclinical literature shows an overall support toward this PRP application. An intra-articular injection does not just target cartilage; instead, PRP might influence the entire joint environment, leading to a short-term clinical improvement. Many biological variables might influence the clinical outcome and have to be studied to optimize PRP injective treatment of cartilage degeneration and osteoarthritis.

  18. A Preclinical Study of Casein Glycomacropeptide as a Dietary Intervention for Acute Mania

    DEFF Research Database (Denmark)

    Liebenberg, Nico; Jensen, Erik; Larsen, Erik Roj

    2018-01-01

    Background: Casein glycomacropeptide is a peptide that lacks phenylalanine, tyrosine, and tryptophan. This profile may enable it to deplete phenylalanine, tyrosine, and tryptophan, and subsequently the synthesis of dopamine and serotonin in the brain. Dopamine- and serotonin-depleting amino acid...... mixtures have shown promise as acute antimanic treatments. In this study, we explore the depleting effects on amino acids, dopamine and serotonin as well as its actions on manic-like and other behavior in rats. Methods: Casein glycomacropeptide and a selection of amino acid mixtures were administered...... orally at 2, 4, or 8 h or for 1 week chronically. Amino acid and monoamine levels were measured in plasma and brain and behavior was assessed in the amphetamine-hyperlocomotion, forced swim, prepulse inhibition, and elevated plus maze tests. Results: Casein glycomacropeptide induced a time...

  19. Preclinical pharmacological study on I-ADAM as a serotonin transporter ligand

    International Nuclear Information System (INIS)

    Wu Chunying; Lu Chunxiong; Jiang Quanfu; Zou Meifen; Chen Zhengping; Wang Songpei; Li Xiaomin; Zhang Tongxing; Zhu Junqing; Lin Xiangtong

    2004-01-01

    Objective: To evaluate the new ligand: I-2-( (22( (dimethylamino) methyl) phenyl) thio)-5- iodophenylamine (ADAM) as a serotonin imaging agent. Methods: Biological evaluations were performed in rats and mice. Results: Biodistribution studies in rats showed that the initial uptake of 131 I-ADAM in the brain was high (1.087%ID/organ at 2 min postinjection), and consistently displayed the highest binding (between 60-240 min postinjection) in hypothalamus, a region with the highest density of serotonin transporter (SERT). The specific binding [(TPCB)-1] of 131 I-ADAM in hypothalamus was 2.94, 3.03 and 3.09 at 60, 120 and 240 min postinjection, respectively. The (TPCB)-1 was significantly blocked by pretreatment with Paroxetine, which is known as a serotonin site reuptake inhibitor, while another nonselective competing drug, Ketanserin, showed no blocking effect. The rat brain autoradiography and analysis showed that there was high 131 I-ADAM uptake in hypothalamus, the ratio of hypothalamus/cerebellum was significantly reduced from 7.94 ± 0.39 to 1.30 ± 0.56 by pretreatment with Paroxetine at 60 min postinjection. Blood clearance kinetics was studied in rats, and the initial half-life of 13.79 min and late half-life of 357.14 min were obtained. The kinetic equation was: C=3.6147·e -0.0725t + 1.0413 e -0.0028t . The thyroid uptake was 0.009 and 1.421% ID/organ at 2 min and 120 min postinjection, respectively, suggesting that in vivo deiodination maybe the major route of metabolism. Toxicity trial showed that the dose per kilogram administered to mice was 1000 times greater than that to human beings, assuming a body-weight of 50 kg. Conclusion: These data suggest that 131 I-ADAM may be useful for SPECT imaging of SERT binding sits in the brain. (authors)

  20. Fractional CO2 laser treatment for vaginal laxity: A preclinical study.

    Science.gov (United States)

    Kwon, Tae-Rin; Kim, Jong Hwan; Seok, Joon; Kim, Jae Min; Bak, Dong-Ho; Choi, Mi-Ji; Mun, Seok Kyun; Kim, Chan Woong; Ahn, Seungwon; Kim, Beom Joon

    2018-05-07

    Various studies have investigated treatment for vaginal laxity with microablative fractional carbon dioxide CO 2 laser in humans; however, this treatment has not yet been studied in an animal model. Herein, we evaluate the therapeutic effects of fractional CO 2 laser for tissue remodeling of vaginal mucosa using a porcine model, with the aim of improving vaginal laxity. The fractional CO 2 laser enables minimally invasive and non-incisional procedures. By precisely controlling the laser energy pulses, energy is sent to the vaginal canal and the introitus area to induce thermal denaturation and contraction of collagen. We examined the effects of fractional CO 2 laser on a porcine model via clinical observation and ultrasound measurement. Also, thermal lesions were histologically examined via hematoxylin-eosin staining, Masson's trichrome staining, and Elastica van Gieson staining and immunohistochemistry. The three treatment groups, which were determined according to the amount of laser-energy applied (60, 90, and 120 mJ), showed slight thermal denaturation in the vaginal mucosa, but no abnormal reactions, such as excessive hemorrhaging, vesicles, or erythema, were observed. Histologically, we also confirmed that the denatured lamina propria induced by fractional CO 2 laser was dose-dependently increased after laser treatment. The treatment groups also showed an increase in collagen and elastic fibers due to neocollagenesis and angiogenesis, and the vaginal walls became firmer and tighter because of increased capillary and vessel formation. Also, use of the fractional CO 2 laser increased HSP (heat shock protein) 70 and collagen type I synthesis. Our results show that microablative fractional CO 2 laser can produce remodeling of the vaginal connective tissue without causing damage to surrounding tissue, and the process of mucosa remodeling while under wound dressings enables collagen to increase and the vaginal wall to become thick and tightened. Lasers Surg. Med

  1. Anterior superior alveolar nerve injury after extended endoscopic medial maxillectomy: a preclinical study to predict neurological morbidity.

    Science.gov (United States)

    Schreiber, Alberto; Mattavelli, Davide; Ferrari, Marco; Rampinelli, Vittorio; Lancini, Davide; Ravanelli, Marco; Bertazzoni, Giacomo; Rodella, Luigi Fabrizio; Buffoli, Barbara; Doglietto, Francesco; Nicolai, Piero

    2017-10-01

    Endoscopic medial maxillectomies (EMMs) are used to optimize exposure of the maxillary sinus and retromaxillary areas. Although in type D EMM (Sturmann-Canfield procedure) the anterior superior alveolar nerve (ASAN) is always at risk of injury, only 29% of patients complained of alveolar process and dental anesthesia. The purpose of this anatomical study is to assess the neural anastomotic network of the ASAN (ASAN-NAN) and describe different extensions of type D EMMs in a preclinical setting. The ASAN and its medial anastomotic branches (MABs) and lateral anastomotic branches (LABs) were evaluated by cone-beam computerized tomography (CBCT). Five different extensions of type D (D1 to D5) EMMs were identified and nerves at risk of injury in each type were assessed by CBCT. Moreover, quantification of surgical corridors was performed on cadaver heads with a neuronavigation system. Fifty-seven CBCT scans were analyzed. The ASAN would be spared in 16.3% of cases with a type D1 EMM, while it would be injured in the majority of type D2 to D5 resections. At least 1 nerve of the ASAN-NAN was spared in 96.6%, 93%, 74.6%, 0%, and 65.8% of type D1 to D5 EMMs, respectively. Two cadaver heads were dissected and the incremental volume and number of maxillary subsites exposed was assessed in type D1 to D5 EMMs. ASAN function impairment is probably compensated by LABs and MABs. If this hypothesis will be validated in a prospective study on patients, preoperative CBCT evaluation could predict neurological morbidity after type D EMM, and allow tailoring the procedure to minimize impairment of the ASAN-NAN. © 2017 ARS-AAOA, LLC.

  2. Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris.

    Directory of Open Access Journals (Sweden)

    Camille Luyet

    Full Text Available The majority of pemphigus vulgaris (PV patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis. The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG, PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice as well as PV patients' biopsies (n=6. A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other

  3. Virtual reality, augmented reality, and robotics applied to digestive operative procedures: from in vivo animal preclinical studies to clinical use

    Science.gov (United States)

    Soler, Luc; Marescaux, Jacques

    2006-04-01

    Technological innovations of the 20 th century provided medicine and surgery with new tools, among which virtual reality and robotics belong to the most revolutionary ones. Our work aims at setting up new techniques for detection, 3D delineation and 4D time follow-up of small abdominal lesions from standard mecial images (CT scsan, MRI). It also aims at developing innovative systems making tumor resection or treatment easier with the use of augmented reality and robotized systems, increasing gesture precision. It also permits a realtime great distance connection between practitioners so they can share a same 3D reconstructed patient and interact on a same patient, virtually before the intervention and for real during the surgical procedure thanks to a telesurgical robot. In preclinical studies, our first results obtained from a micro-CT scanner show that these technologies provide an efficient and precise 3D modeling of anatomical and pathological structures of rats and mice. In clinical studies, our first results show the possibility to improve the therapeutic choice thanks to a better detection and and representation of the patient before performing the surgical gesture. They also show the efficiency of augmented reality that provides virtual transparency of the patient in real time during the operative procedure. In the near future, through the exploitation of these systems, surgeons will program and check on the virtual patient clone an optimal procedure without errors, which will be replayed on the real patient by the robot under surgeon control. This medical dream is today about to become reality.

  4. COMPARATIVE STUDY OF CYTOLOGIC AND COLPOSCOPIC FINDINGS IN PRECLINICAL CERVICAL CANCER

    Directory of Open Access Journals (Sweden)

    Penagaluru

    2015-11-01

    Full Text Available BACKGROUND The cytologic diagnosis of cervical smears has become a very important screening test for the detection of pre-invasive and invasive cervical epithelial abnormalities. MATERIALS AND METHODS It is a prospective study conducted for a period of 1 year in 100 women who fulfilled the inclusion criteria. Colposcopy, PAP smear and biopsy were done. RESULTS Majority 70.5% i.e., (12/17 of CIN occurred in the age group of 30-49 years. Among the 9 women who took OCP, 12% (2/17 had CIN. Incidence of CIN in the permanently sterilized group was 59% (10/17 and among IUCD user was 5.9% (1/17. Among women who were diagnosed to have CIN, 70.5% (12/17 complained of excessive vaginal discharge 11.7% (2/17 of women had post-coital bleeding. PAP smear had a sensitivity of 29% and a specificity of 88% which was attributed to the high number of false, negative smears. Colposcopy showed a sensitivity of 82% and a specificity of 81%. Sensitivity was more than pap smear but specificity was less than pap smear. Accuracy of Colposcopy was found to be 82% which was comparatively more accurate than pap smear (78%. CONCLUSIONS COLPOSCOPY offers an excellent tool in evaluating cervical lesions. It is an easy and perspective method and its importance lies in teaching, diagnosis and management of cervical lesions, both neoplastic and non-neoplastic.

  5. High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies

    Directory of Open Access Journals (Sweden)

    Frank A Giordano

    Full Text Available Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies, it is not useful for large-scale analyses. To explore whether vector integration site (IS recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification–mediated PCR (LAM-PCR or nonrestrictive LAM-PCR (nrLAM-PCR, both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM-PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand.

  6. Diabody construct of ior-CEA1. Pre-clinical studies for therapeutic application

    International Nuclear Information System (INIS)

    Pimentel, G.; Ravelo, R.; Miranda, M.; Sanchez, I.; Perez, L.; Ayala, M.; Gavilondo, J.

    2007-01-01

    -five nanograms of radiolabelled 131 I-(scFv) 2 were incubated with 15-fold excess of CEA for 1 h at room temperature and the sample was analysed by size-exclusion FPLC. Biodistribution studies were carried out with 131 I ior-CEA1-(scFv) 2 in MNRI healthy and nude mice bearing LS174T human CEA-positive tumours, in order to evaluate the in vivo behaviour. Results: The methodology proposed for the radio-iodination attained incorporation over 90% of radioiodine to the protein. Although it is a relative high labelling yield, for the immunoreactivity studies and biodistribution the fragment was purified by means of FPLC. The results showed that the 131 I-(scFv) 2 retain 85% of its immunoreactivity after labelling. This decrease in the immunoreactive capacity could be attributed to the iodine/tyrosine binding in the region of recognition of the molecule. That is, from the 16 tyrosine present in each scFv, four of them are in the complementarity determinant regions (1 in V L CDR1 and 3 en V L CDR3), and due to the voluminous size of the iodine atom, it could produce steric impediments that hinder the formation of the antigenantibody complex. The non-specific union in the study was of 6%. The Scatchard analysis was used to calculate the apparent affinity constant. The binding affinity was of 3,5 x 10 7 M -1 , similar to other biomolecules of this construct. The radiochromatograms of Diabody and immunoconjugate CEA/(scFv)B2B showed a radioactive bulk that is eluted with a lower retention time suggesting the immunocomplex formation. The immunoreactive fraction of the radioiodide fragment can be calculated from radiochromatogram by means of the integration of the area under the curve for the corresponding fractions to the complex antigen-antibody and the P131PI-diabody. The obtained result was 87%, similar to 85% obtained by means of the classic technique. The results in the biodistribution showed a typical behavior for this kind of biomolecules, without significant localization in any

  7. Argan Oil as an Effective Nutri-Therapeutic Agent in Metabolic Syndrome: A Preclinical Study

    Directory of Open Access Journals (Sweden)

    Adil El Midaoui

    2017-11-01

    Full Text Available The present study aims at examining the effects of argan oil on the three main cardiovascular risk factors associated with metabolic syndrome (hypertension, insulin resistance and obesity and on one of its main complications, neuropathic pain. Male Sprague-Dawley rats had free access to a drinking solution containing 10% d-glucose or tap water for 12 weeks. The effect of argan oil was compared to that of corn oil given daily by gavage during 12 weeks in glucose-fed rats. Glucose-fed rats showed increases in systolic blood pressure, epididymal fat, plasma levels of triglycerides, leptin, glucose and insulin, insulin resistance, tactile and cold allodynia in association with a rise in superoxide anion production and NADPH oxidase activity in the thoracic aorta, epididymal fat and gastrocnemius muscle. Glucose-fed rats also showed rises in B1 receptor protein expression in aorta and gastrocnemius muscle. Argan oil prevented or significantly reduced all those anomalies with an induction in plasma adiponectin levels. In contrast, the same treatment with corn oil had a positive impact only on triglycerides, leptin, adiponectin and insulin resistance. These data are the first to suggest that argan oil is an effective nutri-therapeutic agent to prevent the cardiovascular risk factors and complications associated with metabolic syndrome.

  8. The Usefulness of Systematic Reviews of Animal Experiments for the Design of Preclinical and Clinical Studies

    Science.gov (United States)

    de Vries, Rob B. M.; Wever, Kimberley E.; Avey, Marc T.; Stephens, Martin L.; Sena, Emily S.; Leenaars, Marlies

    2014-01-01

    The question of how animal studies should be designed, conducted, and analyzed remains underexposed in societal debates on animal experimentation. This is not only a scientific but also a moral question. After all, if animal experiments are not appropriately designed, conducted, and analyzed, the results produced are unlikely to be reliable and the animals have in effect been wasted. In this article, we focus on one particular method to address this moral question, namely systematic reviews of previously performed animal experiments. We discuss how the design, conduct, and analysis of future (animal and human) experiments may be optimized through such systematic reviews. In particular, we illustrate how these reviews can help improve the methodological quality of animal experiments, make the choice of an animal model and the translation of animal data to the clinic more evidence-based, and implement the 3Rs. Moreover, we discuss which measures are being taken and which need to be taken in the future to ensure that systematic reviews will actually contribute to optimizing experimental design and thereby to meeting a necessary condition for making the use of animals in these experiments justified. PMID:25541545

  9. Contributions of GABA to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

    Science.gov (United States)

    Silveri, Marisa M.

    2015-01-01

    There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders. PMID:24631274

  10. Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer

    Science.gov (United States)

    Hetzel, Fred W.; Chen, Qun; Luck, David; Beckers, Jill; Huang, Zheng

    2004-06-01

    Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the IV infused photosensitizer drug. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week post PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Prostate lesions could be detected by MRI scan as early as 48 h post PDT. Maximum lesion size of 1.5 cm3 and 2.9 cm3 could be achieved at 50 J/cm and 100 J/cm, respectively, with interstitial treatment using a single 1-cm diffuser fiber, suggesting the Tookad-PDT is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat localized prostate cancer.

  11. Novel implant design improves implant survival in multirooted extraction sites: a preclinical pilot study.

    Science.gov (United States)

    Sivan-Gildor, Adi; Machtei, Eli E; Gabay, Eran; Frankenthal, Shai; Levin, Liran; Suzuki, Marcelo; Coelho, Paulo G; Zigdon-Giladi, Hadar

    2014-10-01

    The primary aim is to evaluate clinical, radiographic, and histologic parameters of novel implants with "three roots" design that were inserted into fresh multirooted extraction sockets. A secondary aim is to compare this new implant to standard root-form dental implants. Immediate implantation of novel or standard design 6 × 6-mm implants was performed bilaterally into multirooted sockets in mandibles of mini-pigs. Twelve weeks later, clinical, radiographic, stability, histomorphometric, and microcomputed tomography (micro-CT) analyses were performed. Survival rates were significantly higher in the test implants compared with control (92.8% versus 33.3%, respectively; P micro-CT analyses demonstrated bone fill in the inner part of the test implants. Moreover, bone-to-implant contact was higher in the test implants (55.50% ± 3.68% versus 42.47% ± 9.89%). Contrary to the clinical, radiographic, and histomorphometric results, resonance frequency analysis measurements were greater in the control group (77.74 ± 3.21 implant stability quotient [ISQ]) compared with the test group (31.09 ± 0.28 ISQ), P = 0.008. The novel design implants resulted in significantly greater survival rate in multirooted extraction sites. Further studies will be required to validate these findings.

  12. Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

    Directory of Open Access Journals (Sweden)

    Lin CM

    2015-08-01

    Full Text Available Chien-Min Lin,1,* Jo-Ting Tsai,2,* Chen Kuei Chang,1 Juei-Tang Cheng,3 Jia-Wei Lin11Department of Neurosurgery, 2Department of Radiation Oncology, Shuang Ho Hospital-Taipei Medical University, 3Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan City, Taiwan*These authors contributed equally to this workBackground: Decrease of peroxisome proliferator-activated receptors-δ (PPARδ expression has been observed after spinal cord injury (SCI. Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application.Methods: In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage.Results: Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI.Conclusion: The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI.Keywords: PPARδ, AMPK, spinal cord injury, angiotensin receptor blocker, metformin

  13. Pre-Clinical Model to Study Recurrent Venous Thrombosis in the Inferior Vena Cava.

    Science.gov (United States)

    Andraska, Elizabeth A; Luke, Catherine E; Elfline, Megan A; Henke, Samuel P; Madapoosi, Siddharth S; Metz, Allan K; Hoinville, Megan E; Wakefield, Thomas W; Henke, Peter K; Diaz, Jose A

    2018-06-01

     Patients undergoing deep vein thrombosis (VT) have over 30% recurrence, directly increasing their risk of post-thrombotic syndrome. Current murine models of inferior vena cava (IVC) VT model host one thrombosis event.  We aimed to develop a murine model to study IVC recurrent VT in mice.  An initial VT was induced using the electrolytic IVC model (EIM) with constant blood flow. This approach takes advantage of the restored vein lumen 21 days after a single VT event in the EIM demonstrated by ultrasound. We then induced a second VT 21 days later, using either EIM or an IVC ligation model for comparison. The control groups were a sham surgery and, 21 days later, either EIM or IVC ligation. IVC wall and thrombus were harvested 2 days after the second insult and analysed for IVC and thrombus size, gene expression of fibrotic markers, histology for collagen and Western blot for citrullinated histone 3 (Cit-H3) and fibrin.  Ultrasound confirmed the first VT and its progressive resolution with an anatomical channel allowing room for the second thrombus by day 21. As compared with a primary VT, recurrent VT has heavier walls with significant up-regulation of transforming growth factor-β (TGF-β), elastin, interleukin (IL)-6, matrix metallopeptidase 9 (MMP9), MMP2 and a thrombus with high citrullinated histone-3 and fibrin content.  Experimental recurrent thrombi are structurally and compositionally different from the primary VT, with a greater pro-fibrotic remodelling vein wall profile. This work provides a VT recurrence IVC model that will help to improve the current understanding of the biological mechanisms and directed treatment of recurrent VT. Schattauer GmbH Stuttgart.

  14. Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

    Science.gov (United States)

    Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

    2009-02-15

    Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in

  15. Fiber optic fluorescence detection of low-level porphyrin concentrations in preclinical and clinical studies

    Science.gov (United States)

    Mang, Thomas S.; McGinnis, Carolyn; Khan, S.

    1990-07-01

    A significant clinical problem in the local treatment of cutaneous metastases of breast cancer (by any modality--surgery, radiation therapy or photodynainic therapy) is the fact that the disease almost always extends beyond the boundary of visible lesions in the form of microscopic deposits. These deposits may be distant from the site of visible disease but are often in close proximity to it and are manifested sooner or later by the development of recurrent lesions at the border of the treated area, thus the "marginal miss" in radiation therapy, the "rim recurrence" in photodynamic therapy, and the "incisional recurrence" following surgical excision. More intelligent use of these treatment modalities demands the ability to detect microscopic deposits of tumor cells using non-invasive methodology. In vivo fluorescence measurements have been made possible by the development of an extremely sensitive fiber optic in vivo fluorescence photometer. The instrument has been used to verify that fluorescence correlated with injected porphyrin levels in various tissues. The delivery of light to excite and detect background fluorescence as well as photosensitizer fluorescence in tissues has been accomplished using two HeNe lasers emitting at 632.8 nm and 612 nm delivered through a single quartz fiber optic. Chopping at different frequencies, contributions of fluorescence may be separated. Fluorescence is picked up via a 400 micron quartz fiber optic positioned appropriately near the target tissue. Validation of these levels was made by extraction of the drug from the tissues with resultant quantitation. Recently, an extensive study was undertaken to determine if fluorescence could be used for the detection of occult, clinically non-palpable metastases in the lymph node of rats. This unique model allowed for the detection of micrometastases in lymph nodes using very low injected doses of the photosensitizer Photofrin II. Data obtained revealed the ability to detect on the order

  16. Complete Biological Evaluation of Therapeutical Radiopharmaceuticals in Rodents, Laboratory Beagles and Veterinary Patients - Preclinical Distribution-, Kinetic-, Excretion-, Internal Dosimetry-, Radiotoxicological-, Radiation Safety- and Efficacy Data

    International Nuclear Information System (INIS)

    Balogh, L.; Domokos, M.; Polyak, A.; Thuroczy, J.; Janoki, G.

    2009-01-01

    The research and development of various novel therapeutical radiopharmaceuticals is a huge demand in many laboratories world-wide. Beside of multiple bone metastases pain-palliation and radiosynovectomy agents a number of specific radiopharmaceutical applicants mainly for oncological applications are in the pipeline. Numerous in vitro methods are available in the first line to test the radiolabelling efficiency, the possible radioactive and non-labelled impurities, the stability of the label at different conditions and mediums, and some specific characteristics of radiopharmaceutical applicants eg.: receptor binding assays, antigen-antibody assays. But, still before human clinical trials there are several questions to be solved in regards of toxicology, radiotoxicology, radiation safety and maybe most importantly the efficacy tasks. All these issues cannot be answered without animal tests. Several decades back animal tests in radiopharmacy meant only standard bioassays in a large number of healthy rodents. Later on pathological models eg.: human tumor xenografts in immunodeficient animals came-out and through them radiopharmaceutical tumor-uptake by the targets were available to evaluate in vivo as well. Xenografts are still popular and widely used models in the field but instead of wide-scaled bioassays nowadays repeated scintiscans or hybrid images (SPECT/CT, PET/CT) are more and more often used to answer kinetic-, excretion-, tumor uptake, internal dosimetry (Minimum Effective Dose, Maximum Tolerable Dose, critical organ doses, tumor doses) questions. Greater animals like laboratory Beagles are more closely in size, clinical and metabolic parameters to the human objects so playing a more perfect role of human medical doctor and especially veterinary patients. Easy to understand that many of the spontaneously occurring companion animal diseases are a good model of human pathological diseases. The need of a better diagnosis and treatment of that animals meets with

  17. The prevalence and correlations of medical student burnout in the pre-clinical years: a cross-sectional study.

    Science.gov (United States)

    Mazurkiewicz, Rebecca; Korenstein, Deborah; Fallar, Robert; Ripp, Jonathan

    2012-01-01

    Burnout is a psychological syndrome of emotional exhaustion, depersonalization, and impaired personal accomplishment induced by repeated workplace stressors. Current research suggests that physician burnout may have its origins in medical school. The consequences of medical student burnout include both personal and professional distress, loss of empathy, and poor health. We hypothesized that burnout occurs prior to the initiation of the clinical years of medical education. This was a cross-sectional survey administered to third-year medical students at the Mount Sinai School of Medicine (MSSM) in New York, New York (a traditional-style medical school with a marked division between pre-clinical and clinical training occurring at the beginning of the third year). Survey included an instrument used to measure job burnout, a sleep deprivation screen, and questions related to demographic information, current rotation, psychiatric history, time spent working/studying, participation in extracurricular activities, social support network, autonomy and isolation. Of the 86 medical students who participated, 71% met criteria for burnout. Burnt out students were significantly more likely to suffer from sleep deprivation (p = 0.0359). They were also more likely to disagree with the following statements: "I have control over my daily schedule" (p = 0.0286) and "I am confident that I will have the knowledge and skills necessary to become an intern when I graduate" (p = 0.0263). Our findings show that burnout is present at the beginning of the third year of medical school, prior to the initiation of the clinical years of medical training. Medical student burnout is quite common, and early efforts should be made to empower medical students to both build the knowledge and skills necessary to become capable physicians, as well as withstand the emotional, mental, and physical challenges inherent to medical school.

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

    Science.gov (United States)

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

    2014-03-15

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

  19. Radiochemical studies, pre-clinical investigation and preliminary clinical evaluation of "1"7"0Tm-EDTMP prepared using in-house freeze-dried EDTMP kit

    International Nuclear Information System (INIS)

    Das, Tapas; Shinto, Ajit; Kamaleshwaran, Koramadai K.; Sarma, Haladhar D.; Mohammed, Sahiralam Khan; Mitra, Arpit; Lad, Sangita; Rajan, M.G.R.; Banerjee, Sharmila

    2017-01-01

    The objective of the present work is to formulate "1"7"0Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of "1"7"0Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15 min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration. - Highlights: • Formulation of patient dose of "1"7"0Tm-EDTMP using freeze-dried EDTMP kit. • Radiochemical studies and pre-clinical evaluation of the agent in animal model. • Clinical evaluation in eight cancer patients with disseminated skeletal metastases.

  20. Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

    LENUS (Irish Health Repository)

    Polyzois, Ioannis

    2011-05-01

    The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson\\'s linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level.

  1. Preclinical students’ experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia

    Science.gov (United States)

    2012-01-01

    Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419

  2. Preclinical and clinical studies of photodynamic action on some pathogenic micro-organisms of the oral cavity

    Science.gov (United States)

    Ovchinnikov, Ilya S.; Tuchin, Valery V.; Ivanov, Krill I.; Titorenko, Vladimir A.

    2001-10-01

    The work is devoted to an analysis of pre-clinical and clinical experiments on photodynamic action of HeNe laser radiation in aggregate with a cation thiazinium dye Methylene Blue (MB) on a mix of pathogenic and conditionally pathogenic aerobic bacteria being activators of pyoinflammatory diseases of oral cavity. Concentration of photosensitizes at which there is no own bactericidal influence on dying microflora, and parameters of influence at which the efficiency of irradiated microflora defeat reaches 99% are determined.

  3. Identification of new treatments for epilepsy: issues in preclinical methodology

    Science.gov (United States)

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

    2013-01-01

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

  4. Identification of new epilepsy treatments: issues in preclinical methodology.

    Science.gov (United States)

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

    2012-03-01

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

  5. WE-FG-BRA-06: Systematic Study of Target Localization for Bioluminescence Tomography Guided Radiation Therapy for Preclinical Research

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, B; Reyes, J; Wong, J; Wang, K [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD (United States); Yu, J [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD (United States); School of Physics and Information Technology, Shaanxi Normal University, Shaanxi (China); Iordachita, I [Laboratory for Computational Sensing and Robotics, Johns Hopkins University, Baltimore, MD (United States); Liu, Z [Department of Oncology, Department of Surgery, Johns Hopkins University, Baltimore, MD (United States); Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing (China); Brock, M [Department of Oncology, Department of Surgery, Johns Hopkins University, Baltimore, MD (United States); Patterson, M [McMaster University, Hamilton, Ontario, CA (Canada)

    2016-06-15

    Purpose: To overcome the limitation of CT/CBCT in guiding radiation for soft tissue targets, we developed a bioluminescence tomography(BLT) system for preclinical radiation research. We systematically assessed the system performance in target localization and the ability of resolving two sources in simulations, phantom and in vivo environments. Methods: Multispectral images acquired in single projection were used for the BLT reconstruction. Simulation studies were conducted for single spherical source radius from 0.5 to 3 mm at depth of 3 to 12 mm. The same configuration was also applied for the double sources simulation with source separations varying from 3 to 9 mm. Experiments were performed in a standalone BLT/CBCT system. Two sources with 3 and 4.7 mm separations placed inside a tissue-mimicking phantom were chosen as the test cases. Live mice implanted with single source at 6 and 9 mm depth, 2 sources with 3 and 5 mm separation at depth of 5 mm or 3 sources in the abdomen were also used to illustrate the in vivo localization capability of the BLT system. Results: Simulation and phantom results illustrate that our BLT can provide 3D source localization with approximately 1 mm accuracy. The in vivo results are encouraging that 1 and 1.7 mm accuracy can be attained for the single source case at 6 and 9 mm depth, respectively. For the 2 sources study, both sources can be distinguished at 3 and 5 mm separations at approximately 1 mm accuracy using 3D BLT but not 2D bioluminescence image. Conclusion: Our BLT/CBCT system can be potentially applied to localize and resolve targets at a wide range of target sizes, depths and separations. The information provided in this study can be instructive to devise margins for BLT-guided irradiation and suggests that the BLT could guide radiation for multiple targets, such as metastasis. Drs. John W. Wong and Iulian I. Iordachita receive royalty payment from a licensing agreement between Xstrahl Ltd and Johns Hopkins University.

  6. Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model.

    Science.gov (United States)

    Hinkel, Rabea; Lange, Philipp; Petersen, Björn; Gottlieb, Elena; Ng, Judy King Man; Finger, Stefanie; Horstkotte, Jan; Lee, Seungmin; Thormann, Michael; Knorr, Maike; El-Aouni, Chiraz; Boekstegers, Peter; Reichart, Bruno; Wenzel, Philip; Niemann, Heiner; Kupatt, Christian

    2015-07-14

    Heme oxygenase-1 (HO-1) is an inducible stress-responsive enzyme converting heme to bilirubin, carbon monoxide, and free iron, which exerts anti-inflammatory and antiapoptotic effects. Although efficient cardioprotection after HO-1 overexpression has been reported in rodents, its role in attenuating post-ischemic inflammation is unclear. This study assessed the efficacy of recombinant adenoassociated virus (rAAV)-encoding human heme oxygenase-1 (hHO-1) in attenuating post-ischemic inflammation in a murine and a porcine ischemia/reperfusion model. Murine ischemia was induced by 45 min of left anterior descending occlusion, followed by 24 h of reperfusion and functional as well as fluorescent-activated cell sorting analysis. Porcine hearts were subjected to 60 min of ischemia and 24h of reperfusion before hemodynamic and histologic analyses were performed. Human microvascular endothelial cells transfected with hHO-1 displayed an attenuated interleukin-6 and intercellular adhesion molecule 1 expression, resulting in reduced monocytic THP-1 cell recruitment in vitro. In murine left anterior descending occlusion and reperfusion, the post-ischemic influx of CD45(+) leukocytes, Ly-6G(+) neutrophils, and Ly-6C(high) monocytes was further exacerbated in HO-1-deficient hearts and reversed by rAAV.hHO-1 treatment. Conversely, in our porcine model of ischemia, the post-ischemic influx of myeloperoxidase-positive neutrophils and CD14(+) monocytes was reduced by 49% and 87% after rAAV.hHO-1 transduction, similar to hHO-1 transgenic pigs. Functionally, rAAV.hHO-1 and hHO-1 transgenic left ventricles displayed a smaller loss of ejection fraction than control animals. Whereas HO-1 deficiency exacerbates post-ischemic cardiac inflammation in mice, hHO-1 gene therapy attenuates inflammation after ischemia and reperfusion in murine and porcine hearts. Regional hHO-1 gene therapy provides cardioprotection in a pre-clinical porcine ischemia/reperfusion model. Copyright © 2015 American

  7. Preclinical and Clinical Studies Demonstrate That the Proprietary Herbal Extract DA-5512 Effectively Stimulates Hair Growth and Promotes Hair Health

    Directory of Open Access Journals (Sweden)

    Jae Young Yu

    2017-01-01

    Full Text Available The proprietary DA-5512 formulation comprises six herbal extracts from traditional oriental plants historically associated with therapeutic and other applications related to hair. Here, we investigated the effects of DA-5512 on the proliferation of human dermal papilla cells (hDPCs in vitro and on hair growth in C57BL/6 mice and conducted a clinical study to evaluate the efficacy and safety of DA-5512. DA-5512 significantly enhanced the viability of hDPCs in a dose-dependent manner (p<0.05, and 100 ppm of DA-5512 and 1 μM minoxidil (MXD significantly increased the number of Ki-67-positive cells, compared with the control group (p<0.05. MXD (3% and DA-5512 (1%, 5% significantly stimulated hair growth and increased the number and length of hair follicles (HFs versus the controls (each p<0.05. The groups treated with DA-5512 exhibited hair growth comparable to that induced by MXD. In clinical study, we detected a statistically significant increase in the efficacy of DA-5512 after 16 weeks compared with the groups treated with placebo or 3% MXD (p<0.05. In conclusion, DA-5512 might promote hair growth and enhance hair health and can therefore be considered an effective option for treating hair loss.

  8. Preliminary study on the dye removal efficacy of immobilized marine ...

    African Journals Online (AJOL)

    Preliminary study on the dye removal efficacy of immobilized marine and freshwater microalgal beads from textile wastewater. SD Kumar, P Santhanam, R Nandakumar, S Anath, B Balaji Prasath, A Shenbaga Devi, S Jeyanthi, T Jayalakshima, P Ananthi ...

  9. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence.

    Science.gov (United States)

    Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

    2015-01-01

    An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.

  10. An experimental study about efficacy of the drain catheters

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Bum Gyu; Nho, Joon Young; Woo, Hyo Cheol; Hwang, Woo Cheol; Park, Choong Ki; Yoon, Jong Sup [Hallym University College of Medicine, Seoul (Korea, Republic of)

    1993-09-15

    Although percutaneous abscess drainage has become and accepted alternative from of therapy for selected patients with abscess, it is well known that there are several factors in the failure of adequate drainage such as pre- and post-procedural management, technique itself, various features of abscess, and selection and application of catheters. Among these factors, we made an experiment about drainage efficacy of commonly used various catheters with different viscosities of water-glycerin solution under the two different pressure gradients. The experimental values of flow rate were very lower than the calculated values. An efficacy of experimental value was 4-14%. Because the inner diameter of fittings and stopcocks was usually smaller than the inner diameter of catheters, these factors also affected the drain efficacy. Finally, we thought that it will be very helpful to the treatment of patient as well as to study about the catheter drainage, if the drain efficacy of individual catheters has been notified.

  11. A preclinical study of boron neutron capture therapy (BNCT) of spontaneous tumors in cats at RA-6 in Argentina

    International Nuclear Information System (INIS)

    Trivillin, Veronica A.; Heber, Elisa M.; Itoiz, Maria E.; Schwint, Amanda E.; Calzetta, Osvaldo A.; Blaumann, Hernan R.; Longhino, J.; Rao, Monica; Cantarelli, Maria de los A.

    2005-01-01

    BNCT is a binary treatment modality that combines irradiation with a thermal or epithermal neutron beam with tumor-seeking, boron containing drugs to produce selective irradiation of tumor tissue. Having demonstrated that BNCT mediated by boronophenylalanine (BPA) induced control of experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa with no damage to normal tissue we explored the feasibility and safety of treating spontaneous head and neck tumors, with particular focus on SCC, of terminal feline patients with low dose BPA-BNCT employing the thermal beam of RA-1. Having demonstrated partial tumor control with no radio toxic effects, the aim of the present study was to evaluate the effect of BPA-BNCT on tumor and normal tissue in 3 cases of spontaneous SCC in feline patients employing a higher neutron fluence than in the previous study. The present study was performed at RA-6 with the thermalized epithermal neutron beam. All three irradiations were successful. Except for an initial, moderate and reversible mucositis, no significant radio toxic effects were observed in terms of clinical follow-up, histological examination, biochemical analysis and assessment of autopsy material. Partial tumor control was evidenced in terms of growth inhibition and partial necrosis and improvement in the quality of life during the survival period. Optimization of the therapeutic efficacy of BNCT would require improvement in boron tumor targeting and strategies to increase in-depth dose in large tumors. (author)

  12. A preclinical evaluation of an autologous living hyaline-like cartilaginous graft for articular cartilage repair: a pilot study.

    Science.gov (United States)

    Peck, Yvonne; He, Pengfei; Chilla, Geetha Soujanya V N; Poh, Chueh Loo; Wang, Dong-An

    2015-11-09

    In this pilot study, an autologous synthetic scaffold-free construct with hyaline quality, termed living hyaline cartilaginous graft (LhCG), was applied for treating cartilage lesions. Implantation of autologous LhCG was done at load-bearing regions of the knees in skeletally mature mini-pigs for 6 months. Over the course of this study, significant radiographical improvement in LhCG treated sites was observed via magnetic resonance imaging. Furthermore, macroscopic repair was effected by LhCG at endpoint. Microscopic inspection revealed that LhCG engraftment restored cartilage thickness, promoted integration with surrounding native cartilage, produced abundant cartilage-specific matrix molecules, and re-established an intact superficial tangential zone. Importantly, the repair efficacy of LhCG was quantitatively shown to be comparable to native, unaffected cartilage in terms of biochemical composition and biomechanical properties. There were no complications related to the donor site of cartilage biopsy. Collectively, these results imply that LhCG engraftment may be a viable approach for articular cartilage repair.

  13. Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model

    International Nuclear Information System (INIS)

    Boerma, Marjan; Wang, Junru; Richter, Konrad K.; Hauer-Jensen, Martin

    2006-01-01

    Purpose: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Methods and Materials: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the 'scrotal hernia' was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Results: Orazipone significantly ameliorated histologic injury and transforming growth factor-β immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. Conclusions: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens

  14. The potential of shark bone powder in breast cancer inhibition (pre-clinical study in DMBA-Induced Sprague Dawly Rats)

    Science.gov (United States)

    Bintari, S. H.; Parman, S.; Dafip, M.

    2018-03-01

    Breast cancer is a malignant disease, which lead to second cause of that after cervical cancer in women. To date, lots of drugs and supplement have been developed and consumed by patients. Shark bone is one of the supplements that might inhibit the proliferation of cancer cells. The application of shark bone powder for supplementation in breast cancer cases still becomes controversy; but until now people are still many who consume as a supplement. This study aimed to prove the potency of shark bone powder in the inhibition of breast cancer proliferation and to propose the possibility of its biological mechanism. The pre-clinical experimental study used a controlled posttest controlled design with 25 white rats strains of DML-induced Sprague-Dawley strains. The cancer markers observed were p53, AgNORs, VEGF, Bcl-2, and Cas-3. The test subjects were divided into 3 groups: control group and 2 treatment groups fed modified with 60% and 90% respectively. A pre-clinical trial of shark bone powder showed that there was significant inhibition for the DMBA-induced anti proliferation and breast cell cancer (p breast cancer proliferation lies in concentration 30mg/BB/day.

  15. Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

    Science.gov (United States)

    Kaminski, Krzysztof

    2017-01-01

    The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Adiposity Indexes as Phenotype-Specific Markers of Preclinical Metabolic Alterations and Cardiovascular Risk in Polycystic Ovary Syndrome: A Cross-Sectional Study.

    Science.gov (United States)

    Mario, Fernanda Missio; Graff, Scheila Karen; Spritzer, Poli Mara

    2017-05-01

    Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age. 2 PCOS phenotypes (classic and ovulatory) are currently recognized as the most prevalent, with important differences in terms of cardiometabolic features. We studied the performance of different adiposity indexes to predict preclinical metabolic alterations and cardiovascular risk in 234 women with PCOS (173 with classic and 61 with ovulatory PCOS) and 129 controls. Performance of waist circumference, waist-to-height ratio, conicity index, lipid accumulation product, and visceral adiposity index was assessed based on HOMA-IR ≥ 3.8 as reference standard for screening preclinical metabolic alterations and cardiovascular risk factors in each group. Lipid accumulation product had the best accuracy for classic PCOS, and visceral adiposity index had the best accuracy for ovulatory PCOS. By applying the cutoff point of lipid accumulation productcardiometabolic alterations (Prisk for hypertension, dyslipidemia, and impaired glucose tolerance. In ovulatory PCOS, visceral adiposity index ≥ 1.32 was capable of detecting women with significantly higher blood pressure and less favorable glycemic and lipid variables as compared to ovulatory PCOS with lower visceral adiposity index (Pcardiometabolic risk and secure early interventions. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Investigating the efficacy of practical skill teaching: a pilot-study comparing three educational methods.

    Science.gov (United States)

    Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

    2013-03-01

    Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a randomised controlled trial, with concealed allocation and blinded participants and outcome assessment. Each of the three randomly allocated groups were exposed to a different practical skills teaching method (traditional, pre-recorded video tutorial or student self-video) for two specific practical skills during the semester. Clinical performance was assessed using an objective structured clinical examination (OSCE). The students were also administered a questionnaire to gain the participants level of satisfaction with the teaching method, and their perceptions of the teaching methods educational value. There were no significant differences in clinical performance between the three practical skill teaching methods as measured in the OSCE, or for student ratings of satisfaction. A significant difference existed between the methods for the student ratings of perceived educational value, with the teaching approaches of pre-recorded video tutorial and student self-video being rated higher than 'traditional' live tutoring. Alternative teaching methods to traditional live tutoring can produce equivalent learning outcomes when applied to the practical skill development of undergraduate health professional students. The use of alternative practical skill teaching methods may allow for greater flexibility for both staff and infrastructure resource allocation.

  18. Preclinical Study of 68Ga-DOTATOC: Biodistribution Assessment in Syrian Rats and Evaluation of Absorbed Dose in Human Organs.

    Science.gov (United States)

    Naderi, Mojdeh; Zolghadri, Samaneh; Yousefnia, Hassan; Ramazani, Ali; Jalilian, Amir Reza

    2016-01-01

    Gallium-68 DOTA-DPhe 1 -Tyr 3 -Octreotide ( 68 Ga-DOTATOC) has been applied by several European centers for the treatment of a variety of human malignancies. Nevertheless, definitive dosimetric data are yet unavailable. According to the Society of Nuclear Medicine and Molecular Imaging, researchers are investigating the safety and efficacy of this radiotracer to meet Food and Drug Administration requirements. The aim of this study was to introduce the optimized procedure for 68 Ga-DOTATOC preparation, using a novel germanium-68 ( 68 Ge)/ 68 Ga generator in Iran and evaluate the absorbed doses in numerous organs with high accuracy. The optimized conditions for preparing the radiolabeled complex were determined via several experiments by changing the ligand concentration, pH, temperature and incubation time. Radiochemical purity of the complex was assessed, using high-performance liquid chromatography and instant thin-layer chromatography. The absorbed dose of human organs was evaluated, based on biodistribution studies on Syrian rats via Radiation Absorbed Dose Assessment Resource Method. 68 Ga-DOTATOC was prepared with radiochemical purity of >98% and specific activity of 39.6 MBq/nmol. The complex demonstrated great stability at room temperature and in human serum at 37°C at least two hours after preparation. Significant uptake was observed in somatostatin receptor-positive tissues such as pancreatic and adrenal tissues (12.83 %ID/g and 0.91 %ID/g, respectively). Dose estimations in human organs showed that the pancreas, kidneys and adrenal glands received the maximum absorbed doses (0.105, 0.074 and 0.010 mGy/MBq, respectively). Also, the effective absorbed dose was estimated at 0.026 mSv/MBq for 68 Ga-DOTATOC. The obtained results showed that 68 Ga-DOTATOC can be considered as an effective agent for clinical PET imaging in Iran.

  19. Quetiapine: recent developments in preclinical research

    Directory of Open Access Journals (Sweden)

    Marco Orsetti

    2010-03-01

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

  20. A retrospective study evaluating the efficacy of identification and ...

    African Journals Online (AJOL)

    Full Title: A retrospective study evaluating the efficacy of identification and management of sepsis at a district-level hospital internal medicine department in the Western Cape Province, South Africa, in comparison with the guidelines stipulated in the 2012 Surviving Sepsis Campaign. Background. Currently there is little ...

  1. Efficacy of 22Na turnover in ecopbysiological studies of carnivores

    African Journals Online (AJOL)

    Efficacy of 22Na turnover in ecopbysiological studies of carnivores. loS. Wilkinson and J.D. Skinner*. Mammal Research Institute, University of Pretoria, Pretoria, 0002 Republic of South Africa. Received 8 December 1986; accepted 11 August 1987. 22Na turnover rates gave overestimates of mean 23Na intake in both ...

  2. The Efficacy of Self-Paced Study in Multitrial Learning

    Science.gov (United States)

    de Jonge, Mario; Tabbers, Huib K.; Pecher, Diane; Jang, Yoonhee; Zeelenberg, René

    2015-01-01

    In 2 experiments we investigated the efficacy of self-paced study in multitrial learning. In Experiment 1, native speakers of English studied lists of Dutch-English word pairs under 1 of 4 imposed fixed presentation rate conditions (24 × 1 s, 12 × 2 s, 6 × 4 s, or 3 × 8 s) and a self-paced study condition. Total study time per list was equated for…

  3. Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

    Science.gov (United States)

    Melichar, Jan K; Hume, Susan P; Williams, Tim M; Daglish, Mark R C; Taylor, Lindsay G; Ahmad, Rabia; Malizia, Andrea L; Brooks, David J; Myles, Judith S; Lingford-Hughes, Anne; Nutt, David J

    2005-01-01

    Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

  4. Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

    Science.gov (United States)

    Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J; Williams, Kayode; Guan, Yun

    2018-01-01

    Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology. © 2017 International Neuromodulation Society.

  5. The Self-Efficacy Scale: A Construct Validity Study.

    Science.gov (United States)

    Sherer, Mark; Adams, Carol

    Self-efficacy is defined as the belief that one can successfully perform a behavior. Self-efficacy theory asserts that self-efficacy expectancies exert powerful influence on behavior and behavior change. The Self-efficacy Scale, which was developed to assess generalized self-efficacy expectations, consists of two subscales: general self-efficacy…

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

    International Nuclear Information System (INIS)

    DeNardo, S.J.

    1995-01-01

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

  7. Safety and efficacy of venom immunotherapy: a real life study.

    Science.gov (United States)

    Kołaczek, Agnieszka; Skorupa, Dawid; Antczak-Marczak, Monika; Kuna, Piotr; Kupczyk, Maciej

    2017-04-01

    Venom immunotherapy (VIT) is recommended as the first-line treatment for patients allergic to Hymenoptera venom. To analyze the safety and efficacy of VIT in a real life setting. One hundred and eighty patients undergoing VIT were studied to evaluate the safety, efficacy, incidence and nature of symptoms after field stings and adverse reactions to VIT. Significantly more patients were allergic to wasp than bee venom (146 vs. 34, p bees, and were not associated with angiotensin convertase inhibitors (ACEi) or β-adrenergic antagonists use. Systemic reactions were observed in 4 individuals on wasp VIT (2.7%) and in 6 patients allergic to bees (17.65%). The VIT was efficacious as most patients reported no reactions (50%) or reported only mild local reactions (43.75%) to field stings. The decrease in sIgE at completion of VIT correlated with the dose of vaccine received ( r = 0.53, p = 0.004). Beekeeping (RR = 29.54, p venom allergy. Venom immunotherapy is highly efficacious and safe as most of the adverse events during the induction and maintenance phase are mild and local. Side effects of VIT are more common in subjects on bee VIT. Beekeeping and female sex are associated with a higher risk of allergy to Hymenoptera venom.

  8. The prevalence and consequences of burnout on a group of preclinical dental students.

    Science.gov (United States)

    Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

    2015-01-01

    The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment.

  9. The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction:Combining preclinical evidence with human Positron Emission Tomography (PET studies

    Directory of Open Access Journals (Sweden)

    Sylvia eTerbeck

    2015-03-01

    Full Text Available In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5 activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET and combined the findings with preclinical animal research. This combined view of different methodological approaches — from basic neurobiological approaches to human studies — might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC. Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays in important role in systems for social functioning and the response to social stress. Finally, mGluR5’s important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC’s arousal and modulatory systems domain. Glutamate was previously mostly investigate in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  11. The Economics of Reproducibility in Preclinical Research.

    Directory of Open Access Journals (Sweden)

    Leonard P Freedman

    2015-06-01

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

  12. Study of Self-Efficacy Perceptions of Social Studies Teacher Candidates on Educational Internet Usage

    Science.gov (United States)

    Akman, Özkan

    2016-01-01

    This study aimed at examining the self-efficacy perceptions of social studies teacher candidates with respect to educational internet use. This research was conducted on a sample of 174 social studies teacher candidates enrolled in Gaziantep University Nizip Faculty of Education. The "Educational Internet Self-Efficacy Scale," developed…

  13. Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.

    Science.gov (United States)

    Ishida, Kazuyoshi; Berger, Miles; Nadler, Jacob; Warner, David S

    2014-01-01

    Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

  14. Image-guided drug delivery: preclinical applications and clinical translation

    NARCIS (Netherlands)

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

    2015-01-01

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

  15. School Collective Efficacy and Bullying Behaviour: A Multilevel Study

    Science.gov (United States)

    Olsson, Gabriella; Låftman, Sara Brolin; Modin, Bitte

    2017-01-01

    As with other forms of violent behaviour, bullying is the result of multiple influences acting on different societal levels. Yet the majority of studies on bullying focus primarily on the characteristics of individual bullies and bullied. Fewer studies have explored how the characteristics of central contexts in young people’s lives are related to bullying behaviour over and above the influence of individual-level characteristics. This study explores how teacher-rated school collective efficacy is related to student-reported bullying behaviour (traditional and cyberbullying victimization and perpetration). A central focus is to explore if school collective efficacy is related similarly to both traditional bullying and cyberbullying. Analyses are based on combined information from two independent data collections conducted in 2016 among 11th grade students (n = 6067) and teachers (n = 1251) in 58 upper secondary schools in Stockholm. The statistical method used is multilevel modelling, estimating two-level binary logistic regression models. The results demonstrate statistically significant between-school differences in all outcomes, except traditional bullying perpetration. Strong school collective efficacy is related to less traditional bullying perpetration and less cyberbullying victimization and perpetration, indicating that collective norm regulation and school social cohesion may contribute to reducing the occurrence of bullying. PMID:29261114

  16. School Collective Efficacy and Bullying Behaviour: A Multilevel Study

    Directory of Open Access Journals (Sweden)

    Gabriella Olsson

    2017-12-01

    Full Text Available As with other forms of violent behaviour, bullying is the result of multiple influences acting on different societal levels. Yet the majority of studies on bullying focus primarily on the characteristics of individual bullies and bullied. Fewer studies have explored how the characteristics of central contexts in young people’s lives are related to bullying behaviour over and above the influence of individual-level characteristics. This study explores how teacher-rated school collective efficacy is related to student-reported bullying behaviour (traditional and cyberbullying victimization and perpetration. A central focus is to explore if school collective efficacy is related similarly to both traditional bullying and cyberbullying. Analyses are based on combined information from two independent data collections conducted in 2016 among 11th grade students (n = 6067 and teachers (n = 1251 in 58 upper secondary schools in Stockholm. The statistical method used is multilevel modelling, estimating two-level binary logistic regression models. The results demonstrate statistically significant between-school differences in all outcomes, except traditional bullying perpetration. Strong school collective efficacy is related to less traditional bullying perpetration and less cyberbullying victimization and perpetration, indicating that collective norm regulation and school social cohesion may contribute to reducing the occurrence of bullying.

  17. School Collective Efficacy and Bullying Behaviour: A Multilevel Study.

    Science.gov (United States)

    Olsson, Gabriella; Låftman, Sara Brolin; Modin, Bitte

    2017-12-20

    As with other forms of violent behaviour, bullying is the result of multiple influences acting on different societal levels. Yet the majority of studies on bullying focus primarily on the characteristics of individual bullies and bullied. Fewer studies have explored how the characteristics of central contexts in young people's lives are related to bullying behaviour over and above the influence of individual-level characteristics. This study explores how teacher-rated school collective efficacy is related to student-reported bullying behaviour (traditional and cyberbullying victimization and perpetration). A central focus is to explore if school collective efficacy is related similarly to both traditional bullying and cyberbullying. Analyses are based on combined information from two independent data collections conducted in 2016 among 11th grade students ( n = 6067) and teachers ( n = 1251) in 58 upper secondary schools in Stockholm. The statistical method used is multilevel modelling, estimating two-level binary logistic regression models. The results demonstrate statistically significant between-school differences in all outcomes, except traditional bullying perpetration. Strong school collective efficacy is related to less traditional bullying perpetration and less cyberbullying victimization and perpetration, indicating that collective norm regulation and school social cohesion may contribute to reducing the occurrence of bullying.

  18. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy

    Science.gov (United States)

    Dechavanne, Sebastien; Sousa, Patrícia M.; Barateiro, André; Cunha, Sónia F.; Nunes-Silva, Sofia; Lima, Flávia A.; Murillo, Oscar; Marinho, Claudio R. F.; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A.; Janse, Chris J.; Gamain, Benoit; Penha-Gonçalves, Carlos

    2016-01-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 104 P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei. At doses of 105 and 106 IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6–EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA. PMID:27045035

  19. Collective efficacy versus self-efficacy in coping responses to stressors and control: a cross-cultural study.

    Science.gov (United States)

    Schaubroeck, J; Lam, S S; Xie, J L

    2000-08-01

    This study examined how cultural differences and efficacy perceptions influence the role of job control in coping with job demands. Perceiving higher control mitigated the effects of demands on psychological health symptoms and turnover intentions only among American bank tellers reporting high job self-efficacy. Among American tellers reporting low job self-efficacy, perceived control exacerbated the effects of demands. However, in a matched Hong Kong sample, collective efficacy interacted in the same way with control and demands as job self-efficacy had in the American sample. These differences appear to be explained by the individual attributes of idiocentrism and allocentrism that are linked to the societal norms of individualism and collectivism, respectively.

  20. Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.

    Science.gov (United States)

    Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A; Jond-Necand, Carole; Gaudet, Marilène; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, Jørgen Søberg; Gaillard, Pascale; Ji, Hong

    2014-01-01

    SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.

  1. A Study on Emotional Healing Efficacy of Fiction for Undergraduate

    Directory of Open Access Journals (Sweden)

    Chen Su-May Sheih

    2014-01-01

    Full Text Available In modern society, undergraduates may encounter multiple pressures and thus feel the sense of alienation, anxiety, disturbance and depression. For undergraduates, reading can be independently conducted without the intervention of an instructor; therefore, undergraduates who feel reluctant to expose private emotions to counselors can help themselves through the reading of emotional healing books. This is the application of bibliotherapy. Among various resources, fiction can serve as an appropriate emotional reading material. The researcher deployed semi-structured in-depth interview, and interviewed 21 undergraduates in Taipei City and Taipei County. This study is aimed to understand the kinds of fictions undergraduates read when they are upset and to analyze the emotional healing process of identification, catharsis, and insight so that the emotional healing efficacy can be evaluated. The findings showed that romance, realistic fiction, fantasy, martial arts novel, inspirational fiction, historical fiction, and science fiction can provide full process of emotional healing efficacy. However, detective fiction, online novel, psychological fiction, and horror fiction can only provide parts of the healing process. Besides, the healing efficacy of a specific fiction is different from reader to reader.

  2. Alflutop clinical efficacy assessment in osteoarthritis (two-years study

    Directory of Open Access Journals (Sweden)

    V. N. Chodyrev

    2003-01-01

    Full Text Available Objective. To assess alflutop clinical efficacy and safety during long-term course treatment of knee osteoarthritis. Methods. 51 pts with definite knee osteoarthritis of I-III stage according to Kellgren-Lawrence classification were included in an open controlled study. 20 pts received 6 intra-articular injections of alflutop 2 ml with subsequent intramuscular treatment during 3 months. Such courses were repeated 6 months apart for 2 years. 31 pts of control group received nonsteroidal anti-inflammatory drugs (NSAID only. Pain on visual analog scale, Leken functional score, changes of NSAID treatment and radiological picture were used for assessment of efficacy. Clinical examination was performed before and after every treatment course and 3 months after the last course. Results. Every alflutop treatment course provided significant stepwise decrease of pain with improvement of mobility, reduction of NSAID requirement and absence of osteoarthritis radiological progression. Doctor and pts clinical efficacy and safety assessment coincided. Conclusion. Alflutop is an effective drug for knee osteoarthritis treatment. It has anti-inflammatory and probably chondroprotective activity with good safety.

  3. Premarket safety and efficacy studies for ADHD medications in children.

    Directory of Open Access Journals (Sweden)

    Florence T Bourgeois

    Full Text Available Attention-deficit hyperactivity disorder (ADHD is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing.We identified all ADHD medications approved by the Food and Drug Administration (FDA and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug's clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials.A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419. Eleven drugs (55% were approved after <100 participants were studied and 14 (70% after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9, with 5 (38% drugs approved after participants were studied <4 weeks and 10 (77% after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed.Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved.

  4. Radiochemistry, pre-clinical studies and first clinical investigation of 90Y-labeled hydroxyapatite (HA) particles prepared utilizing 90Y produced by (n,γ) route

    International Nuclear Information System (INIS)

    Vimalnath, K.V.; Chakraborty, Sudipta; Rajeswari, A.; Sarma, H.D.; Nuwad, Jitendra; Pandey, Usha; Kamaleshwaran, K.; Shinto, Ajit; Dash, Ashutosh

    2015-01-01

    Introduction: The scope of using no carrier added (NCA) 90 Y [T 1/2 = 64.1 h, E β(max) = 2.28 MeV] obtained from 90 Sr/ 90 Y generator in radiation synovectomy (RSV) is widely accepted. In the present study, the prospect of using 90 Y produced by (n,γ) route in a medium flux research reactor for use in RSV was explored. Methods: Yttrium-90 was produced by thermal neutron irradiation of Y 2 O 3 target at a neutron flux of ~ 1 × 10 14 n/cm 2 .s for 14 d. The influence of various experimental parameters were systematically investigated and optimized to arrive at the most favorable conditions for the formulation of 90 Y labeled hydroxyapatite (HA) using HA particles of 1–10 μm size range. An optimized kit formulation strategy was developed for convenient one-step compounding of 90 Y-HA, which is easily adaptable at hospital radiopharmacy. The pre-clinical biological evaluation of 90 Y-HA particles was studied by carrying out biodistribution and bioluminiscence imaging studies in Wistar rats. The first clinical investigation using the radiolabeled preparation was performed on a patient suffering from chronic arthritis in knee joint by administering 185 MBq 90 Y-HA formulated at the hospital radiopharmacy deploying the proposed strategy. Results: Yttrium-90 was produced with a specific activity of 851 ± 111 MBq/mg and radionuclidic purity of 99.95 ± 0.02%. 90 Y-labeled HA particles (185 ± 10 MBq doses) were formulated in high radiochemical purity (> 99%) and excellent in vitro stability. The preparation showed promising results in pre-clinical studies carried out in Wistar rats. The preliminary results of the first clinical investigation of 90 Y-HA preparation in a patient with rheumatoid arthritis in knee joints demonstrated the effectiveness of the formulation prepared using 90 Y produced via (n,γ) route in the management of the disease. Conclusion: The studies revealed that effective utilization of 90 Y produced via (n,γ) route in a medium flux research

  5. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies.

    Science.gov (United States)

    Kühl, Susanne J; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R; Kühl, Michael

    2017-01-01

    Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee "New Media" [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the

  6. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies

    Directory of Open Access Journals (Sweden)

    Kühl, Susanne J.

    2017-08-01

    Full Text Available Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC method can address this deficiency. The goal of this study was: We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee “New Media” in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students, but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the acquisition of knowledge by MC exams.Results: On a Likert scale from 1 (strongly disagree to 6 (strongly agree, the students in the IC intervention groups could be seen to be much more motivated (5.53 than students in the control group (4.01. Students in the IC intervention groups also recognised the

  7. Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder.

    Science.gov (United States)

    Gamache, Karine; Pitman, Roger K; Nader, Karim

    2012-12-01

    Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α₂-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.

  8. The impact of weakly bound 89Zr on preclinical studies: Non-specific accumulation in solid tumors and aspergillus infection

    DEFF Research Database (Denmark)

    Severin, Gregory; Jørgensen, Jesper T.; Wiehr, Stefan

    2015-01-01

    free or weakly bound 89Zr released in circulation. 89Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT and PET/MR imaging...... followed to quantify the distribution of the radionuclide in the disease models. Results 89Zr oxalate was found to have a plasma half-life of 5.1 ± 2.3 h, accumulating mainly in the bones of all animals. Both tumor types accumulated 89Zr on the order of 2-4% ID/cm3, which is comparable to EPR...... in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free 89Zr in any preclinical study employing 89Zr where bone uptake is observed. Aqueous 89Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where...

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

    Science.gov (United States)

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

    2017-02-01

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

  10. Preclinical study of SZ2080 material 3D microstructured scaffolds for cartilage tissue engineering made by femtosecond direct laser writing lithography

    International Nuclear Information System (INIS)

    Mačiulaitis, Justinas; Darinskas, Adas; Šimbelytė, Agnė; Mačiulaitis, Romaldas; Deveikytė, Milda; Rekštytė, Sima; Malinauskas, Mangirdas; Bratchikov, Maksim; Daunoras, Gintaras; Laurinavičienė, Aida; Laurinavičius, Arvydas; Gudas, Rimtautas

    2015-01-01

    Over the last decade DLW employing ultrafast pulsed lasers has become a well-established technique for the creation of custom-made free-form three-dimensional (3D) microscaffolds out of a variety of materials ranging from proteins to biocompatible glasses. Its potential applications for manufacturing a patient’s specific scaffold seem unlimited in terms of spatial resolution and geometry complexity. However, despite few exceptions in which live cells or primitive organisms were encapsulated into a polymer matrix, no demonstration of an in vivo study case of scaffolds generated with the use of such a method was performed. Here, we report a preclinical study of 3D artificial microstructured scaffolds out of hybrid organic-inorganic (HOI) material SZ2080 fabricated using the DLW technique. The created 2.1 × 2.1 × 0.21 mm 3 membrane constructs are tested both in vitro by growing isolated allogeneic rabbit chondrocytes (Cho) and in vivo by implanting them into rabbit organisms for one, three and six months. An ex vivo histological examination shows that certain pore geometry and the pre-growing of Cho prior to implantation significantly improves the performance of the created 3D scaffolds. The achieved biocompatibility is comparable to the commercially available collagen membranes. The successful outcome of this study supports the idea that hexagonal-pore-shaped HOI microstructured scaffolds in combination with Cho seeding may be successfully implemented for cartilage tissue engineering. (paper)

  11. Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer

    International Nuclear Information System (INIS)

    Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Frédéric

    2014-01-01

    Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets

  12. The preclinical discovery and development of quetiapine for the treatment of mania and depression.

    Science.gov (United States)

    Miranda, Aline Silva de; Moreira, Fabrício A; Teixeira, Antônio Lúcio

    2017-05-01

    Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

  13. Multiple comparisons in drug efficacy studies: scientific or marketing principles?

    Science.gov (United States)

    Leo, Jonathan

    2004-01-01

    When researchers design an experiment to compare a given medication to another medication, a behavioral therapy, or a placebo, the experiment often involves numerous comparisons. For instance, there may be several different evaluation methods, raters, and time points. Although scientifically justified, such comparisons can be abused in the interests of drug marketing. This article provides two recent examples of such questionable practices. The first involves the case of the arthritis drug celecoxib (Celebrex), where the study lasted 12 months but the authors only presented 6 months of data. The second case involves the NIMH Multimodal Treatment Study (MTA) study evaluating the efficacy of stimulant medication for attention-deficit hyperactivity disorder where ratings made by several groups are reported in contradictory fashion. The MTA authors have not clarified the confusion, at least in print, suggesting that the actual findings of the study may have played little role in the authors' reported conclusions.

  14. NCI Pediatric Preclinical Testing Consortium

    Science.gov (United States)

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

  15. In situ study of the impact of inter- and intra-reader variability on region of interest (ROI) analysis in preclinical molecular imaging.

    Science.gov (United States)

    Habte, Frezghi; Budhiraja, Shradha; Keren, Shay; Doyle, Timothy C; Levin, Craig S; Paik, David S

    2013-01-01

    We estimated reader-dependent variability of region of interest (ROI) analysis and evaluated its impact on preclinical quantitative molecular imaging. To estimate reader variability, we used five independent image datasets acquired each using microPET and multispectral fluorescence imaging (MSFI). We also selected ten experienced researchers who utilize molecular imaging in the same environment that they typically perform their own studies. Nine investigators blinded to the data type completed the ROI analysis by drawing ROIs manually that delineate the tumor regions to the best of their knowledge and repeated the measurements three times, non-consecutively. Extracted mean intensities of voxels within each ROI are used to compute the coefficient of variation (CV) and characterize the inter- and intra-reader variability. The impact of variability was assessed through random samples iterated from normal distributions for control and experimental groups on hypothesis testing and computing statistical power by varying subject size, measured difference between groups and CV. The results indicate that inter-reader variability was 22.5% for microPET and 72.2% for MSFI. Additionally, mean intra-reader variability was 10.1% for microPET and 26.4% for MSFI. Repeated statistical testing showed that a total variability of CV variability has been observed mainly due to differences in the ROI placement and geometry drawn between readers, which may adversely affect statistical power and erroneously lead to negative study outcomes.

  16. Pre-clinical and clinical development of the first placental malaria vaccine

    DEFF Research Database (Denmark)

    Pehrson, Caroline; Salanti, Ali; Theander, Thor G

    2017-01-01

    the condition.  Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical...... vaccine development. However, all papers from these searches were not systematically included.  Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy...

  17. Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis.

    Science.gov (United States)

    Quist, S R; Heimburg, A; Bank, U; Mahnkopf, D; Koch, G; Gollnick, H; Täger, M; Ansorge, S

    2017-08-01

    Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. To test the penetration and dermal bioavailability of galenic formulations of the small-molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up. © 2017 British Association of Dermatologists.

  18. Preclinical Evaluation of the Immunomodulatory Properties of Cardiac Adipose Tissue Progenitor Cells Using Umbilical Cord Blood Mesenchymal Stem Cells: A Direct Comparative Study

    Directory of Open Access Journals (Sweden)

    Isaac Perea-Gil

    2015-01-01

    Full Text Available Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs. Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNFα, and IFNγ was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells.

  19. EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms

    International Nuclear Information System (INIS)

    Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard; Dittmann, Klaus; Doerr, Wolfgang; Kasten-Pisula, Ulla; Rodemann, H. Peter

    2007-01-01

    Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with EGFR inhibitors. These include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Effects and mechanisms may differ for different classes of EGFR inhibitors, for different tumours and for normal tissues. The mechanisms underlying this heterogeneity are currently poorly understood, and predictive assays are not available yet. Importantly, mechanisms and predictors for the combined effects of radiation with EGFR inhibitors appear to be considerably different to those for application of EGFR inhibitors alone or in combination with chemotherapy. Therefore to further evaluate the efficacy and mechanisms of EGFR-inhibition in combined treatments, radiotherapy-specific preclinical research strategies, which include in vivo experiments using local tumour control as an endpoint, as well as animal studies on normal tissue toxicity are needed

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

    Science.gov (United States)

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

    2017-03-01

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

  1. A preclinical evaluation of an autologous living hyaline-like cartilaginous graft for articular cartilage repair: a pilot study

    OpenAIRE

    Yvonne Peck; Pengfei He; Geetha Soujanya V. N. Chilla; Chueh Loo Poh; Dong-An Wang

    2015-01-01

    In this pilot study, an autologous synthetic scaffold-free construct with hyaline quality, termed living hyaline cartilaginous graft (LhCG), was applied for treating cartilage lesions. Implantation of autologous LhCG was done at load-bearing regions of the knees in skeletally mature mini-pigs for 6 months. Over the course of this study, significant radiographical improvement in LhCG treated sites was observed via magnetic resonance imaging. Furthermore, macroscopic repair was effected by LhCG...

  2. Correlational Study between Teacher Perceived High School Principal Leadership Style and Teacher Self-Efficacy

    Science.gov (United States)

    Riggs, Robert

    2017-01-01

    This quantitative correlational study addressed the concept that teacher-perceived high school principal leadership style correlated with teacher self-efficacy. A relationship existed between teacher self-efficacy and student outcomes and research indicated a relationship between leadership style and teacher self-efficacy. Also, the effect of…

  3. Preclinical and Clinical Studies on Antioxidative, Antihypertensive and Cardioprotective Effect of Marine Proteins and Peptides—A Review

    Directory of Open Access Journals (Sweden)

    Ida-Johanne Jensen

    2016-11-01

    Full Text Available High seafood consumption has traditionally been linked to a reduced risk of cardiovascular diseases, mainly due to the lipid lowering effects of the long chained omega 3 fatty acids. However, fish and seafood are also excellent sources of good quality proteins and emerging documentation show that, upon digestion, these proteins are sources for bioactive peptides with documented favorable physiological effects such as antioxidative, antihypertensive and other cardioprotective effects. This documentation is mainly from in vitro studies, but also animal studies are arising. Evidence from human studies evaluating the positive health effects of marine proteins and peptides are scarce. In one study, a reduction in oxidative stress after intake of cod has been documented and a few human clinical trials have been performed evaluating the effect on blood pressure. The results are, however, inconclusive. The majority of the human clinical trials performed to investigate positive health effects of marine protein and lean fish intake, has focused on blood lipids. While some studies have documented a reduction in triglycerides after intake of lean fish, others have documented no effects.

  4. The efficacy of acupuncture on menopausal symptoms (ACOM study)

    DEFF Research Database (Denmark)

    Lund, Kamma Sundgaard; Brodersen, John; Siersma, Volkert

    2017-01-01

    INTRODUCTION: Around 75% of menopausal women experience hot flushes (HF) and 10-20% of all postmenopausal women find this very distressing. The aim of this study is to evaluate the efficacy of acupuncture on moderate-to-severe menopausal symptoms in general and HF in particular. METHODS: An un......-blinded randomised trial (cross-over) with 1:1 allocation to early (intervention) versus late (control) acupuncture. The included women suffer from moderate-to-severe HF and will receive a weekly treatment during five consecutive weeks in the following predefined acupuncture points: CV-3, CV-4, LR-8, SP-6, SP-9. All...... acupuncturists will be medical doctors educated in acupuncture. The primary outcome is change in HF from baseline to week 6 measured by the HF scale from the MenoScores Questionnaire (MSQ). Secondary outcomes are change in other menopausal symptoms, in particular day and night sweats and menopausal...

  5. Synthesis, development and preclinical study of EDDA based 99mTc-5-fluorouracil for brain imaging

    International Nuclear Information System (INIS)

    Ahmed, N.; Nuclear Medicine, Oncology and Radiotherapy Institute; Saeed, A.M.; Fatima, S.; Irfan, J.; Zia, M.; Zia, N.; Raza, A.

    2016-01-01

    5-Fluorouracil is used as an antineoplastic agent in solid tumors. The study was conducted to analyze the effect of EDDA on synthesis of 5-fluorouracil with 99m Tc. The 99m Tc-5-flurouracil was formulated using stannous agent, and EDDA. This complex was stable for 4 h, with post labeling efficiency of 92 %. The distribution study in animal model showed that after 30 min 35 ± 8 % of injected dose cross the blood brain barrier and excreted through kidney with no sign of toxicity. It was concluded that the addition of EDDA modified the labeling side in 5-fluorouracil for 99m Tc, which localized in brain and hence can be used further for brain imaging study. (author)

  6. The role of radiolabelled compounds in preclinical drug development

    International Nuclear Information System (INIS)

    Hawkins, D.R.

    1988-01-01

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

  7. Preclinical studies on the use of medicinal mushroom Ganoderma lucidum as an adjuvant in radiotherapy of cancer

    International Nuclear Information System (INIS)

    Gopakumar, G.; Martin, Femy; Antony, Sherin K.; Pillai, Thulasi G.; Nair, Cherupally Krishnan K.

    2010-01-01

    Our previous studies have demonstrated that an extract of Ganoderma lucidum occurring in South India possesses significant radioprotective property ex vivo. The present study describes the in vivo radioprotection of normal cells in tumour-bearing mice exposed to gamma radiation. Oral administration of G. lucidum extract (GLE) to tumour-bearing Swiss albino mice along with exposure to gamma radiation resulted in tumour regression. Single-cell gel electrophoresis (comet assay) on cells of normal and tumour tissues from tumour-bearing animals treated with GEE and radiation, revealed that there was significant reduction in radiation-induced damage to cellular DNA in normal tissues compared to the tumour, indicating preferential protection to normal tissues. The findings suggest the potential use of this mushroom extract as an adjuvant in radiotherapy, for tumour regression and prevention of radiation-induced cellular damages in normal tissues. (author)

  8. Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: First pre-clinical study on a murine model

    International Nuclear Information System (INIS)

    Dallaudière, Benjamin; Lempicki, Marta; Pesquer, Lionel; Louedec, Liliane; Preux, Pierre Marie; Meyer, Philippe; Hess, Agathe; Durieux, Marie Hèlène Moreau; Hummel, Vincent; Larbi, Ahmed; Deschamps, Lydia

    2013-01-01

    Purpose: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. Materials and method: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1 ® (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T−) after injecting AA in 40 (AAT−). Results: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p < 0.004), and less disorganized collagen fibers and neovessels on histology (p < 0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p > 0.05). Comparison between AAT− and T− showed no AA toxicity on tendon (p = 0.18). Conclusion: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity

  9. Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: First pre-clinical study on a murine model

    Energy Technology Data Exchange (ETDEWEB)

    Dallaudière, Benjamin, E-mail: bendallau64@hotmail.fr [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Inserm U698, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Lempicki, Marta [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Pesquer, Lionel [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Louedec, Liliane [Inserm U698, Hôpital universitaire Bichat, Paris (France); Preux, Pierre Marie [Laboratoire de Biostatistiques, Faculté de médecine, Limoges (France); Meyer, Philippe [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hess, Agathe [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Durieux, Marie Hèlène Moreau [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hummel, Vincent; Larbi, Ahmed [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Deschamps, Lydia [Service d’ Anatomopathologie, Hôpital universitaire Bichat, Paris (France); and others

    2013-12-01

    Purpose: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. Materials and method: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1{sup ®} (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T−) after injecting AA in 40 (AAT−). Results: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p < 0.004), and less disorganized collagen fibers and neovessels on histology (p < 0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p > 0.05). Comparison between AAT− and T− showed no AA toxicity on tendon (p = 0.18). Conclusion: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity.

  10. Cartilage Health in Knees Treated with Metal Resurfacing Implants or Untreated Focal Cartilage Lesions: A Preclinical Study in Sheep.

    Science.gov (United States)

    Martinez-Carranza, Nicolas; Hultenby, Kjell; Lagerstedt, Anne Sofie; Schupbach, Peter; Berg, Hans E

    2017-07-01

    Background Full-depth cartilage lesions do not heal and the long-term clinical outcome is uncertain. In the symptomatic middle-aged (35-60 years) patient, treatment with metal implants has been proposed. However, the cartilage health surrounding these implants has not been thoroughly studied. Our objective was to evaluate the health of cartilage opposing and adjacent to metal resurfacing implants. Methods The medial femoral condyle was operated in 9 sheep bilaterally. A metallic resurfacing metallic implant was immediately inserted into an artificially created 7.5 mm defect while on the contralateral knee the defect was left untreated. Euthanasia was performed at 6 months. Six animals, of similar age and study duration, from a previous study were used for comparison in the evaluation of cartilage health adjacent to the implant. Cartilage damage to joint surfaces within the knee, cartilage repair of the defect, and cartilage adjacent to the implant was evaluated macroscopically and microscopically. Results Six animals available for evaluation of cartilage health within the knee showed a varying degree of cartilage damage with no statistical difference between defects treated with implants or left untreated ( P = 0.51; 95% CI -3.7 to 6.5). The cartilage adjacent to the implant (score 0-14; where 14 indicates no damage) remained healthy in these 6 animals showing promising results (averaged 10.5; range 9-11.5, SD 0.95). Cartilage defects did not heal in any case. Conclusion Treatment of a critical size focal lesion with a metal implant is a viable alternative treatment.

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

    Science.gov (United States)

    Steward, Oswald; Balice-Gordon, Rita

    2014-11-05

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

  12. A novel pre-clinical murine model to study the life cycle and progression of cervical and anal papillomavirus infections.

    Directory of Open Access Journals (Sweden)

    Nancy M Cladel

    Full Text Available Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice.The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and "Doctor's BrushPicks" and MmuPV1 was delivered into the vaginal tract or the anal canal.Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals.Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system.

  13. A comparative study of students' performance in preclinical physiology assessed by multiple choice and short essay questions.

    Science.gov (United States)

    Oyebola, D D; Adewoye, O E; Iyaniwura, J O; Alada, A R; Fasanmade, A A; Raji, Y

    2000-01-01

    This study was designed to compare the performance of medical students in physiology when assessed by multiple choice questions (MCQs) and short essay questions (SEQs). The study also examined the influence of factors such as age, sex, O/level grades and JAMB scores on performance in the MCQs and SEQs. A structured questionnaire was administered to 264 medical students' four months before the Part I MBBS examination. Apart from personal data of each student, the questionnaire sought information on the JAMB scores and GCE O' Level grades of each student in English Language, Biology, Chemistry, Physics and Mathematics. The physiology syllabus was divided into five parts and the students were administered separate examinations (tests) on each part. Each test consisted of MCQs and SEQs. The performance in MCQs and SEQs were compared. Also, the effects of JAMB scores and GCE O/level grades on the performance in both the MCQs and SEQs were assessed. The results showed that the students performed better in all MCQ tests than in the SEQs. JAMB scores and O' level English Language grade had no significant effect on students' performance in MCQs and SEQs. However O' level grades in Biology, Chemistry, Physics and Mathematics had significant effects on performance in MCQs and SEQs. Inadequate knowledge of physiology and inability to present information in a logical sequence are believed to be major factors contributing to the poorer performance in the SEQs compared with MCQs. In view of the finding of significant association between performance in MCQs and SEQs and GCE O/level grades in science subjects and mathematics, it was recommended that both JAMB results and the GCE results in the four O/level subjects above may be considered when selecting candidates for admission into the medical schools.

  14. Entrepreneurial Self-Efficacy of University Students: A Cross-Cultural Study

    Directory of Open Access Journals (Sweden)

    Oguz Basol

    2017-03-01

    Full Text Available The present study investigated the entrepreneurial self-efficacy perceptions among university students across two countries, i.e., Poland and Turkey. Data were obtained through questionnaires designed to assess the perceptions of entrepreneurial self-efficacy. In all, 365 Polish and 278 Turkish students completed the questionnaires. Results indicated that Polish and Turkish students did not differ significantly in regard to the overall measure of entrepreneurial self-efficacy. Our study contributed to the entrepreneurship literature by performing a cross-cultural comparison of the perceptions of entrepreneurial self-efficacy. Thus, it provided recommendations for fostering entrepreneurial self efficacy among university students.

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

    Science.gov (United States)

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

    2016-01-01

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

  16. Development of 18F-FDG ([F-18]-2-fluoro-2-deoxy-D-glucose) injection for imaging of tumor reflecting glucose metabolism. Results of preclinical studies

    International Nuclear Information System (INIS)

    Ino, Sento; Shimada, Takayuki; Kanagawa, Masaru; Suzuki, Noriaki; Kondo, Susumu; Shirakami, Yoshifumi; Ito, Osamu; Kato-Azuma, Makoto

    1999-01-01

    Fluorine-18-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) injection was prepared by a modification of a method originally developed by Hamacher et al. The dosage form is the injectable solution (2 ml) containing 185 MBq of 18 F-FDG at a calibration time. Preclinical studies of the agent were performed. Its radiochemical purity is more than 95% and expiration time is 4 hours after the calibration time at ambient temperature. No toxicity was observed with up to 200 mg/kg and 100 mg/kg of non-radioactive FDG intravenously injected to rats and dogs in single dose toxicity tests, respectively. Biodistribution studies demonstrated that the radioactivity was mainly distributed into brain (3.0 to 3.3% I.D./Organ at 30 minutes) and heart (4.2 to 5.8% I.D./Organ at 1 to 3 hours) after intravenous injection of the agent to normal rats. In a tumor transplanted mouse model (colon 26), tumor uptake was 10.9±3.5% I.D./g at 1 hr after intravenous injection of the agent, the radioactivity was retained until 3 hours. The radiation absorbed dose was estimated according to the MIRD Pamphlet based on the biodistribution data both in humans reported by Mejia et al. and rats described in this report. The radiation absorbed dose was not higher than those of commercially available radiopharmaceuticals. In conclusion, the 18 F-FDG injection is expected to be useful for further clinical application. (author)

  17. Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans.

    Science.gov (United States)

    Uno, Yasuhiro; Uehara, Shotaro; Yamazaki, Hiroshi

    2017-12-23

    Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzymes in cynomolgus monkey and common marmoset like human P450 enzymes. Information on rhesus monkeys (Macaca mulatta), another macaque species used in drug metabolism studies, is also included for comparison. Among a variety of cynomolgus monkey P450 variants investigated, typical examples include individual pharmacokinetic data for efavirenz and R-warfarin associated with cynomolgus monkey P450 2C9 (formerly 2C43) and 2C19 (2C75) variants, respectively, and for R-omeprazole and S-warfarin associated with marmoset P450 2C19 variants. These findings provide a foundation for understanding the individual pharmacokinetic and toxicological results in non-human primates as preclinical models and will help to further support understanding of molecular mechanisms of human P450 function. In addition to these polymorphic P450 enzymes, effects of aging on some drug clearances mediated by cynomolgus monkey and common marmoset P450 enzymes were found in elder animals or animals pretreated with rifampicin. This review describes genetic and acquired individual differences in cynomolgus monkey and common marmoset P450 enzymes involved in drug oxidation associated with pharmacological and/or toxicological effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Does standoff material affect acoustic radiation force impulse elastography? A preclinical study of a modified elastography phantom

    Directory of Open Access Journals (Sweden)

    Katharina Hollerieth

    2018-04-01

    Full Text Available Purpose This study was conducted to determine the influence of standoff material on acoustic radiation force impulse (ARFI measurements in an elasticity phantom by using two different probes. Methods Using ARFI elastography, 10 observers measured the shear wave velocity (SWV, m/sec in different lesions of an elasticity phantom with a convex 4C1 probe and a linear 9L4 probe. The experimental setup was expanded by the use of an interposed piece of porcine muscle as standoff material. The probe pressure on the phantom was registered. Results Faulty ARFI measurements occurred more often when quantifying the hardest lesion (74.0 kPa 4.97 m/sec by the 9L4 probe with the porcine muscle as a standoff material interposed between the probe and the phantom. The success rate for ARFI measurements in these series was 52.4%, compared with 99.5% in the other series. The SWV values measured with the 9L4 probe were significantly higher (3.33±1.39 m/sec vs. 2.60±0.74 m/sec, P<0.001 in the group without muscle and were closer to the reference value than those measured with the 4C1 probe (0.25±0.23 m/sec vs. 0.85±1.21 m/sec, P<0.001 in the same group. The SWV values measured when using the muscle as a standoff material were lower than those without the muscle (significant for 9L4, P=0.040. The deviation from the reference value and the variance increased significantly with the 9L4 probe if the muscle was in situ (B=0.27, P=0.004 and B=0.32, P<0.001. In our study, the pressure exerted by the operator had no effect on the SWV values. Conclusion The presence of porcine muscle acting as a standoff material influenced the occurrence of failed measurements as well as the variance and the accuracy of the measured values. The linear high-frequency probe was particularly affected.

  19. Resilience to the effects of social stress: Evidence from clinical and preclinical studies on the role of coping strategies

    Science.gov (United States)

    Wood, Susan K.; Bhatnagar, Seema

    2014-01-01

    The most common form of stress encountered by people stems from one's social environment and is perceived as more intense than other types of stressors. One feature that may be related to differential resilience or vulnerability to stress is the type of strategy used to cope with the stressor, either active or passive coping. This review focuses on models of social stress in which individual differences in coping strategies produce resilience or vulnerability to the effects of stress. Neurobiological mechanisms underlying these individual differences are discussed. Overall, the literature suggests that there are multiple neural mechanisms that underlie individual differences in stress-induced resilience and vulnerability. How these mechanisms interact with one another to produce a resilient or vulnerable phenotype is not understood and such mechanisms have been poorly studied in females and in early developmental periods. Finally, we propose that resilience may be stress context specific and resilience phenotypes may need to be fine-tuned to suit a shifting environment. PMID:25580450

  20. Assessment of tobacco heating product THP1.0. Part 9: The placement of a range of next-generation products on an emissions continuum relative to cigarettes via pre-clinical assessment studies.

    Science.gov (United States)

    Murphy, James; Liu, Chuan; McAdam, Kevin; Gaҫa, Marianna; Prasad, Krishna; Camacho, Oscar; McAughey, John; Proctor, Christopher

    2018-03-01

    This series of nine papers described the operation and pre-clinical assessment of a tobacco heating product THP1.0. This last paper contextualises the pre-clinical assessment data on THP1.0 with data from other next generation products relative to cigarette smoke. The tobacco and nicotine risk continuum is a concept that ranks products according to their potential harm, with cigarettes at the highest risk extreme and Nicotine Replacement Therapy at the least risky extreme. Data generated in pre-clinical studies on THP1.0 and a range of Next Generation Products (NGPs) may provide some initial indication of potential ranking of these products, although importantly, data from such studies are limited and cannot take into consideration several important aspects for risk such as long term product use patterns. In each of the studies, the responses to the emissions from THP1.0 were substantially reduced relative to cigarette smoke. Additionally, responses from THP1.0 were very similar to those from the other NGP emissions. A comparison of the results clearly showed the emissions from all the NGPs were considerably lower than those from cigarettes and all in around the same emissions level. These results show that THP1.0 could have the potential to be a reduced risk product compared to cigarettes, though further studies assessing the exposure, individual and population risk reduction profile would be required to substantiate this potential. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Preclinical study of diagnostic performances of contrast-enhanced spectral mammography versus MRI for breast diseases in China.

    Science.gov (United States)

    Wang, Qingguo; Li, Kangan; Wang, Lihui; Zhang, Jianbing; Zhou, Zhiguo; Feng, Yan

    2016-01-01

    To evaluate diagnostic performances of CESM for breast diseases with comparison to breast MRI in China. Sixty-eight patients with 77 breast lesions underwent MR and CESM. Two radiologists interpreted either MRI or CESM images, separately and independently. BI-RADS 1-3 and BI-RADS 4-5 were classified into the suspicious benign and suspicious malignant groups. Diagnostic accuracy parameters were calculated. Receiver operating characteristic (ROC) curves were constructed for the two modalities. The agreement and correlation between maximum lesion diameter based on CESM and MRI, or CESM and pathology were analyzed. Diagnostic accuracy parameters for CESM were sensitivity 95.8 %, specificity 65.5 %, PPV 82.1 %, NPV 90.5 % and accuracy 84.4 %. The diagnostic accuracy parameters for breast MRI were sensitivity 93.8 %, specificity 82.8 %, PPV 88.2 %, NPV 92.3 %and accuracy 89.6 %. Area under the curve (AUC) of ROC was 0.96 for breast MRI and 0.88 for CESM. The Bland-Altman plots showed a mean difference of 0.7 mm with 95 % limits of agreement of 11.4 mm in tumor diameter measured using CESM and breast MRI. The differences of size measurement between CESM and breast MRI were significant, whereas no difference was observed between CESM and pathology as well as between breast MRI and pathology. The better correlation with pathological results was found in CESM than breast MRI. Our study demonstrates that CESM possesses better diagnostic performances than breast MRI in terms of diagnostic sensitivity and lesion size assessment. And CESM is a good alternative method of screening breast cancer in high-risk people.

  2. Preclinical study of mouse pluripotent parthenogenetic embryonic stem cell derivatives for the construction of tissue-engineered skin equivalent.

    Science.gov (United States)

    Rao, Yang; Cui, Jihong; Yin, Lu; Liu, Wei; Liu, Wenguang; Sun, Mei; Yan, Xingrong; Wang, Ling; Chen, Fulin

    2016-10-22

    Embryonic stem cell (ESC) derivatives hold great promise for the construction of tissue-engineered skin equivalents (TESE). However, harvesting of ESCs destroys viable embryos and may lead to political and ethical concerns over their application. In the current study, we directed mouse parthenogenetic embryonic stem cells (pESCs) to differentiate into fibroblasts, constructed TESE, and evaluated its function in vivo. The stemness marker expression and the pluripotent differentiation ability of pESCs were tested. After embryoid body (EB) formation and adherence culture, mesenchymal stem cells (MSCs) were enriched and directed to differentiate into fibroblastic lineage. Characteristics of derived fibroblasts were assessed by quantitative real-time PCR and ELISA. Functional ability of the constructed TESE was tested by a mouse skin defects repair model. Mouse pESCs expressed stemness marker and could form teratoma containing three germ layers. MSCs could be enriched from outgrowths of EBs and directed to differentiate into fibroblastic lineage. These cells express a high level of growth factors including FGF, EGF, VEGF, TGF, PDGF, and IGF1, similar to those of ESC-derived fibroblasts and mouse fibroblasts. Seeded into collagen gels, the fibroblasts derived from pESCs could form TESE. Mouse skin defects could be successfully repaired 15 days after transplantation of TESE constructed by fibroblasts derived from pESCs. pESCs could be induced to differentiate into fibroblastic lineage, which could be applied to the construction of TESE and skin defect repair. Particularly, pESC derivatives avoid the limitations of political and ethical concerns, and provide a promising source for regenerative medicine.

  3. Preclinical models in radiation oncology

    Directory of Open Access Journals (Sweden)

    Kahn Jenna

    2012-12-01

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

  4. SU-D-304-04: Pre-Clinical Feasibility Study for Intensity Modulated Grid Proton Therapy (IMgPT) Using a Newly Developed Delivery System

    International Nuclear Information System (INIS)

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J

    2015-01-01

    Purpose: The purpose of the current study was to characterize and evaluate intensity-modulated proton grid therapy (IMgPT) using a clinical proton beam. Methods: A TOPAS MC model of a new developmental mode (pre-clinical) of the Hitachi proton therapy system (PROBEAT) was used for simulation and characterization of proton grid therapy. TOPAS simulations of different energy ranges, depths and spot separation distances were performed. LET spectra for various energies and depths were produced with FLUKA MC code for evaluation potential interplay between planning parameters and their effect on the characterization of areas (valley) between spots. IMgPT planning aspects (spot spacing, skin dose, peak-to-valley ratios, beam selection, etc.) were evaluated for different phantom and patient cases. Raysearch software (v4.51) was used to perform the evaluation. Results: Calculated beam peak-to-valley ratios scenarios showed strong energy and depth dependence with ratios to be larger for higher energies and shallower depths. Peak-to-valley ratios for R90 range and for spot spacing of 1cm varied from 30% (E = 221.3 MeV, depth 30.6 cm) to 80% (E = 70.3 MeV, depth 4 cm). LET spectra calculations showed spectral hardening with depth, which might potential increase, spot separation distance and improve peak-to-valley ratios. IMgPT optimization, using constant spot spacing, showed skin dose reduction between peak regions of dose due to the irradiation of less skin. Single beam for bulky shallower tumors might be a potential candidate for proton grid therapy. Conclusions: Proton grid therapy using a clinical beam is a promising technique that reduces skin dose between peak regions of dose and may be suitable for the treatment of shallow tumors. IMgPT may be considered for use when bystander effects in off peak regions would be appropriate

  5. SU-D-304-04: Pre-Clinical Feasibility Study for Intensity Modulated Grid Proton Therapy (IMgPT) Using a Newly Developed Delivery System

    Energy Technology Data Exchange (ETDEWEB)

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J [St. Jude Children’s Research Hospital, Memphis, TN (United States)

    2015-06-15

    Purpose: The purpose of the current study was to characterize and evaluate intensity-modulated proton grid therapy (IMgPT) using a clinical proton beam. Methods: A TOPAS MC model of a new developmental mode (pre-clinical) of the Hitachi proton therapy system (PROBEAT) was used for simulation and characterization of proton grid therapy. TOPAS simulations of different energy ranges, depths and spot separation distances were performed. LET spectra for various energies and depths were produced with FLUKA MC code for evaluation potential interplay between planning parameters and their effect on the characterization of areas (valley) between spots. IMgPT planning aspects (spot spacing, skin dose, peak-to-valley ratios, beam selection, etc.) were evaluated for different phantom and patient cases. Raysearch software (v4.51) was used to perform the evaluation. Results: Calculated beam peak-to-valley ratios scenarios showed strong energy and depth dependence with ratios to be larger for higher energies and shallower depths. Peak-to-valley ratios for R90 range and for spot spacing of 1cm varied from 30% (E = 221.3 MeV, depth 30.6 cm) to 80% (E = 70.3 MeV, depth 4 cm). LET spectra calculations showed spectral hardening with depth, which might potential increase, spot separation distance and improve peak-to-valley ratios. IMgPT optimization, using constant spot spacing, showed skin dose reduction between peak regions of dose due to the irradiation of less skin. Single beam for bulky shallower tumors might be a potential candidate for proton grid therapy. Conclusions: Proton grid therapy using a clinical beam is a promising technique that reduces skin dose between peak regions of dose and may be suitable for the treatment of shallow tumors. IMgPT may be considered for use when bystander effects in off peak regions would be appropriate.

  6. Modeling the Western Diet for Preclinical Investigations.

    Science.gov (United States)

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

    2018-05-01

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

  7. Sibutramine in weight control: a dose-ranging, efficacy study.

    Science.gov (United States)

    Weintraub, M; Rubio, A; Golik, A; Byrne, L; Scheinbaum, M L

    1991-09-01

    We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 +/- 2.1 kg (n = 19); 5 mg sibutramine, 2.9 +/- 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 +/- 2.7 kg (n = 18) (p less than 0.05 sibutramine, 5 and 20 mg, versus placebo; p less than 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events; placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or "excitation." Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight.

  8. Preclinical electrogastrography in experimental pigs

    Science.gov (United States)

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

    2010-01-01

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

  9. Plaque removal efficacy of Colgate 360 toothbrush: A clinical study

    Directory of Open Access Journals (Sweden)

    Nageshwar Iyer

    2016-01-01

    Full Text Available Aim: The aim of this clinical study was to confirm the plaque removal efficacy of the Colgate 360 Whole Mouth Clean Toothbrush. Study Design: This was a single-center, monadic, case-controlled study with the 7 days duration. Materials and Methods: A total of eighty participants (56 male and 24 female aged between 18 and 45 years with a minimum of 20 permanent teeth (excluding the third molars without any prosthetic crowns and an initial plaque score of minimum 1.5 as determined by Modified Quigley-Hein Plaque Index (1970 participated in the study. There were two dropouts during the study duration, one male and one female. The participants were instructed to brush for 1 min, after which plaque index was recorded again. They were then instructed to brush their teeth twice a day for 1 min with the assigned toothbrush (Colgate 360 Whole Mouth Clean Toothbrush and a commercially available fluoride toothpaste for the next 7 days. On the 7 th day, all the participants were recalled for follow-up and plaque examination. The plaque index scores (pre- and post-brushing were recorded, tabulated, and analyzed statistically. Results: The mean plaque indices reduced after brushing both on day 1 and day 7. There was also a reduction in mean plaque indices from day 1 to day 7. All these reductions were statistically significant (P < 0.001. The reduction in plaque scores was independent of the gender of the participants however female participants showed lower scores as compared to male participants (P < 0.001. Conclusion: The present study demonstrated a significant reduction in plaque scores with the use of Colgate 360 Whole Mouth Clean Soft Toothbrush throughout the study period. Continued use resulted in a further significant reduction in plaque scores irrespective of the gender of participants.

  10. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

    Science.gov (United States)

    Barajaz, Ashley M; Kliethermes, Christopher L

    2017-12-01

    Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Efficacy of zolpidem for dystonia: a study among different subtypes

    Directory of Open Access Journals (Sweden)

    Yoshimichi eMiyazaki

    2012-04-01

    Full Text Available Although there are some newly-developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1(ω1 , was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5-20mg in 34 patients suffering from miscellaneous types of dystonia using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS. Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous 2 successive visits. After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2±7.9 to 5.5±5.0 (P=0.042. Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8%, 17.8% and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome and hand dystonia including musician’s. Drowsiness was the dose-limiting factor.

  12. Efficacy of Zolpidem for Dystonia: A Study Among Different Subtypes

    Science.gov (United States)

    Miyazaki, Yoshimichi; Sako, Wataru; Asanuma, Kotaro; Izumi, Yuishin; Miki, Tetsuro; Kaji, Ryuji

    2012-01-01

    Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor. PMID:22529836

  13. Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

    Science.gov (United States)

    López-Rubalcava, Carolina; Estrada-Camarena, Erika

    2016-06-20

    Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding

  14. Efficacy of glutathione mesotherapy in burns: an experimental study.

    Science.gov (United States)

    Buz, A; Görgülü, T; Olgun, A; Kargi, E

    2016-12-01

    Thermal burns are the leading cause of trauma worldwide. Currently, no consensus on optimal treatment of deep partial-thickness (second-degree) burns has emerged, as reflected by the wide variability in available wound-care materials. The relative efficacies of products used for treatment of partial-thickness thermal burns remain unclear. Mesotherapy features intradermal administration of various agents, depending on burn location. In the present experimental study, we explored the efficacy of mesotherapy used to treat partial-thickness thermal burns in 50 male Wistar rats divided into five groups of equal number. No procedure was performed after infliction of thermal burns in control group (Group 1). Mesotherapy was applied with physiological saline in sham group (Group 2), glutathione, taurine, and L-carnitine were separately applied in Group 3, Group 4, and Group 5, respectively. Mesotherapeutic agents were injected intradermally into the reticular layer of the dermis using the point technique. The first course of mesotherapy was given within the first 2 h after infliction of thermal burns, and therapy was continued to day 10. On day 22, unhealed thermal burn areas were measured prior to sacrifice, and biopsies covering the total areas of burns were performed to allow of pathological evaluation. Group 3 (the glutathione group) showed the best extent of healing, followed by Group 4 (the taurine group) and Group 5 (the L-carnitine group). The healed thermal burn areas in these groups were significantly greater than those in the control and sham groups (P = 0.001). All of healing, acute and chronic inflammation, the amount of granulation tissue, the level of fibroblast maturation, the amount of collagen, the extent of re-epithelization and neovascularization, and ulcer depth were scored upon pathological examination of tissue cross-sections. The best outcomes were evident in the glutathione group, with statistical significance. Although wound healing in the L

  15. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    International Nuclear Information System (INIS)

    Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

    2014-01-01

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10 10 VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10 10 VP/kg) and beagles (2.5 × 10 9 VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10 10 VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10 8 VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad-hTERT-E1a-Apoptin

  16. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Yanxin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Guo, Huanhuan [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Changchun Brother Biotech Co., Ltd., Changchun, 130000 (China); Hu, Ningning; He, Dongyun [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Zhang, Shi [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); School of Clinical Medicine, Jilin University, Changchun 130001 (China); Chu, Yunjie [Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021 (China); Huang, Yubin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Li, Xiao, E-mail: lixiao06@mails.jlu.edu.cn [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Sun, LiLi, E-mail: linjiaxiaoya@163.com [Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun 130012 (China); Jin, Ningyi, E-mail: ningyij@126.com [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China)

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

  17. Fostering efficacy and toxicity evaluation of traditional Chinese medicine and natural products: Chick embryo as a high throughput model bridging in vitro and in vivo studies.

    Science.gov (United States)

    Wu, Tong; Yu, Gui-Yuan; Xiao, Jia; Yan, Chang; Kurihara, Hiroshi; Li, Yi-Fang; So, Kwok-Fai; He, Rong-Rong

    2018-04-19

    Efficacy and safety assessments are essential thresholds for drug candidates from preclinical to clinical research. Conventional mammalian in vivo models cannot offer rapid pharmacological and toxicological screening, whereas cell-based or cell-free in vitro systems often lead to inaccurate results because of the lack of physiological environment. Within the avian species, gallus gallus is the first bird to have its genome sequencing. Meantime, chick embryo is an easily operating, relatively transparent and extensively accessible model, whose physiological and pathological alterations can be visualized by egg candler, staining and image technologies. These features facilitate chick embryo as a high-throughput screening platform bridging in vivo and in vitro gaps in the pharmaceutical research. Due to the complicated ingredients and multiple-targets natures of traditional Chinese medicine (TCM), testing the efficacy and safety of TCM by in vitro methods are laborious and inaccurate, while testing in mammalian models consume massive cost and time. As such, the productive living organism chick embryo serves as an ideal biological system for pharmacodynamics studies of TCM. Herein, we comprehensively update recent progresses on the specialty of chick embryo in evaluation of efficacy and toxicity of drugs, with special concerns of TCM. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Preclinical and the first clinical studies on [11C]ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography

    International Nuclear Information System (INIS)

    Toyohara, Jun; Sakata, Muneyuki; Fujinaga, Masayuki; Yamasaki, Tomoteru; Oda, Keiichi; Ishii, Kenji; Zhang, Ming Rong; Moriguchi Jeckel, Cristina Maria; Ishiwata, Kiichi

    2013-01-01

    Introduction: Preclinical studies and first positron emission tomography (PET) imaging studies were performed using N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[ 11 C] methoxy-N-methylbenzamide ([ 11 C]ITMM) to map metabotropic glutamate receptor type 1 (mGluR1) in the human brain. Methods: [ 11 C]ITMM was synthesized by O-methylation of the desmethyl precursor with [ 11 C]methyl triflate in the presence of NaOH at room temperature. In vitro selectivity and brain distributions of [ 11 C]ITMM in mice were characterized. Radiation absorbed-dose by [ 11 C]ITMM in humans was calculated from mouse distribution data. Acute toxicity of ITMM at 4.72 mg/kg body weight (> 74,000-fold clinical equivalent dose of [ 11 C]ITMM) was evaluated. Mutagenicity of ITMM was studied by the Ames test. Clinical PET imaging of mGluR1 with [ 11 C] ITMM was performed in a healthy volunteer. Results: ITMM had low activity for a 28-standard receptor binding profile. Regional brain uptake of [ 11 C]ITMM in mice was heterogeneous and consistent with known mGluR1 distributions. The radiation absorbed-dose by [ 11 C]ITMM in humans was sufficiently low for clinical use, and no acute toxicity or mutagenicity of ITMM occurred. A 90-min dynamic PET scan with [ 11 C]ITMM in a healthy volunteer showed a gradual increase of radioactivity in the cerebellum. Total distribution volume of [ 11 C]ITMM was highest in the cerebellum, followed by thalamus, cerebral cortex, and striatum; regional differences in brain radioactivity corresponded to the mGluR1 distribution in the brain. Peripherally, [ 11 C]ITMM was stable in humans: 60% of the plasma radioactivity remained in the unchanged form for 60 min. Conclusions: [ 11 C] ITMM is a suitable radioligand for imaging mGluR1 in the human brain providing acceptable dosimetry and pharmacological safety at the dose required for PET

  19. Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

    Science.gov (United States)

    Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

    2010-07-01

    Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

  20. Preclinical evaluation of natural antioxidants for development of radioprotector

    International Nuclear Information System (INIS)

    Chaudhury, N.K.; Adhikary, J.S.; Mishra, K.

    2014-01-01

    Whole body gamma ray exposure is harmful to all organs and systems. Various health effects depend on the radiation dose and dose rate and nature of exposure. Natural antioxidants have desired properties for development of radioprotector. However poor bioavailability and relatively low efficacy require high dose for intended applications. Selection of appropriate antioxidant is an important step for undertaking detailed preclinical evaluation in recommended animal models. Our focus is on natural antioxidants for development of radioprotector. We have performed extensive studies on selection of antioxidants using standard assay methods and during the course of these studies we have modified a number of assays. A number of antioxidants were considered for screening of potential radioprotectors. The antioxidants studied are available commercially as chemically pure compound. The outcome was selection of sesamol, component of sesame oil. Toxicity studies were carried out using OECD 423 toxicity guideline and undertaken efficacy studies in C57BL/6 mice and compared with another antioxidant melatonin. Sesamol (250 mg/kg body weight) has shown survival about 76% which was comparable to 86% with melatonin at lethal radiation dose. Further evaluation studies have been performed using radiation doses at LD 50/30 and sub lethal range and the antioxidant dose was also lowered. Sesamol has increased antioxidant level in mice, lowered radiation induced damages in radiosensitive organs, facilitated recovery of haematopoietic and gastrointestinal systems. Sesamol also provided protection in germs cells. Bacterial translocation from GI in irradiated mice was also inhibited in the presence of sesamol. Chromosomal aberrations and micronuclei formation were lowered in bone marrow of mice and in human peripheral blood lymphocytes. Interestingly, both the antioxidants are from different origin but demonstrated similar trend in all measured parameters. Pharmacokinetic studies are in

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

    Science.gov (United States)

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

    2012-12-01

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

  2. Assessment of [18F]-fluoroacetate PET/CT as a tumor-imaging modality. Preclinical study in healthy volunteers and clinical evaluation in patients with liver tumor

    International Nuclear Information System (INIS)

    Takemoto, Kenji; Hatano, Etsuro; Nishii, Ryuichi

    2014-01-01

    Although [ 18 F]-FDG is a useful oncologic PET tracer, FDG uptake is known to be low in a certain type of hepatocellular carcinoma (HCC). [ 18 F]-fluoroacetate ( 18 F-FACE) is an [ 18 F] fluorinated acetate, which is known to be converted into fatty acids, incorporated in membrane and is expected to be a promising oncologic PET tracer. The aim of this study was to evaluate the usefulness of 18 F-FACE as an oncologic PET tracer in preclinical study in healthy volunteers and in patients with liver tumors. Twenty-four healthy volunteers (age 48.2 ± 12.9 years old; 15 male and 9 female) and ten patients with liver tumor (age 72.1 ± 7.0 years old; 6 male and 4 female) were included. We performed whole-body static PET/CT scan using 18 F-FACE (n=34) and 18 F-FDG (n=5 for volunteers, n=8 for patients) on each day, respectively. Qualitative analysis and quantitative analysis of tumors (5 HCCs, 1 cholangiocellular carcinoma, 4 metastatic tumors from colon cancer and P-NET) were performed using SUVmax and tumor-to-normal liver ratio (TNR). In healthy volunteers, 18 F-FACE was metabolically stable in vivo and its biodistribution was almost similar to blood pool, basically uniformly independent of age and gender during PET scan time (up to 3 h). Normal physiological uptake of 18 F-FACE at each organ including liver (SUVmean 1.8 ± 0.2) was lower than that of blood pool (SUVmean 2.3 ± 0.3) at 1 h after injection. Chronic inflammatory uptake around femur of post-operative state of femoral osteotomy and faint uptake of benign hemangioma were observed in a case of healthy volunteer. 18 F-FACE (SUVmax 2.7 ± 0.6, TNR 1.5 ± 0.4) of liver tumors was significantly lower than those of 18 F-FDG uptake (6.5 ± 4.2, 2.6 ± 1.7, respectively). In qualitative analysis, 18 F-FDG was positive in 4 tumors (3 HCCs, 1 CCC) and negative in the other 6 tumors, while 18 F-FACE was also positive in 4 tumors which were the same tumors with positive 18 F-FDG uptake. Biodistribution of 18 F-FACE was

  3. Study on the relationship between project management and organizational efficacy in nonprofit organizations

    Directory of Open Access Journals (Sweden)

    Kao I-Chan

    2018-01-01

    Full Text Available This study treats the members in nonprofit organizations (NPOs as subjects, and explores the origination, planning, control, and completion of project management in NPOs, as well as the general performance of organizational efficacy, such as environmental satisfaction, organizational atmosphere, operational performance, job engagement, and work quality. It also probes into the relationship and effect. By various research methods, such as literature review and questionnaire survey, this study attempts to determine if project management in NPOs can significantly enhance organizational efficacy. This study finds that different NPOs have significant differences in the general performance of project management and organizational efficacy. When the performance of project management in NPOs is more significant, organizational efficacy is higher. Project management in NPOs has a significant path relationship to organizational efficacy; therefore, reinforcement of vocational training in the project management of NPOs could improve performance, which would have significant effect on enhancing organizational efficacy.

  4. Alflutop clinical efficacy in vertebral osteochondrosis (12-mohth study

    Directory of Open Access Journals (Sweden)

    V N Hodyrev

    2005-01-01

    Full Text Available Objective. To study clinical efficacy of aiflutop (A in lumbar osteochondrosis (LO with chronic back pain syndrome. Material and Methods. 32 pts with LO were included. 14 from them (group 1 during a year received 2 courses of A intramuscular injections (I ml/day, 30 ml total and nonsteroidal anti-inflammatory drugs (NSAIDs if necessary. 18 pts (group 2 received NSAIDs only. Clinical examination of pts was performed at the stert of the study, before and after each A course and in 3 months after the last course. Results. Pain in the spine at rest and forward bending significantly decreased in group 1 pts (p<0,05 after each A course. Full pain disappearance after the first A course was achieved in 7,1% and after the second course - in 35,7% of group I pts and was not shown in control group. Significant stepped decrease of Thomayer's test value (p<0,00l was also shown in group 1: 3,6 times decrease in comparison with baseline was achieved in 3 months after completion of treatment with A. During treatment period these pts showed 2-2,5 times increase of static and dynamic spine load (according to Vxdel chronic inability index. 42,9% of group I pts stopped NSAIDs after A treatment completion. Only 5,6% of control group pts stopped NSAIDs during follow up. A tolerability was good. It can be combined with any other medications the pts received due to comorbid diseases.

  5. THE STUDY THE EFFICACY AND SAFETY OF ANTIMICROBIAL AGENTS

    Directory of Open Access Journals (Sweden)

    V. V. Bagaeva

    2015-01-01

    Full Text Available Abstract:Effective treatment of patients with infectious and inflammatory diseases of the skin and mucous membranes often involves the use of antimicrobial agents.The purpose of the study was an in vitro estimation of cytotoxicity and the efficiency of national resources for local use: gel with bacteriophages («Otofag», «Fagogin», «Fagoderm», «Fagodent» and antiseptic — «Сhlorhexidine» and «Miramistin».Materials and Methods. To study the effectiveness of antimicrobial agents they used to provide crop strains of Staphylococcus aureus and Streptococcus pyogenes as one of the most common representatives of pathogens. The study of cell viability and cytotoxicity antimicrobials performed on cell lines KB — epidermoid carcinoma of the oral cavity of a human. For this purpose we use mikrotetrazoly test, which is widely used in the assessment of the effects on the cells of toxins, pharmaceuticals, adverse environmental factors, allowing to evaluate the toxicity of investigational drugs in vitro.The results showed that the efficacy against pathogens Staphylococcus aureus and Streptococcus pyogenes, has even a 10‑fold dilution of «Сhlorhexidine» 0.05% and gels with bacteriophages. Antiseptic «Miramistin» is effective only on the initial concentration. The study of cytotoxicity showed that the processing of epidermoid carcinoma cells with «Chlorhexidine» and «Мiramistin» invokes the irreversible reactions, while the composition processing of gels based on bacteriophages not further affect cell viability.Conclusions The results of the experiment confirmed the significant toxicity of tools such as «Сhlorhexidine» and «Miramistin» in proposed concentrations in the pharmacy network. Despite the high efficiency of these vehicles with regard to the studied pathogens, their long-term use in treatment of inflammatory diseases of the skin and mucous membranes can cause a slowing of repair processes. Gel means with bacteriophages

  6. An Empirical Study to Determine The Relationship between Occupational Self-Efficacy and Organizational Silence

    Directory of Open Access Journals (Sweden)

    Cem KAHYA

    2015-06-01

    Full Text Available The concept of occupational self-efficacy means the efficacy perceptions of employees in their occupational fields, and the concept of organizational silence means the employees avoid to voice their ideas and suggestions about organizational issues. The main aim of this study is to examine the relationship between the concepts of occupational self-efficacy and organizational silence by revealing employees’ perceptions of occupational self-efficacy and organizational silence level. With this aim, the survey study was conducted on total 114 academicians who work in University of Bayburt. As a result of research, while the significant relationship was found between employees’ perceptions of occupational self-efficacy and organizational silence level, there was reached a result that this relationship incurred the negatively relationship between perceptions of occupational self-efficacy and negative silence.

  7. Studies on bactericidal efficacy of pumpkin (Cucurbita moschata Duchesne peel

    Directory of Open Access Journals (Sweden)

    El Zawane Kamarudin

    2014-02-01

    Full Text Available Objective: T o explore the in vitro antibacterial potential of the peel of Cucurbita moschata D uchesne ( tropical pumpkin ( C. moschata against human pathogenic bacteria. Methods: I n the present study, dichloromethane ( DCM , methanol ( MEOH and aqueous extracts of C. moschata peel were examined for in vitro antibacterial potency against eight bacterial strains i.e. Bacillus cereus, Burkholderia cepacia, Escherichia coli, Enterococcus faecalis, Staphyloccocus aureus, Pseudomonas aerugenosa, Vibrio alginolyticus, Vibrio parahaemolyticus using K irby- B auer disk diffusion susceptibility and broth micro-dilution methods. Results: DCM extract of pumpkin peel exhibited the maximum zone of inhibition against Staphyloccocus aureus ( 21 mm whereas aqueous extract of pumpkin peel revealed the least zone of inhibition against Escherichia coli ( 8 mm . MEOH extract gave maximum zone of inhibition against Pseudomonas aerugenosa ( 19 mm . B roth micro-dilution method showed minimum inhibitory concentration for the DCM extract against Burkholderia cepacia at 6 . 25 mg/m L . T he minimum bactericidal concentrations were also determined to know the nature of all extracts. DCM and MEOH extracts exhibited bactericidal nature to all bacterial strains except for the Vibrio alginolyticus. T he minimum bactericidal concentrations values exhibited bactericidal nature ranging from 3 . 12 mg/m L to 100 . 00 mg/m L . T he screening of antimicrobial properties of different extracts of C. moschata peel revealed that the DCM extract possessed good antimicrobial efficacy compared to MEOH and aqueous extracts. Conclusions: P eel of C. moschata possesses antibacterial compounds and could be potential source for a new class of antibiotics.

  8. Study of the efficacy of carboxytherapy in alopecia.

    Science.gov (United States)

    Doghaim, Noha Nabil; El-Tatawy, Rania Ahmed; Neinaa, Yomna Mazid El-Hamd; Abd El-Samd, Marwa Mohsen

    2018-02-20

    Management of alopecia areata (AA) and androgenetic alopecia (AGA) is often challenging. The use of carboxytherapy may be a novel therapeutic option for such cases. To evaluate the clinical efficacy and safety of carboxytherapy in alopecia areata and androgenetic alopecia. This study was conducted on 80 patients with alopecia divided into two groups; Group I included 40 AA patients (Group IA received carboxytherapy and Group IB control received placebo), and Group II included 40 AGA patients (Group IIA received carboxytherapy and Group IIB control received placebo), and followed up monthly for 3 months. They were evaluated clinically (by assessment of Severity of Alopecia Tool (SALT) score in group I, and Sinclair scale and Norwood-Hamilton scale in group II), by dermoscopy and digital dermoscopy at each visit. Group IA patients showed significant clinical improvement in SALT score and dermoscopic improvement after carboxytherapy and at the end of follow-up period with significant reduction in dystrophic hair, black dots, yellow dots, and tapered hair coinciding with significant emergence of regrowing hair. Group IIA patients showed significant clinical and dermoscopic improvement after carboxytherapy with significant increase in hair density measured by digital dermoscopy. However, regression of these results was observed during the follow-up period but was still significantly better than before treatment. There were statistically significant improvements in clinical score, global assessments, dermoscopic, and digital dermoscopic findings in both group IA and group IIA received carboxytherapy in comparison with group IB and group IIB received placebo injections, respectively. Carboxytherapy seems to be a promising therapeutic option for patchy AA and could be helpful as an adjuvant therapy of AGA but more than 6 sessions are required and adjuvants are recommended for maintenance of the results. © 2018 Wiley Periodicals, Inc.

  9. Preliminary studies on the phytochemistry and efficacy of extracts of ...

    African Journals Online (AJOL)

    Phytochemistry of Spondias mombin bark, a known anti –tumour plant used traditionally, revealed the presence of alkaloids, saponins, tannins, phenolic compound and eugenol. The efficacy of the plant material tested on induced cancer in rats showed significant recovery using water extract treatment when compared with ...

  10. Teacher Perceptions of the Impact of Self-Efficacy on Classroom Management Style: A Case Study

    Science.gov (United States)

    McCain, Patty Jo

    2017-01-01

    The purpose of this qualitative case study was to develop an understanding of how current and former middle school teachers in a suburban school district in northeast Georgia perceive low self-efficacy impacts their classroom management style. The theory guiding this study was Bandura's (1977) self-efficacy theory as it supported the idea that…

  11. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Science.gov (United States)

    2010-04-01

    ... labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Efficacy Study § 201.200 Disclosure of drug efficacy study evaluations in labeling and advertising. (a)(1... bringing to the attention of the prescribers of prescription items the conclusions of the expert panels...

  12. A Study on the Relationship between Teacher Self Efficacy and Burnout

    Science.gov (United States)

    Savas, Ahmet Cezmi; Bozgeyik, Yunus; Eser, Ismail

    2014-01-01

    The major purpose of the study was to examine the relationship between teacher self efficacy and burnout. In order to collect the related data, "Maslach Burnout Inventory" and "Teacher Sense of Efficacy Scale" were used. The sample of the study consisted of 163 randomly chosen teachers who worked in various primary and…

  13. The Effect of Teacher's Assistance on Malaysian Rural Learners' Writing Self-Efficacy: A Case Study

    Science.gov (United States)

    Jalaluddin, Ilyana; Yunus, Melor Md.; Yamat, Hamidah

    2011-01-01

    The purpose of the study is to explore the Malaysian rural learners' self-efficacy in writing after assistance given by a teacher. The social cognitive theory and socio-cultural theory are used as the theoretical framework to pursue the discussion on the effects of teacher's assistance on learners' writing self-efficacy. A case study approach is…

  14. Electronic Cigarettes Efficacy and Safety at 12 Months: Cohort Study.

    Directory of Open Access Journals (Sweden)

    Lamberto Manzoli

    Full Text Available To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes (e-cigarettes, directly comparing users of e-cigarettes only, smokers of tobacco cigarettes only, and smokers of both.Prospective cohort study. Final results are expected in 2019, but given the urgency of data to support policies on electronic smoking, we report the results of the 12-month follow-up.Direct contact and structured questionnaires by phone or via internet.Adults (30-75 years were included if they were smokers of ≥1 tobacco cigarette/day (tobacco smokers, users of any type of e-cigarettes, inhaling ≥50 puffs weekly (e-smokers, or smokers of both tobacco and e-cigarettes (dual smokers. Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence.Sustained smoking abstinence from tobacco smoking at 12 months, reduction in the number of tobacco cigarettes smoked daily.We used linear and logistic regression, with region as cluster unit.Follow-up data were available for 236 e-smokers, 491 tobacco smokers, and 232 dual smokers (overall response rate 70.8%. All e-smokers were tobacco ex-smokers. At 12 months, 61.9% of the e-smokers were still abstinent from tobacco smoking; 20.6% of the tobacco smokers and 22.0% of the dual smokers achieved tobacco abstinence. Adjusting for potential confounders, tobacco smoking abstinence or cessation remained significantly more likely among e-smokers (adjusted OR 5.19; 95% CI: 3.35-8.02, whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption. E-smokers showed a minimal but significantly higher increase in self-rated health than other smokers. Non significant differences were found in self-reported serious adverse events (eleven overall.Adding e-cigarettes to tobacco smoking did not facilitate smoking cessation or reduction. If e-cigarette safety will be confirmed, however, the use of e

  15. Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

    Science.gov (United States)

    Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

    This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.

  16. Loss and gain cycles? A longitudinal study about burnout, engagement and self-efficacy

    Directory of Open Access Journals (Sweden)

    Susana Llorens-Gumbau

    2014-06-01

    Full Text Available The present longitudinal study (two waves, conducted on a population of 274 secondary-school teachers, expands on previous research on burnout and work engagement. Accordingly, the effect of organizational factors (obstacles, facilitators as well as personal resources (self-efficacy on burnout and engagement is tested longitudinally following the Social Cognitive Theory. More specifically, we test the loss and gain cycles, and reciprocal relationships concerning burnout, engagement, and self-efficacy over time. Four questions are addressed: (1 Are obstacles positively related to burnout and work self-efficacy over time? (2 Are facilitators positively related to engagement and self-efficacy over time? (3 Is work self-efficacy negatively related to burnout and obstacles over time? and (4 Is work self-efficacy positively related to engagement and facilitators over time? The results of a hard-copy survey carried out at two waves (8 months between the two times, which were computed on Structural Equation Modeling show that obstacles are positively related to burnout, which in turn is positively related to self-efficacy over time. Likewise, facilitators are positively related to engagement and self-efficacy, which in turn is positively related to facilitators over time. These findings suggest a positive gain cycle in which self-efficacy plays a central role.

  17. Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors

    Science.gov (United States)

    Morris, David B.; Usher, Ellen L.

    2011-01-01

    The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that…

  18. Mindfulness predicts student nurses' communication self-efficacy: A cross-national comparative study.

    Science.gov (United States)

    Sundling, Vibeke; Sundler, Annelie J; Holmström, Inger K; Kristensen, Dorte Vesterager; Eide, Hilde

    2017-08-01

    The aim of this study was to compare student nurses' communication self-efficacy, empathy, and mindfulness across two countries, and to analyse the relationship between these qualities. The study had a cross-sectional design. Data was collected from final year student nurses in Norway and Sweden. Communication self-efficacy, empathy, and mindfulness were reported by questionnaires; Clear-cut communication with patients, Jefferson Scale of Empathy, and Langer 14 items mindfulness scale. The study included 156 student nurses, 94 (60%) were Swedish. The mean communication self-efficacy score was 119 (95% CI 116-122), empathy score 115 (95% CI 113-117) and mindfulness score 79 (95% CI 78-81). A Mann-Whitney test showed that Swedish students scored significantly higher on communication self-efficacy, empathy, and mindfulness than Norwegian students did. When adjusted for age, gender, and country in a multiple linear regression, mindfulness was the only independent predictor of communication self-efficacy. The Swedish student nurses in this study scored higher on communication self-efficacy, empathy, and mindfulness than Norwegian students did. Student nurses scoring high on mindfulness rated their communication self-efficacy higher. A mindful learning approach may improve communication self-efficacy and possibly the effect of communication skills training. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. A Longitudinal Study on Mathematics Teaching Efficacy: Which Factors (Un)Support the Development?

    Science.gov (United States)

    Isiksal-Bostan, Mine

    2016-01-01

    The aim of this longitudinal study was to examine prospective teachers' mathematics teaching efficacy belief during their enrollment in teacher education program and at the end of their first year of teaching. In addition, the factors that enhance or inhibit participants' efficacy belief and how these factors affect their mathematics teaching…

  20. Developing Self-Efficacy through a Massive Open Online Course on Study Skills

    Science.gov (United States)

    Padilla Rodriguez, Brenda Cecilia; Armellini, Alejandro

    2017-01-01

    Self-efficacy is a strong predictor of academic performance, and an area of interest for higher education institutions. This paper reports on a massive open online course (MOOC) on study skills, aimed at increasing self-efficacy. Participants (n = 32) were from Mexico and Colombia, with ages ranging from 21 to 45 years. At the beginning and the…

  1. Organizational Structure, Collegial Trust, and College Faculty Teaching Efficacy: A Case Study

    Science.gov (United States)

    Okpogba, Desmond

    2011-01-01

    The purpose of this mixed-method study was to explore the relationship between faculty self-efficacy, organizational structure, and collegial trust. The concepts of teacher self-efficacy, organizational structure, and collegial trust were used to investigate any possible empirical relationships existing between these variables in a private,…

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

    OpenAIRE

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

    2016-01-01

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

  3. The interplay between motivation, self-efficacy, and approaches to studying.

    Science.gov (United States)

    Prat-Sala, Mercè; Redford, Paul

    2010-06-01

    The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to studying (deep, strategic, and surface). The study also examined changes in approaches to studying over time. A total of 163 first-year undergraduate students in psychology at a UK university took part in the study. Participants completed the Work Preference Inventory motivation questionnaire, self-efficacy in reading and writing questionnaires and the short version of the Revised Approaches to Study Inventory. The results showed that both intrinsic and extrinsic motivation orientations were correlated with approaches to studying. The results also showed that students classified as high in self-efficacy (reading and writing) were more likely to adopt a deep or strategic approach to studying, while students classified as low in self-efficacy (reading and writing) were more likely to adopt a surface approach. More importantly, changes in students' approaches to studying over time were related to their self-efficacy beliefs, where students with low levels of self-efficacy decreased in their deep approach and increased their surface approach across time. Students with high levels of self-efficacy (both reading and writing) demonstrated no such change in approaches to studying. Our results demonstrate the important role of self-efficacy in understanding both motivation and learning approaches in undergraduate students. Furthermore, given that reading academic text and writing essays are essential aspects of many undergraduate degrees, our results provide some indication that focusing on self-efficacy beliefs amongst students may be beneficial to improving their approaches to study.

  4. Preliminary studies of adaptation of Self- efficacy Scale for Sources of Mathematics

    Directory of Open Access Journals (Sweden)

    Ramírez Flores, Celia María

    2011-07-01

    Full Text Available In the field of educational psychologically the construct of self-efficacy has received special attention. It has been shown that those students who trust in their own abilities get better academic performance. However, few studies analyze the sources of self-efficacy. Self-efficacy believes are developed according to how people interpret information coming from four different sources: experience skills, vicarious learning, social persuasion, and physiological states. Recently, Usher & Pajares (2009 developed an instrument to assess sources of self-efficacy in Math. The goal of the present work was to evaluate psychometric properties of this scale in a local sample of adolescents from 13 to 15 years old. Preliminary results supported the use of this measure as an adequate alternative to assess self-efficacy in Math. However, more studies are needed in order to obtain a measure more contextualized to the educational system of local students.

  5. Gender fairness in self-efficacy? A Rasch-based validity study of the General Academic Self-efficacy scale (GASE)

    DEFF Research Database (Denmark)

    Nielsen, Tine; Vang, Maria Louison; Dammeyer, Jesper

    2018-01-01

    Studies have reported gender differences in academic self-efficacy. However, how and if academic self-efficacy questionnaires are gender-biased has not been psychometrically investigated. The psychometric properties of a general version of The Physics Self-Efficacy Questionnaire – the General...... Academic Self-Efficacy Scale (GASE) – were analyzed using Rasch measurement models, with data from 1018 Danish university students (psychology and technical), focusing on gender invariance and the sufficiency of the score. The short 4-item GASE scale was found to be essentially objective and construct...... valid and satisfactorily reliable, though differential item functioning was found relative to gender and academic discipline, and can be used to assess students’ general academic self-efficacy. Research on gender and self-efficacy needs to take gender into account and equate scores appropriately...

  6. Leading by Example: A Case Study of the Influence of Principal Self-Efficacy on Collective Efficacy

    Science.gov (United States)

    Versland, Tena M.; Erickson, Joanne L.

    2017-01-01

    Self-efficacy is a perceived judgment that one has the ability to execute a course of action that brings about a desired result. Principal self-efficacy describes a set of beliefs that enable a principal to enact policies and procedures that promote the effectiveness of a school. Principal self-efficacy beliefs are also important because they…

  7. Prior Self-Efficacy Interacts with Experiential Valence to Influence Self-Efficacy among Engineering Students: An Experimental Study

    Science.gov (United States)

    Chang, Yevvon Yi-Chi; Chiou, Wen-Bin

    2017-01-01

    Self-efficacy toward science learning has been shown to play a crucial role in determining students' motivation and achievements. Social cognitive theory proposes that positive and negative task outcomes affect mastery experiences from which self-efficacy develops. The current research examined whether prior level of self-efficacy would serve as a…

  8. The impact of subacute whiplash-associated disorders on functional self-efficacy: a cohort study.

    Science.gov (United States)

    Bunketorp-Käll, Lina Sofia; Andersson, Caroline; Asker, Barbita

    2007-09-01

    Self-efficacy is increasingly being recognized as an important factor to consider in medical research, especially in different pain conditions such as whiplash-associated disorders (WAD). When pain is not effectively treated or relieved, it may negatively affect patients' life situation and cause a decline in perceived self-efficacy. Knowledge of what level of self-efficacy can be considered an actual deficit in patients with WAD is, however, sparse. The purpose of this study is to analyze whether subacute WAD has an impact on self-efficacy beliefs. A cohort study was designed to identify the impact of WAD on self-efficacy beliefs. The exposed group consisted of 47 patients with subacute WAD following a whiplash trauma. The control group representing the general population consisted of 212 participants, and was randomly selected to match the distribution of age and sex in the exposed group. The Self-Efficacy Scale was used to assess the individuals' confidence in their ability to successfully carry out activities of daily living. In the exposed group, 47 responded (100%), and in the control group, 113 (53%) responded. The results show that the total scores on the Self-Efficacy Scale were significantly lower in the exposed group compared with the control group, concerning both the mean (P<0.001) and median (P<0.001) scores. In conclusion, patients with subacute WAD experience a decline in functional self-efficacy, which stresses the importance of incorporating these beliefs in clinical practice and research.

  9. Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

    Science.gov (United States)

    Siegler, Elizabeth Louise; Wang, Pin

    2018-05-01

    Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

  10. The influence of freeze drying and ϒ-irradiation in pre-clinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using D-(+-trehalose and polyethylene glycol

    Directory of Open Access Journals (Sweden)

    Ramos Yacasi GR

    2016-08-01

    Full Text Available Gladys Rosario Ramos Yacasi, María Luisa García López, Marta Espina García, Alexander Parra Coca, Ana Cristina Calpena Campmany Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain Abstract: This study investigated the suspension of poly(ε-caprolactone nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5% and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350 and d-(+-trehalose (TRE. Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE. IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over .30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics

  11. Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    John K Thuita

    Full Text Available There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness. A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD. In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino-2-pyridyl]furan (DB868; CPD-007-10, in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median C(max (dosing regimen that was 12-fold (3 mg/kg/day for 7 days, 15-fold (10 mg/kg/day for 7 days, and 31-fold (20 mg/kg/day for 5 days greater than the IC50 (14 nmol/L against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days, oral regimen for first stage HAT.

  12. Shared Relationship Efficacy of Dyad Can Increase Life Satisfaction in Close Relationships: Multilevel Study

    Science.gov (United States)

    Ito, Kenichi; Yoshida, Toshikazu

    2016-01-01

    Characteristics of relationship itself play an important role in determining well-being of individuals who participate in the relationship. We used efficacy expectations mutually shared between close friends or romantic partners as a characteristic of relationship and investigated its impact on their life satisfaction. In Study 1, we conducted a cross-sectional study among 137 pairs of close same-sex friends to test whether the efficacy expectations shared between friends are associated with levels of life satisfaction. In Study 2, we conducted a longitudinal study among 114 heterosexual romantic couples to test predictive validity of the efficacy expectations shared between couples predict levels of life satisfaction 2 month later. In both studies we found a consistent result that as degrees of the efficacy expectations shared between individuals in a relationship increased, the degree of their life satisfaction also increased. Underlying mechanisms that explain how characteristics of relationship itself increase life satisfaction are discussed. PMID:27437946

  13. A study of self-efficacy in job-related context

    Directory of Open Access Journals (Sweden)

    Špela Frlec

    2005-04-01

    Full Text Available The article stems from an attempt to transfer the Bandura's social cognitive theory into organisational praxis. Beliefs of self-efficacy, which is defined as people's judgments of their capabilities to organize and execute courses of action required to attain designated types of performances, are constructed from 4 principal sources of information: enactive mastery experiences; vicarious experiences that alter efficacy beliefs through transmission of competencies and comparison with the attainment of others; verbal persuasion and allied types of social influences that one possesses certain capabilities; and physiological and affective states from which people partly judge their capableness, strength, and vulnerability to dysfunction. The study of self-efficacy in job-related context involved 295 employees from 3companies belonging to the same business group. Self-efficacy was assed using Schwarzer's scale, while rating scales were used for assessing the 4 principal sources of influence upon it. First, differences between companies regarding demographic characteristics of the employees, job characteristics and self-efficacy were analyzed. Dependence of employee's self-efficacy on his/her age, gender, education, work experience, employment status, job type and the four principal influence sources was tested using a regression model. Finally, we identified typical employee profiles with respect to the studied factors. We hope that our study will help human-resources specialists design appropriate interventions for developing a resilient sense of self-efficacy in the employees.

  14. Characterization of novel preclinical dose distributions for micro irradiator

    International Nuclear Information System (INIS)

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

    2017-01-01

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

  15. Characterization of novel preclinical dose distributions for micro irradiator

    Science.gov (United States)

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

    2017-05-01

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

  16. Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results

    International Nuclear Information System (INIS)

    Baumann, Michael; Krause, Mechthild

    2004-01-01

    Background and purpose: Inhibition of the epidermal growth factor receptor (EGFR) is a fastly developing field in preclinical and clinical cancer research. This review presents the current status of knowledge and discusses radiobiological mechanisms which may underly the efficacy of EGFR inhibitors combined with irradiation. Materials and methods: Preclinical and clinical results on combined targeting of the EGFR and irradiation from the literature and from this laboratory are reviewed. Focus is given to the radiobiological rationale of this approach and to endpoints of experimental radiotherapy. Results: Overexpression of the EGFR is associated with decreased local tumour control after radiotherapy, especially when the overall treatment time is long. Inhibition of the EGFR either alone or in combination with irradiation decreases the growth rate of tumours expressing this receptor. Preclinical data provide proof-of-principle that local tumour control may be improved by combining irradiation with C225 mAb. In a randomised phase III clinical trial, simultaneous irradiation and treatment with the EGFR antibody Cetuximab (Erbitux[reg]; C225) in head and neck cancer patients resulted in significantly improved locoregional tumour control and survival compared to curative irradiation alone. Acute skin reactions increased in the experimental arm. The underlying mechanisms of enhanced radiation effects of combined EGFR inhibition with irradiation and of the partly conflicting results in different studies are poorly understood. There is increasing evidence, that important intertumoral heterogeneity in the response to EGFR inhibition alone and combined with irradiation exists, which appears to be at least partly dependent on specific mutations of the receptor as well as of molecules that are involved in the intracellular signal transduction pathway. Conclusions and outlook: Further investigations at all levels of the translational research chain exploring the mechanisms of

  17. Comparative assessment of antimicrobial efficacy of different hand sanitizers: An in vitro study

    OpenAIRE

    Jain, Vardhaman Mulchand; Karibasappa, Gundabaktha Nagappa; Dodamani, Arun Suresh; Prashanth, Vishwakarma K.; Mali, Gaurao Vasant

    2016-01-01

    Background: To evaluate the antimicrobial efficacy of four different hand sanitizers against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis as well as to assess and compare the antimicrobial effectiveness among four different hand sanitizers. Materials and Methods: The present study is an in vitro study to evaluate antimicrobial efficacy of Dettol, Lifebuoy, PureHands, and Sterillium hand sanitizers against clinical i...

  18. General self-efficacy and posttraumatic stress after a natural disaster: a longitudinal study.

    Science.gov (United States)

    Nygaard, Egil; Hussain, Ajmal; Siqveland, Johan; Heir, Trond

    2016-04-06

    Self-efficacy may be an important factor in individuals' recovery from posttraumatic stress reactions after a natural disaster. However, few longitudinal studies have investigated whether self-efficacy predicts the course of posttraumatic recovery beyond lower initial levels of distress. The purpose of the present study was to investigate whether general self-efficacy is related to recovery from posttraumatic stress reactions from a longitudinal perspective. A total of 617 Norwegians exposed to the 2004 Southeast Asian tsunami completed self-report questionnaires measuring their level of disaster exposure and general self-efficacy at 6 months and posttraumatic stress reactions 6 months and 2 years post-disaster. Predictors of changes in posttraumatic stress reactions were analyzed with multivariate mixed effects models. Self-efficacy at 6 months post-disaster was unrelated to trauma exposure and inversely related to posttraumatic stress reactions at 6 months and 2 years post-disaster. However, self-efficacy was not related to recovery from posttraumatic stress reactions between 6 months and 2 years post-disaster. In conclusion, general self-efficacy is related to lower levels of posttraumatic stress reactions in the first months after a disaster but does not appear to be related to improved recovery rates over the longer term.

  19. A multilevel study on the relationships between work characteristics, self-efficacy, collective efficacy, and organizational citizenship behavior: the case of Taiwanese police duty-executing organizations.

    Science.gov (United States)

    Chen, Chun-Hsi Vivian; Kao, Rui-Hsin

    2011-01-01

    Public security, traffic management, and service for the people are the 3 major functions of policing in Taiwan. This definition encompasses not only the traditional job characteristics, but also the level of contextual characteristics and social characteristics because of police work's characteristics and its frequent interaction with the public. Thus, the present study conducted a multilevel model analysis by taking self-efficacy and collective efficacy as the mediating variables. The purpose was to investigate the influences of motivational work characteristics (knowledge-oriented) and social work characteristics (socially and contextually oriented) of work-design model on the police officers' organizational citizenship behavior (OCB), by using first-line police officers in Taiwan as the research objects. The study showed not only that knowledge characteristics will influence the self-efficacy of a police officer and that self-efficacy can in turn influence individual police officers' OCB, but also the contextual effect of social characteristics, contextual characteristics, and collective efficacy on self-efficacy and individuals' OCB. Additionally, there was a crosslevel moderating effect from contextual characteristics on the relationship between knowledge characteristics and self-efficacy and the relationship between self-efficacy and the individuals' OCB. The authors conclude the article with research implications.

  20. Benefits of Case-Based versus Traditional Lecture-Based Instruction in a Preclinical Removable Prosthodontics Course.

    Science.gov (United States)

    Samuelson, David B; Divaris, Kimon; De Kok, Ingeborg J

    2017-04-01

    This study compared the acceptability and relative effectiveness of case-based learning (CBL) versus traditional lecture-based (LB) instruction in a preclinical removable prosthodontics course in the University of North Carolina at Chapel Hill School of Dentistry DDS curriculum. The entire second-year class (N=82) comprised this crossover study's sample. Assessments of baseline comprehension and confidence in removable partial denture (RPD) treatment planning were conducted at the beginning of the course. Near the end of the course, half of the class received CBL and LB instruction in an RPD module in alternating sequence, with students serving as their own control group. Assessments of perceived RPD treatment planning efficacy, comprehension, and instruction method preference were administered directly after students completed the RPD module and six months later. Analyses of variance accounting for period, carryover, and sequence effects were used to determine the relative effects of each approach using a peffects, CBL was also associated with higher gains in RPD treatment planning comprehension (p=0.04) and perceived efficacy (p=0.01) compared to LB instruction. These gains diminished six months after the course-a finding based on a 49% follow-up response rate. Overall, the students overwhelmingly preferred CBL to LB instruction, and the findings suggest small albeit measurable educational benefits associated with CBL. This study's findings support the introduction and further testing of CBL in the preclinical dental curriculum, in anticipation of possible future benefits evident during clinical training.

  1. An Exploratory Study into the Efficacy of Learning Objects

    Directory of Open Access Journals (Sweden)

    Nicholas W. Farha, Ph.D.

    2009-07-01

    Full Text Available Learning objects have quickly become a widely accepted approach to instructional technology, particularly in on-line and computer-based learning environments. While there is a substantial body of literature concerning learning objects, very little of it verifies their efficacy. This research investigated the effectiveness of learning objects by comparing learning outcomes using a learning object with outcomes using a traditional textbook-based method of instruction. Participants were 327 undergraduate college students at a traditional public four-year coed institution, a private four-year women’s college, a private four-year engineering institution, and a public two-year community college. Through a series of independent samples t-tests and Analyses of Variance, results revealed mean scores for the learning object group that were nearly three times higher than the mean scores for the textbook-taught group. Gaming experience, age, gender, and learner preference were evaluated for their potential influence on the results; no statistically significant differences were found, implying that the learning object itself was central to the outcomes achieved. The future of learning objects is bright, and more empirical research is called for in the area of learning object effectiveness.

  2. The basics of preclinical drug development for neurodegenerative disease indications.

    Science.gov (United States)

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  3. The basics of preclinical drug development for neurodegenerative disease indications

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

  4. Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.

    Directory of Open Access Journals (Sweden)

    Douglas W McMillin

    Full Text Available Polo-like kinases (PLKs play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM. We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM and rapid (commitment to cell death <24 hrs in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM

  5. Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

    Science.gov (United States)

    Poirier, Nicolas; Mary, Caroline; Le Bas-Bernardet, Stephanie; Daguin, Veronique; Belarif, Lyssia; Chevalier, Melanie; Hervouet, Jeremy; Minault, David; Ville, Simon; Charpy, Vianney; Blancho, Gilles; Vanhove, Bernard

    2014-01-01

    Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo. PMID:24598534

  6. Physiological remodeling of bifurcation aneurysms: preclinical results of the eCLIPs device.

    Science.gov (United States)

    Marotta, Thomas R; Riina, Howard A; McDougall, Ian; Ricci, Donald R; Killer-Oberpfalzer, Monika

    2018-02-01

    OBJECTIVE Intracranial bifurcation aneurysms are complex lesions for which current therapy, including simple coiling, balloon- or stent-assisted coiling, coil retention, or intrasaccular devices, is inadequate. Thromboembolic complications due to a large burden of intraluminal metal, impedance of access to side branches, and a high recurrence rate, due largely to the unmitigated high-pressure flow into the aneurysm (water hammer effect), are among the limitations imposed by current therapy. The authors describe herein a novel device, eCLIPs, and its use in a preclinical laboratory study that suggests the device's design and functional features may overcome many of these limitations. METHODS A preclinical model of wide-necked bifurcation aneurysms in rabbits was used to assess functional features and efficacy of aneurysm occlusion by the eCLIPs device. RESULTS The eCLIPs device, in bridging the aneurysm neck, allows coil retention, disrupts flow away from the aneurysm, leaves the main vessel and side branches unencumbered by intraluminal metal, and serves as a platform for endothelial growth across the neck, excluding the aneurysm from the circulation. CONCLUSIONS The eCLIPs device permits physiological remodeling of the bifurcation.

  7. Feasibility of spatial frequency domain imaging (SFDI) for optically characterizing a preclinical oncology model.

    Science.gov (United States)

    Tabassum, Syeda; Zhao, Yanyu; Istfan, Raeef; Wu, Junjie; Waxman, David J; Roblyer, Darren

    2016-10-01

    Determination of chemotherapy efficacy early during treatment would provide more opportunities for physicians to alter and adapt treatment plans. Diffuse optical technologies may be ideally suited to track early biological events following chemotherapy administration due to low cost and high information content. We evaluated the use of spatial frequency domain imaging (SFDI) to characterize a small animal tumor model in order to move towards the goal of endogenous optical monitoring of cancer therapy in a controlled preclinical setting. The effects of key measurement parameters including the choice of imaging spatial frequency and the repeatability of measurements were evaluated. The precision of SFDI optical property extractions over repeat mouse measurements was determined to be within 3.52% for move and replace experiments. Baseline optical properties and chromophore values as well as intratumor heterogeneity were evaluated over 25 tumors. Additionally, tumor growth and chemotherapy response were monitored over a 45 day longitudinal study in a small number of mice to demonstrate the ability of SFDI to track treatment effects. Optical scattering and oxygen saturation increased as much as 70% and 25% respectively in treated tumors, suggesting SFDI may be useful for preclinical tracking of cancer therapies.

  8. Developing Self-Efficacy through a Massive Open Online Course on Study Skills

    Directory of Open Access Journals (Sweden)

    Brenda Cecilia Padilla Rodriguez

    2017-09-01

    Full Text Available Self-efficacy is a strong predictor of academic performance, and an area of interest for higher education institutions. This paper reports on a massive open online course (MOOC on study skills, aimed at increasing self-efficacy. Participants (n=32 were from Mexico and Colombia, with ages ranging from 21 to 45 years. At the beginning and the end of the MOOC, learners answered a survey that included the General Self-Efficacy Scale, items on specific study skills, and space for optional comments. Findings show statistically significant increases in general self-efficacy after completing the MOOC, as well as in the perceived self-efficacy related to five out of six study skills. Comments suggest that participants are aware of and value their own improvement. For students, MOOCs can represent low-risk, formative opportunities to widen their knowledge and increase their self-efficacy. For academic institutions, well-designed MOOCs on study skills provide a means to support students.

  9. An oral Salmonella-based vaccine inhibits liver metastases by promoting tumor-specific T cell-mediated immunity in celiac & portal lymph nodes. A preclinical study.

    Directory of Open Access Journals (Sweden)

    Alejandrina eVendrell

    2016-03-01

    Full Text Available Primary tumor excision is one of the therapies of cancer most widely used. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent source of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally-administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was immunized with CVD 915 via o.g. while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac & portal lymph nodes (LDLN 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4+ and DC cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8+IFN-γ+ were found in the celiac & portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

  10. Teaching efficacy of nurses in clinical practice education: A cross-sectional study.

    Science.gov (United States)

    Kim, Eun-Kyeung; Shin, Sujin

    2017-07-01

    Clinical nurses play a vital role in clinical practice education; thus, it is necessary to help clinical nurses have teaching efficacy through the development and application of systematic education programs. To identify nurses' teaching efficacy for clinical education and analyze the influencing factors of teaching efficacy. The study used a cross-sectional design. We used a convenience sample of 263 nurses from two hospitals. Teaching efficacy, general characteristics, and perception of clinical practice education were collected via self-reported questionnaires. Teaching efficacy was measured using Hwang's (2006) questionnaire, while perception of clinical practice education was measured using the Clinical Nurse Teacher Survey developed by Nishioka et al. (2014). Participants completed the questionnaire directly. The collected data were then analyzed using descriptive statistics, t-tests, ANOVAs, and multiple regression analysis with PASW Statistics 18.0. The mean total score of teaching efficacy was 72.5 (range 21-105). The leadership for students subscale had the highest score (3.56±0.59). The factors influencing teaching efficacy were length of clinical career (β=0.26, pteaching efficacy in nurses. Based on these results, nursing educators might need to develop greater confidence in their knowledge and enhance control of their teaching strategies. Nursing schools and hospitals might need to provide greater support and educational opportunities to nurse clinical practice instructors. Furthermore, constructing a system of cooperation between these colleges and educational hospitals, developing programs to enhance teaching efficacy, and identifying the clinical instructor's role are all necessary to promote clinical practice education. Copyright © 2017. Published by Elsevier Ltd.

  11. The Relationship between Pedagogical Beliefs and Teacher Efficacy: A Case Study of Chinese Foreign Language Teachers in Texas

    Science.gov (United States)

    Liu, I-Chun

    2012-01-01

    This study investigated an emerging language learning culture by examining the relationship between teachers' pedagogical beliefs and perceived efficacy in two cities in southern Texas. Drawing on Bandura's (1994) theory of self-efficacy and Ashton and Webb's (1986) notions about teacher efficacy, a multi-sited case study was conducted to explore…

  12. A Study of Self-efficacy in Patients with Coronary Artery Disease and Its Predictors

    OpenAIRE

    Ezzat Paryad; Touba Hosseinzade; Ehsan Kazemnejad; Shahla Asiri

    2013-01-01

    Background and Objectives: Enhancement of empowerment in patients with coronary artery disease has a major role in the promotion of their health behaviors. Promotion of self-efficacy is a one of the ways for improving this skill, which has a significant impact on improving patients’ condition and on preventing complications and readmission. The objective of this study was to determine the predictors of general, exercise, and diet behavior self-efficacies in coronary artery disease patients.Me...

  13. Measuring Efficacy of Information Security Policies : A Case Study of UAE based company

    OpenAIRE

    Qureshi, Muhammad Sohail

    2012-01-01

    Nowadays information security policies are operative in many organizations. Currently few organizations take the pain of verifying the efficacy of these policies. Different standards and procedures exist about methods of measuring efficacy of information security policies. Choosing and implementing them depends mainly on the key performance indicators (KPIs) and key risk indicators (KRIs) of any particular organization. This thesis is a case study of an organization in United Arab Emirates (U...

  14. Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial

    International Nuclear Information System (INIS)

    Pardanani, A; Tefferi, A; Guglielmelli, P; Bogani, C; Bartalucci, N; Rodríguez, J; Extremera, S; Pérez, I; Alfaro, V; Vannucchi, A M

    2015-01-01

    Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m 2 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2–41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m 2 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted

  15. Comparative study of root-canal shaping with stainless steel and rotary NiTi files performed by preclinical dental students.

    Science.gov (United States)

    Alrahabi, Mothanna

    2015-01-01

    We evaluated the use of NiTi rotary and stainless steel endodontic instruments for canal shaping by undergraduate students. We also assessed the quality of root canal preparation as well as the occurrence of iatrogenic events during instrumentation. In total, 30 third-year dental students attending Taibah University Dental College prepared 180 simulated canals in resin blocks with NiTi rotary instruments and stainless steel hand files. Superimposed images were prepared to measure the removal of material at different levels from apical termination using the GSA image analysis software. Preparation time, procedural accidents, and canal shape after preparation were analyzed using χ 2 and t-tests. The statistical significance level was set at P instruments and stainless steel files; the former was associated with shorter preparation time, less ledge formation (1.1% vs. 14.4%), and greater instrument fracture (5.56% vs. 1.1%). These results indicate that NiTi rotary instruments result in better canal geometry and cause less canal transportation. Manual instrumentation using stainless steel files is safer than rotary instrumentation for inexperienced students. Intensive preclinical training is a prerequisite for using NiTi rotary instruments. These results prompted us to reconsider theoretical and practical coursework when teaching endodontics.

  16. A short-term increase in cancer risk associated with daytime napping is likely to reflect pre-clinical disease: prospective cohort study.

    Science.gov (United States)

    Cairns, B J; Travis, R C; Wang, X-S; Reeves, G K; Green, J; Beral, V

    2012-07-24

    Sleep disturbance, a correlate of which is daytime napping, has been hypothesised to be associated with risk of breast and other cancers. We estimated relative risks (RR) of breast and other invasive cancers by the reported frequency of daytime napping in a large prospective cohort of middle-aged women in the UK. During an average of 7.4 years of follow-up, 20 058 breast cancers and 31 856 other cancers were diagnosed. Over the first 4 years of follow-up, daytime napping (sometimes/usually vs rarely/never) was associated with slightly increased risks of breast cancer (RR=1.10, 95% CI 1.06-1.15) and of other cancers (RR=1.12, 1.08-1.15), but the RRs decreased significantly with increasing follow-up time (P=0.001 and P=0.01, respectively, for trend). Four or more years after baseline, there was no elevated risk of breast cancer (RR=1.00, 0.96-1.05), and only marginally greater risk of other cancers (RR=1.04, 1.01-1.07). The effect of pre-clinical disease is a likely explanation for the short-term increased risk of breast and other cancers associated with daytime napping. © 2012 Cancer Research UK

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

    Science.gov (United States)

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

    2017-02-09

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

  18. Concurrent progressive-ratio schedules: built-in controls in the study of delayed reward efficacy.

    Science.gov (United States)

    Jarmolowicz, David P; Hudnall, Jennifer L

    2014-08-15

    Delayed rewards maintain lower rates of operant responding than immediate rewards, and when given a choice between immediate and delayed rewards, individuals typically choose the immediate reward, even when it is smaller (a phenomenon called delay discounting). The behavioral and neural mechanisms underlying these behavioral patterns, however, are not conclusively understood. The present study developed a method to examine the efficacy of delayed rewards in a way that is suitable for pharmacological manipulation of delayed reward efficacy (while controlling for general changes in reward efficacy). The progressive ratio (PR) paradigm often used to examine reward efficacy was modified such that two PR schedules for lever pressing concurrently yet independently were presented. Across a series of conditions, a range of delays (3-81s) were arranged on one of the levers while the reward on the other lever remained immediate. PR breakpoints (the highest ratio completed on each lever, our measure of reward efficacy) systematically decreased on the delayed, but not on the immediate reward lever, suggesting that delays decreased reward efficacy. This decrease in breakpoint resulted in bias in within-session responding that was accounted for by models that adjusted reward value by the delay to that reward. Unlike the standard PR paradigm, the present arrangement provided the controls needed to differentiate delay specific from general changes in reward efficacy. The present method should be helpful in the study of the behavioral and neural mechanisms of delayed reward efficacy. Modifications of the present paradigm should be useful for pharmacological studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Developing Potential Candidates of Preclinical Preeclampsia

    Directory of Open Access Journals (Sweden)

    Sandra Founds

    2015-11-01

    Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    International Nuclear Information System (INIS)

    Wang, Weining; Iyer, N. Gopalakrishna; Tay, Hsien Ts’ung; Wu, Yonghui; Lim, Tony K. H.; Zheng, Lin; Song, In Chin; Kwoh, Chee Keong; Huynh, Hung; Tan, Patrick O. B.; Chow, Pierce K. H.

    2015-01-01

    Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long

  2. The New 3D Printed Left Atrial Appendage Closure with a Novel Holdfast Device: A Pre-Clinical Feasibility Animal Study.

    Directory of Open Access Journals (Sweden)

    M Brzeziński

    pericarditis or macroscopic signs of inflammation at the site of the device were found. All pigs were in good condition with normal weight gain and no other clinical symptoms.This novel 3D printed left atrial appendage closure technique with a novel holdfast device was proven to be safe and feasible in all pigs. A benign healing process without inflammation and damage to the surrounding structures or evidence of new thrombi formation was observed. Moreover, the uncomplicated survival and full LAA exclusion in all animals demonstrate the efficacy of this novel and relatively cheap device. Further clinical evaluation and implementation studies should be performed to introduce this new technology into clinical practice.

  3. Toward making the invisible visible: Studying science teaching self-efficacy beliefs

    Science.gov (United States)

    Perkins, Catherine J.

    This dissertation consists of two articles to be submitted for publication. The first, a literature review, makes visible common influences on science teaching self-efficacy beliefs and also points to potentially invisible validation concerns regarding the instrument used. The second investigates the participants' invisible science teaching self-efficacy beliefs and, through the use of a more focused interview, makes those beliefs visible. Science teaching self-efficacy beliefs are science teachers' perceptions of their abilities to teach science effectively. The construct "teaching self-efficacy" originated in social cognitive theory (Bandura, 1977). The first article reviews the mixed results from teaching self-efficacy research in science contexts. The review focuses upon factors that facilitate or inhibit the development of self-efficacy beliefs among science teachers across stages of their careers. Although many studies of science teaching self-efficacy beliefs have utilized the Science Teaching Efficacy Belief Instrument - STEBI (Enochs & Riggs, 1990; Riggs & Enochs, 1990), this review also includes non-STEBI studies in order to represent diverse lines of research methodology. The review's findings indicate that antecedent factors such as science activities in and out of school, teacher preparation, science teaching experiences and supportive job contexts are significant influences on the development of science teaching self-efficacy beliefs. The review also indicates that the majority of these studies are short term and rely on a single STEBI administration with the collection of antecedent/demographic and/or interview data. The second article documents a study that responded to the above literature review findings. This study utilized multiple STEBI administrations during the preservice and beginning year of teaching for two science teachers. Rather than general questions, these participants were asked item specific, yet open-ended, questions to determine

  4. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Shuhua Chen

    Full Text Available Previously, we demonstrated that allopregnanolone (APα promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD. In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R, three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing

  5. Series of selenoid valve pneumatic AC 220 volts with disposable contra angle as a replacement for micromotor in preclinic laboratory (experimental study on the health ministry of health polytechnic course D-III department of dental nursing Tasikmalaya

    Directory of Open Access Journals (Sweden)

    Hadiyat Miko

    2016-06-01

    Full Text Available To report on the essential performance characteristics of disposable air turbine handpiece and on aspect of their convenience and safety for preclinical use. The disposable handpiece is not recommended drilling in oral cavity. We use for student practical  in Operative Dentistry at preclinic laboratory. The other side micromotor low speed handpiece used as bur device on the phantom, the problem usually found in preclinik laboratory on practical conservation with the use of micromotor frequent damage to the handpiece (contra angel. Micromotor tend to heat up faster and have a low-speed, so it took a long time to complete the drilling, using the micromotor tend to be less safe because of the power generated from the flow of electricity at any time could damage. The price of  micromotor also is quite expensive. The limitations of the budget funds for maintenance, repair and procurement of mikromotor also became a problem. Based on these problems, the research team made a solution in the form of a replacement tool (substitute micromotor with the aim to resolve the existing problems as well as creating practices preclinic more effectively and efficiently. The use of a simple drill tool in the form of a series of Pneumatic Valve 220 volt (include electric compressor and Selenoid Disposible Handpiece Contra-angles as a new innovation in the laboratory of Dental Nursing. Majors preclinik Health Polytechnic Tasikmalaya  have been applied for last 3 years and have been able to more efficient cost of procurement tool of 70%. This disposible tool is apparently able to drill up to 20 times preparasicavity. This research uses descriptive method. Data collection techniques are used through the question form or questionnaire. Population and sample the study is a students collage 2nd years D-III of department of dental nursing Health Polytechnic Tasikmalaya. From the results of research that the majority of students expressed pleased and satisfied. This

  6. EFFICACY OF IBUPROFEN IN TREATMENT OF PAIN IN CHILDREN: SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED STUDIES

    Directory of Open Access Journals (Sweden)

    R.T. Saygitov

    2010-01-01

    Full Text Available The article presents results of systematic review of data on prophylactic and therapeutic efficacy of ibuprofen. Data search was performed by PubMed database and Google search. 27 publications for analysis were available. Prophylactic efficacy of ibuprofen was studied in 14 studies. Summarizing of the results showed that ibuprofen prevents pain and decreases its following intensity after different surgical or dental operations. There is no significant difference in prophylactic efficacy of single dose ibuprofen and acetaminophen. Therapeutic efficacy of ibuprofen was described in 13 studies. Administration of the drug for pain stopping in children is reasonable. The analgesic effect of ibuprofen compared to placebo was shown in all studies of patients with migraine and diseases of ENT-organs. 5 studies performed in last 5 years showed efficacy of ibuprofen in trauma patients, including children with non-complicated fractures of extremities.Key words: children, pain, ibuprofen, prophylaxis, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2010;9(6:52-62

  7. Self-efficacy and quality of life after low-intensity neuropsychological rehabilitation: A pre-post intervention study.

    Science.gov (United States)

    Brands, Ingrid; Custers, Maud; van Heugten, Caroline

    2017-01-01

    Being highly self-efficacious is a key factor in successful chronic disease self-management. It is unknown whether neuropsychological rehabilitation improves self-efficacy in managing the consequences of brain injury. To investigate whether levels of general and brain injury specific self-efficacy and quality of life (QoL) increased after neuropsychological rehabilitation and whether cognitive performance was associated with self-efficacy. We conducted a retrospective clinical cohort study of 62 patients with acquired brain injury and cognitive complaints with measurements before start and after completion of treatment. QoL was measured with the visual analogue scale (EQ VAS) of the EuroQol (EQ-5D); self-efficacy with the TBI Self-efficacy Questionnaire (SEsx) and the General Self-efficacy Scale (GSES). Cognitive performance was measured as a compound score of tests for memory, attention and information processing speed. Self-efficacy for managing brain injury-specific symptoms and QoL increased significantly after neuropsychological rehabilitation. Both general and brain injury-specific self-efficacy were positively associated with QoL after completion of the programme. Cognitive performance was not associated with self-efficacy for managing brain injury-specific symptoms nor with general self-efficacy. Self-efficacy and QoL improve after treatment. Further research is needed to identify the specific ingredients responsible for improvement of self-efficacy in patients with cognitive complaints.

  8. Outcomes of usual chiropractic, harm & efficacy, the ouch study: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Walker Bruce F

    2011-10-01

    Full Text Available Abstract Background Previous studies have demonstrated that adverse events occur during chiropractic treatment. However, because of these studies design we do not know the frequency and extent of these events when compared to sham treatment. The principal aims of this study are to establish the frequency and severity of adverse effects from short term usual chiropractic treatment of the spine when compared to a sham treatment group. The secondary aim of this study is to establish the efficacy of usual short term chiropractic care for spinal pain when compared to a sham intervention. Methods One hundred and eighty participants will be randomly allocated to either usual chiropractic care or a sham intervention group. To be considered for inclusion the participants must have experienced non-specific spinal pain for at least one week. The study will be conducted at the clinics of registered chiropractors in Western Australia. Participants in each group will receive two treatments at intervals no less than one week. For the usual chiropractic care group, the selection of therapeutic techniques will be left to the chiropractors' discretion. For the sham intervention group, de-tuned ultrasound and de-tuned activator treatment will be applied by the chiropractors to the regions where spinal pain is experienced. Adverse events will be assessed two days after each appointment using a questionnaire developed for this study. The efficacy of short term chiropractic care for spinal pain will be examined at two week follow-up by assessing pain, physical function, minimum acceptable outcome, and satisfaction with care, with the use of the following outcome measures: Numerical Rating Scale, Functional Rating Index, Neck Disability Index, Minimum Acceptable Outcome Questionnaire, Oswestry Disability Index, and a global measure of treatment satisfaction. The statistician, outcome assessor, and participants will be blinded to treatment allocation. Trial

  9. Astronomy Teaching Self-Efficacy Belief Scale: The Validity and Reliability Study

    Science.gov (United States)

    Demirci, Filiz; Ozyurek, Cengiz

    2018-01-01

    The purpose of this study is to develop a reliable and safe scale for determining the self-efficacy levels of science teachers in the teaching of astronomy subjects. The study used a survey approach, which is a qualitative research method. The study was conducted with a total of 106 science teachers working in the secondary schools of Ordu city…

  10. A Study on Physical Education Teachers: The Correlation between Self-Efficacy and Job Satisfaction

    Science.gov (United States)

    Yildirim, Irfan

    2015-01-01

    The aim of the study was to determine the correlation between self-efficacy and job satisfaction among the physical education teachers. The study was carried out in correlational survey model and the study sample was made up by 306 physical education teachers who worked in different geographical regions of Turkey. The data were assessed using SPSS…

  11. Lesson study: Professional development and its impact on science teacher self-efficacy

    Science.gov (United States)

    Roberts, Megan Rae

    This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal

  12. Multi-disciplinary data organization and visualization models for clinical and pre-clinical studies: A case study in the application of proton beam radiosurgery for treating spinal cord injury related pain

    Science.gov (United States)

    Verma, Sneha K.; Liu, Brent J.

    2016-03-01

    An increasing adoption of electronic medical records has made information more accessible to clinicians and researchers through dedicated systems such as HIS, RIS and PACS. The speed and the amount at which information are generated in a multi-institutional clinical study make the problem complicated compared to day-to-day hospital workflow. Often, increased access to the information does not translate into the efficient use of that information. Therefore, it becomes crucial to establish models which can be used to organize and visualize multi-disciplinary data. Good visualization in turn makes it easy for clinical decision-makers to reach a conclusion within a small span of time. In a clinical study involving multi-disciplinary data and multiple user groups who need access to the same data and presentation states based on the stage of the clinical trial or the task are crucial within the workflow. Therefore, in order to demonstrate the conceptual system design and system workflow, we will be presenting a clinical trial based on application of proton beam for radiosurgery which will utilize our proposed system. For demonstrating user role and visualization design purposes, we will be focusing on three different user groups which are researchers involved in patient enrollment and recruitment, clinicians involved in treatment and imaging review and lastly the principle investigators involved in monitoring progress of clinical study. Also datasets for each phase of the clinical study including preclinical and clinical data as it related to subject enrollment, subject recruitment (classifier), treatment (DICOM), imaging, and pathological analysis (protein staining) of outcomes.

  13. Stress, Burnout and Coping Strategies in Preclinical Medical Students

    Science.gov (United States)

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

    2016-01-01

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

  14. Stress, Burnout and Coping Strategies in Preclinical Medical Students.

    Science.gov (United States)

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

    2016-02-01

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

  15. Preliminary study of the efficacy of the combination of tamsulosin ...

    African Journals Online (AJOL)

    A.S. Abdelaziz

    2016-12-13

    day) and combinations of it with trospium .... Hence, we left with a total of. 126 patients: ..... symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int.

  16. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

    Science.gov (United States)

    Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J

    2016-01-01

    The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

  17. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

    Directory of Open Access Journals (Sweden)

    Pirow Bekker

    Full Text Available The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan, an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

  18. The Effect of Teacher's Assistance on Malaysian Rural L Writing Self-efficacy: A Case Study

    Directory of Open Access Journals (Sweden)

    Ilyana Jalaluddin

    2011-01-01

    Full Text Available The purpose of the study is to explore the Malaysian rural learners self-efficacy in writing after assistance given by a teacher. The social cognitive theory aid socio-cultural theory are used as the theoretical framework to pursue the discussion on the effects of teacher’s assistance on learners writing self-efficacy. A case study approach is adopted where three learners and a teacher were chosen from a form four class through purposive sampling. Learnei-s’ Titing self-efficacy is evaluated using a writing self-efficacy scale adapted from Bottomley. Henk and Melnick (1998 and also classroom observation. Wang and Pape (2007 categories were used as guidelines to analyze observation data in order to understand the participants self-efficacy phenomena in their learning to write. Overall, this study places a heavy emphasis on the perceptions and actions of the selected form four learners and teacher through non-participant classroom observations, interviews with each learner and teacher.

  19. The efficacy of the 'mind map' study technique.

    Science.gov (United States)

    Farrand, Paul; Hussain, Fearzana; Hennessy, Enid

    2002-05-01

    To examine the effectiveness of using the 'mind map' study technique to improve factual recall from written information. To obtain baseline data, subjects completed a short test based on a 600-word passage of text prior to being randomly allocated to form two groups: 'self-selected study technique' and 'mind map'. After a 30-minute interval the self-selected study technique group were exposed to the same passage of text previously seen and told to apply existing study techniques. Subjects in the mind map group were trained in the mind map technique and told to apply it to the passage of text. Recall was measured after an interfering task and a week later. Measures of motivation were taken. Barts and the London School of Medicine and Dentistry, University of London. 50 second- and third-year medical students. Recall of factual material improved for both the mind map and self-selected study technique groups at immediate test compared with baseline. However this improvement was only robust after a week for those in the mind map group. At 1 week, the factual knowledge in the mind map group was greater by 10% (adjusting for baseline) (95% CI -1% to 22%). However motivation for the technique used was lower in the mind map group; if motivation could have been made equal in the groups, the improvement with mind mapping would have been 15% (95% CI 3% to 27%). Mind maps provide an effective study technique when applied to written material. However before mind maps are generally adopted as a study technique, consideration has to be given towards ways of improving motivation amongst users.

  20. Comparison of non-HDL-cholesterol versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: the CARITALY study.

    Science.gov (United States)

    Di Bonito, P; Valerio, G; Grugni, G; Licenziati, M R; Maffeis, C; Manco, M; Miraglia del Giudice, E; Pacifico, L; Pellegrin, M C; Tomat, M; Baroni, M G

    2015-05-01

    Lipid ratios to estimate atherosclerotic disease risk in overweight/obese children are receiving great attention. We aimed to compare the performance of non-high-density lipoprotein-cholesterol (HDL-C) versus triglycerides-to-HDL-C ratio (Tg/HDL-C) in identifying cardiometabolic risk factors (CMRFs) or preclinical signs of organ damage in outpatient Italian overweight/obese children. In this retrospective, cross-sectional study, 5505 children (age 5-18 years) were recruited from 10 Italian centers for the care of obesity, of which 4417 (78%) showed obesity or morbid obesity. Anthropometric, biochemical, and blood pressure variables were analyzed in all children. Liver ultrasound scan, carotid artery ultrasound, and echocardiography were performed in 1257, 601, and 252 children, respectively. The entire cohort was divided based on the 75th percentile of non-HDL-C (≥130 mg/dl) or Tg/HDL-C ratio (≥2.2). The odds ratio for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increased levels of carotid intima-media thickness (cIMT) and concentric left ventricular hypertrophy (cLVH) was higher in children with high levels of Tg/HDL-C with respect to children with high levels of non-HDL-C. In an outpatient setting of overweight/obese children, Tg/HDL-C ratio discriminated better than non-HDL-C children with CMRFs or preclinical signs of liver steatosis, and increased cIMT and cLVH. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Longitudinal Study: Efficacy of Online Technology Tools for Instructional Use

    Science.gov (United States)

    Uenking, Michael D.

    2011-01-01

    Studies show that the student population (secondary and post secondary) is becoming increasingly more technologically savvy. Use of the internet, computers, MP3 players, and other technologies along with online gaming has increased tremendously amongst this population such that it is creating an apparent paradigm shift in the learning modalities of these students. Instructors and facilitators of learning can no longer rely solely on traditional lecture-based lesson formals. In order to achieve student academic success and satisfaction and to increase student retention, instructors must embrace various technology tools that are available and employ them in their lessons. A longitudinal study (January 2009-June 2010) has been performed that encompasses the use of several technology tools in an instructional setting. The study provides further evidence that students not only like the tools that are being used, but prefer that these tools be used to help supplement and enhance instruction.

  2. Legislature agrees to fund study of marijuana efficacy.

    Science.gov (United States)

    1999-10-01

    California could be the first State to conduct a research study on medical uses for marijuana under the "Medical Research Act of 1999". S.B. 847 would authorize a three-year program, administered by the University of California, to study which methods of ingesting marijuana are most effective in treating pain and side effects of treatments for AIDS, cancer, glaucoma and seizures. The sponsor of the bill, Sen. John Vasconcellos, initially wanted $1 million in annual funding, but the program will be funded through the normal appropriations process.

  3. Preclinical models for obesity research

    Directory of Open Access Journals (Sweden)

    Perry Barrett

    2016-11-01

    Full Text Available A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity.

  4. Ethical Considerations of Preclinical Testing

    Directory of Open Access Journals (Sweden)

    Allen Goldenthal

    2015-12-01

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

  5. Characteristics of caring self-efficacy in pediatric nurses: a qualitative study.

    Science.gov (United States)

    Alavi, Azam; Bahrami, Masoud; Zargham-Boroujeni, Ali; Yousefy, Alireza

    2015-07-01

    The present study was conducted to clarify pediatric nurses' characteristics of caring self-efficacy. This study was conducted using a qualitative content analysis approach. The participants included 27 pediatric nurses and clinical instructors, selected purposively. Data were collected using semi-structured interviews and were analyzed using the content analysis method. Data analysis generated four main themes as attributes of a self-efficient pediatric nurse including: (a) professional communications; (b) management of care; (c) altruism; and (d) proficiency. Nursing managers and instructors can use these results to help develop nurses' empowerment and self-efficacy, especially in pediatric care. © 2015, Wiley Periodicals, Inc.

  6. Flowing together : a longitudinal study of collective efficacy and collective flow among workgroups.

    NARCIS (Netherlands)

    Salanova, Marisa; Rodríguez-Sánchez, Alma M.; Schaufeli, Wilmar B.; Cifre, Eva

    2014-01-01

    The aim of this study is to extend the Channel Model of Flow (Csikszentmihalyi, 1975, 1990) at the collective level (workgroups) by including collective efficacy beliefs as a predictor of collective flow based on the Social Cognitive Theory (Bandura, 1997, 2001). A two-wave longitudinal lab study

  7. Testing the Efficacy of a Tier 2 Mathematics Intervention: A Conceptual Replication Study

    Science.gov (United States)

    Doabler, Christian T.; Clarke, Ben; Kosty, Derek B.; Kurtz-Nelson, Evangeline; Fien, Hank; Smolkowski, Keith; Baker, Scott K.

    2016-01-01

    The purpose of this closely aligned conceptual replication study was to investigate the efficacy of a Tier 2 kindergarten mathematics intervention. The replication study differed from the initial randomized controlled trial on three important elements: geographical region, timing of the intervention, and instructional context of the…

  8. The Interplay between Motivation, Self-Efficacy, and Approaches to Studying

    Science.gov (United States)

    Prat-Sala, Merce; Redford, Paul

    2010-01-01

    Background: The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. Aims: The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to…

  9. Textbook-Bundled Metacognitive Tools: A Study of LearnSmart's Efficacy in General Chemistry

    Science.gov (United States)

    Thadani, Vandana; Bouvier-Brown, Nicole C.

    2016-01-01

    College textbook publishers increasingly bundle sophisticated technology-based study tools with their texts. These tools appear promising, but empirical work on their efficacy is needed. We examined whether LearnSmart, a study tool bundled with McGraw-Hill's textbook "Chemistry" (Chang & Goldsby, 2013), improved learning in an…

  10. Value of 1.0-M gadolinium chelates: review of preclinical and clinical data on gadobutrol

    International Nuclear Information System (INIS)

    Tombach, Bernd; Heindel, Walter

    2002-01-01

    Several preclinical and clinical studies with the first commercially available highly concentrated Gd-chelate gadobutrol (1 mol/l) are reviewed. Physicochemical, pharmacological, and pharmacokinetic properties, safety analysis, as well as experimental and clinical efficacy studies are highlighted in comparison with 0.5-M Gd-chelates. The 1-mol gadobutrol has been proven to be safe in an examined dose range from 0.04 up to 0.5 mmol/kg body weight (b.w.). Even in patients with chronic renal impairment, including hemodialysis, gadobutrol can safely be applied at doses up to 0.3 mmol/kg b.w. For contrast-enhanced MRI in the equilibrium phase, efficacy data analysis shows comparable results to other commercially available extracellular Gd-chelates with lower Gd-concentrations (0.5 M). Studies focused on the potential benefit of a tighter bolus, such as brain perfusion imaging using T2*-effects, document the superiority of a highly concentrated Gd contrast agent. For contrast-enhanced MRA, clinical studies are still ongoing; therefore, the ultimate potential of a more compact bolus, using 1-M Gd-chelates, for contrast-enhanced MRI, has still to be analyzed, especially for time-resolved magnetic resonance angiography. (orig.)

  11. [Immunological and clinical study on therapeutic efficacy of inosine pranobex].

    Science.gov (United States)

    Gołebiowska-Wawrzyniak, Maria; Markiewicz, Katarzyna; Kozar, Agata; Derentowicz, Piotr; Czerwińska-Kartowicz, Iwona; Jastrzebska-Janas, Krystyna; Wacławek, Jolanta; Wawrzyniak, Zbigniew M; Siwińska-Gołebiowska, Henryka

    2005-09-01

    Many studies in vitro and in vivo have shown immunomodulating and antiviral activities of inosine pranobex. The object of this research was to examine the potential beneficial effects of inosine pranobex (Groprinosin) on immune system in children with cellular immunodeficiency as a prophylaxis of recurrent infections, mainly of viral origin. 50 mg/kg b.w/day of inosine pranobex in divided doses was given to the group of 30 children aged 3-15 years for 10 days in 3 following months. Clinical and immunological investigations were done before and after the treatment. Statistically significant rise of CD3T lymphocytes number (p = 0.02) and in this CD4T lymphocytes number (p = 0.02) as well as statistically significant improvement of their function (p = 0.005) evaluated with blastic transformation method were found. These laboratory findings were parallel to clinical benefits. Control study was performed in the group of children completed by randomization and treated in the same way with garlic (Alliofil).

  12. Efficacy study of multimedia rheumatoid arthritis patient education program.

    Science.gov (United States)

    Unk, Julie A; Brasington, Richard

    2014-07-01

    The research goal of improving patient adherence was assessed in this randomized controlled trial of the outcomes of a 15-min multimedia educational program when compared to educational literature for rheumatoid arthritis (RA) patients. One hundred eight RA patients from a Midwestern rheumatology outpatient clinic completed the self-reported Medication Adherence Questionnaire (MAQ), the Brief Illness Perception Questionnaire (BIPQ), and Health Assessment Questionnaire (HAQ) at baseline and 1 month after education. A paired samples t-test was use for data analyses to determine if there was a significant difference in the change between the groups at preintervention and 1-month postintervention. There were no significant differences in the scores between the two groups from pretest to posttest. Results from this study showed that medication adherence, illness perception, and disability were not improved by use of multimedia or the literature within 1 month. Findings from this research study showed that a short multimedia educational program is as effective as printed materials to educate patients with RA about their disease and treatment. However, neither multimedia nor literature affects medication adherence, illness perception, or disability as self-reported by patients with RA. ©2013 American Association of Nurse Practitioners.

  13. Efficacy of Arthroscopic Teaching Methods: A Prospective Randomized Controlled Study.

    Science.gov (United States)

    Robinson, Luke; Spanyer, Jonathon; Yenna, Zachary; Burchell, Patrick; Garber, Andrew; Riehl, John

    Arthroscopic education research recently has been focused on the use of skills labs to facilitate resident education and objective measure development to gauge technical skill. This study evaluates the effectiveness of three different teaching methods. Medical students were randomized into three groups. The first group received only classroom-based lecture. The second group received the same lecture and 28 minutes of lab-based hands-off arthroscopy instruction using a cadaver and arthroscopy setup. The final group received the same lecture and 7 minutes of hands-on arthroscopy instruction in the lab on a cadaver knee. The arthroscopic knee exam that followed simulated a diagnostic knee exam and subjects were measured on task completion and by the number of look downs. The number of look downs and the number of tasks completed did not achieve statistical significance between groups. Posttest survey results revealed that the hands-on group placed significantly more value on their educational experience as compared with the other two groups. (Journal of Surgical Orthopaedic Advances.

  14. Studies examining the efficacy of ankle foot orthoses should report activity level and mechanical evidence.

    Science.gov (United States)

    Harlaar, Jaap; Brehm, Merel; Becher, Jules G; Bregman, Daan J J; Buurke, Jaap; Holtkamp, Fred; De Groot, Vincent; Nollet, Frans

    2010-09-01

    Ankle Foot Orthoses (AFOs) to promote walking ability are a common treatment in patients with neurological or muscular diseases. However, guidelines on the prescription of AFOs are currently based on a low level of evidence regarding their efficacy. Recent studies aiming to demonstrate the efficacy of wearing an AFO in respect to walking ability are not always conclusive. In this paper it is argued to recognize two levels of evidence related to the ICF levels. Activity level evidence expresses the gain in walking ability for the patient, while mechanical evidence expresses the correct functioning of the AFO. Used in combination for the purpose of evaluating the efficacy of orthotic treatment, a conjunct improvement at both levels reinforces the treatment algorithm that is used. Conversely, conflicting outcomes will challenge current treatment algorithms and the supposed working mechanism of the AFO. A treatment algorithm must use relevant information as an input, derived from measurements with a high precision. Its result will be a specific AFO that matches the patient's needs, specified by the mechanical characterization of the AFO footwear combination. It is concluded that research on the efficacy of AFOs should use parameters from two levels of evidence, to prove the efficacy of a treatment algorithm, i.e., how to prescribe a well-matched AFO.

  15. Emotional energy, work self-efficacy, and perceived similarity during the Mars 520 study.

    Science.gov (United States)

    Solcová, Iva; Gushin, Vadim; Vinokhodova, Alla; Lukavský, Jirí

    2013-11-01

    The objective of the present research was to study the dynamics of changes in emotional energy, work self-efficacy and perceived similarity in the crew of the Mars 520 experimental study. The study comprised six volunteers, all men, between 27-38 yr of age (M = 32.16; SD = 4.99). The Mars 520 experimental study simulated all the elements of the proposed Mars mission that could be ground simulated, i.e., traveling to Mars, orbiting it, landing, and returning to Earth. During the simulation, measures of emotional energy, work self-efficacy, and perceived similarity were repeated every month. The data were analyzed using linear mixed effect models. Emotional energy, work self-efficacy, and perceived similarity gradually increased in the course of the simulation. There was no evidence for a so-called third quarter phenomenon (the most strenuous period of group isolation, psychologically, emotionally, and socially) in our data. On the contrary, work self-efficacy, emotional energy, and group cohesion (indexed here by the subject's perceived similarity to others) increased significantly in the course of the simulation, with the latter two variables showing positive growth in the group functioning.

  16. Influence of endodontic instrument-holder on sterilization efficacy. A pilot in-vitro study.

    Directory of Open Access Journals (Sweden)

    Angelo Carrizo

    2013-08-01

    Full Text Available Infection control is crucial in dentistry and various methods have been designed to assure its efficacy. However, little information exists regarding the influence it could have the instrument-holder of endodontic files. The aim of this research was to determine the influence of three instruments-holders on sterilization efficacy of endodontic files. Methods: A pilot in-vitro study. 60 endodontic files were contaminated by biomechanical preparation of extracted molars with periapical abscess, then processed according to the standard washing method. The endodontic files were divided into 3 groups (n=20 and assigned to 3 instrument-holders: Metallic box (MB, surgical gauze (SG and synthetic sponge (SS. Then, the files were packaged and sterilized by autoclaving (134°C/45min. Microbiological culture was performed in thioglycolate solution for each endodontic file (37ºC/5days. Results: The overall sterilization efficacy was 91.7%, 80% for MB, 100% for SS, and 95% for SG, with no statistically significant differences (p=0.06 between the groups. Conclusions: The lack of differences in the efficacy of sterilization may be due to the reduced sample; therefore, a full-size study is necessary to confirm this outcomes. The results of this study discourage the use of the MB as instrument-holder until a full-size study can confirm this data.

  17. Exercise Self-Efficacy and Perceived Wellness among College Students in a Basic Studies Course

    Science.gov (United States)

    Sidman, Cara L.; D'Abundo, Michelle Lee; Hritz, Nancy

    2009-01-01

    University basic studies courses provide a valuable opportunity for facilitating the knowledge, skills, and beliefs that develop healthy behaviors to last a lifetime. Belief in one's ability to participate in physical activity, exercise self-efficacy, is a psychological construct that has had a documented impact on physical activity. Although…

  18. Traditional-Aged College Juniors' Career Planning Self-Efficacy: A Case Study

    Science.gov (United States)

    Sherman, Dawn C.

    2012-01-01

    The purpose of this single-site case study was to explore and describe traditional-age college juniors' reports of self-efficacy (Bandura, 1997) regarding Career Planning (Barker & Kellen, 1998). More specifically, the career planning confidence levels of college juniors enrolled in a required career development course at a private business…

  19. Collaborative Curriculum Design to Increase Science Teaching Self-Efficacy: A Case Study

    NARCIS (Netherlands)

    Velthuis, C.H.; Fisser, Petra; Pieters, Julius Marie

    2015-01-01

    The purpose of this study was to establish whether participation in a teacher design team (TDT) is an effective way to increase the science teaching self-efficacy of primary school teachers who vary in their levels of experience and interest in science. A TDT is a group of at least 2 teachers from

  20. Collaborative Curriculum Design to Increase Science Teaching Self-Efficacy: A Case Study

    Science.gov (United States)

    Velthuis, Chantal; Fisser, Petra; Pieters, Jules

    2015-01-01

    The purpose of this study was to establish whether participation in a teacher design team (TDT) is an effective way to increase the science teaching self-efficacy of primary school teachers who vary in their levels of experience and interest in science. A TDT is a group of at least 2 teachers from the same or related subjects working together to…

  1. Safety and Efficacy of Ferric Carboxymaltose in Anemic Pregnant Women: A Retrospective Case Control Study

    NARCIS (Netherlands)

    Pels, Anouk; Ganzevoort, Wessel

    2015-01-01

    Background. Anemia during pregnancy is commonly caused by iron deficiency and can have severe consequences for both the mother and the developing fetus. The aim of this retrospective study was to assess the safety and efficacy of intravenous ferric carboxymaltose (FCM) in pregnant women. Methods.

  2. Bullying Behaviors and Self Efficacy among Nursing Students at Clinical Settings: Comparative Study

    Science.gov (United States)

    Kassem, Awatef Hassan

    2015-01-01

    Background: Nursing students who experienced bullying behaviors feel anger and missing their concentration, their capability to achieve a desired outcome. Also self-efficacy, often referred to as self-confidence, is essential to nursing students' ability and performance in the clinical setting. Aim: Study aimed to examine relation between bullying…

  3. Spinal cord stimulation in chronic intractable angina pectoris : A randomized, controlled efficacy study

    NARCIS (Netherlands)

    Hautvast, RWM; DeJongste, MJL; Staal, MJ; van Gilst, WH; Lie, KI

    1998-01-01

    Background Spinel cord stimulation is known to be a successful treatment for chronic intractable angina pectoris. its effect may be anti-ischemic. It is uncertain if the clinical effect is partly caused by a placebo effect of surgery For implantation of a stimulator. In this study, clinical efficacy

  4. L2 Motivational Self-System and Self-Efficacy: A Quantitative Survey-Based Study

    Science.gov (United States)

    Roshandel, Javad; Ghonsooly, Behzad; Ghanizadeh, Afsaneh

    2018-01-01

    The present study explored English as a foreign language (EFL) students' motivation and self-efficacy. This is accomplished by incorporating the ten subfactors of L2 motivational self-system namely; criterion measures, ideal L2 self, ought-to L2 self, family influence, instrumentality promotion, instrumentality prevention, attitudes towards…

  5. A Cross-Cultural Study of CKCM Efficacy in an Undergraduate Chemistry Classroom

    Science.gov (United States)

    Çalik, Muammer; Cobern, William W.

    2017-01-01

    The aim of this study was to cross-culturally investigate the instructional efficacy of the Common Knowledge Construction Model (CKCM) with college students learning about "factors affecting solubility" focusing on students' conceptual understanding, attitudes and scientific habits of mind. Even though the CKCM is a decade old, there has…

  6. Practice, efficacy, and costs of thyroid nodule evaluation: a retrospective study in a Dutch university hospital

    NARCIS (Netherlands)

    Hooft, Lotty; Hoekstra, Otto S.; Boers, Maarten; van Tulder, Maurits W.; van Diest, Paul; Lips, Paul

    2004-01-01

    Fine-needle aspiration (FNA) of thyroid nodules has markedly reduced the role of thyroid scintigraphy. This is often limited to nondiagnostic or follicular (tumor) FNA classifications. In this study, we evaluated the efficacy and cost of such a strategy in a university center. From 1992-1998, 995

  7. Math and Science Pursuits: A Self-Efficacy Intervention Comparison Study

    Science.gov (United States)

    Cordero, Elizabeth D.; Porter, Sarah H.; Israel, Tania; Brown, Michael T.

    2010-01-01

    This study compared two interventions to increase math self-efficacy among undergraduate students. Ninety-nine first-year undergraduate students participated in an intervention involving performance accomplishment or an intervention combining performance accomplishment and belief-perseverance techniques in which participants constructed a…

  8. Comparative Study on the Efficacy of Two Regimens of Single-Shot ...

    African Journals Online (AJOL)

    Objective: To assess and compare the satisfaction and efficacy of two regimens of single-shot spinal blocks for the relief of labor pain in women who present in active phase of labour. Design: A prospective randomised single-blind observational study. Setting: Labour ward of Kenyatta National Hospital, Nairobi. Subjects: All ...

  9. A Quantitative Study Examining Teacher Stress, Burnout, and Self-Efficacy

    Science.gov (United States)

    Stephenson, Timar D.

    2012-01-01

    The purpose of this quantitative, correlational study was to examine the relationships between stress, burnout, and self-efficacy in public school teachers in the Turks and Caicos Islands. The Teacher Stress Inventory was used to collect data on teacher stress, the Maslach Burnout Inventory Educators Survey was used to obtain data on teacher…

  10. Researching Learner Self-Efficacy and Online Participation through Speech Functions: An Exploratory Study

    Science.gov (United States)

    Sánchez-Castro, Olga; Strambi, Antonella

    2017-01-01

    This study explores the potential contribution of Eggins and Slade's (2004) Speech Functions as tools for describing learners' participation patterns in Synchronous Computer-Mediated Communication (SCMC). Our analysis focuses on the relationship between learners' self-efficacy (i.e. personal judgments of second language performance capabilities)…

  11. A Correlational Study of iPad Efficacy and 21st Century Teaching among Elementary School Teachers

    Science.gov (United States)

    Shultz, Christopher F.

    2017-01-01

    This study was a longitudinal correlational study that applied the quantitative methodology of bi-variate correlation as well as a paired-samples "t"-test to the data. The purpose was to study the nature of the relationship between iPad efficacy, 21st century teaching, teacher efficacy, and teacher characteristics. The study also…

  12. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

    Science.gov (United States)

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-09-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  13. Targeted therapies for non-small-cell lung cancer: biology, rationale, and preclinical results from a radiation oncology perspective

    International Nuclear Information System (INIS)

    Raben, David; Helfrich, Barb; Bunn, Paul A.

    2004-01-01

    The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small-cell lung cancers (NSCLCs). This presents an opportune target for new treatment strategies designed to selectively interfere with the cancer cell growth cycle. Recent investigations into the biology of the EGFR and its downstream signaling pathways have reminded us of the complexity of cancer cell communications from the cytoplasm to the nucleus. Multiple pathways are activated with stimulation of the autocrine and paracrine EGFR loop, from the ras-raf-MEK activation of ERK 1/2 to the P13K-Akt pathway, each playing an important role in cancer cell survival, invasion, and angiogenesis. Preclinical studies have demonstrated that molecules targeting the EGFR, either through extracellular blockade or intracellular interference with the EGFR-associated tyrosine kinase, reversibly or irreversibly, inhibit cancer cell growth. Potent antitumor effects have been observed in human tumor xenograft models. Preclinical studies have also demonstrated cooperative effects when anti-EGFR agents are combined with radiation or chemotherapy. Many of these agents have now entered into advanced human clinical trials with modest dose-related toxicity despite chronic administration. Encouraging response rates with single-agent targeted therapy have been reported in heavily pretreated patients with advanced NSCLC. In addition, agents targeting the angiogenic pathway, which plays a key role in the regulation of angiogenesis, may play an important role in enhancing the efficacy of anti-EGFR agents. This article will focus on the biology, rationale, and preclinical studies with targeted anti-EGFR and antiangiogenic therapies for the management of NSCLC

  14. To evaluate the efficacy of biodegradable plating system for fixation of maxillofacial fractures: A prospective study

    OpenAIRE

    Bali, Rishi K.; Sharma, Parveen; Jindal, Shalu; Gaba, Shivani

    2013-01-01

    Aims: The present study was undertaken to evaluate the efficacy of biodegradable plating system for fixation of maxillofacial fractures and to study the morbidity associated with the use of biodegradable plates and screws. Materials and Methods: This prospective study consisted of 10 patients with maxillofacial fractures requiring open reduction and internal fixation. Fractures with infection, comminuted and pathological fractures were excluded. All were plated with biodegradable system (Inio...

  15. Does self-efficacy causally influence initial smoking cessation? An experimental study.

    Science.gov (United States)

    Shadel, William G; Martino, Steven C; Setodji, Claude; Cervone, Daniel; Witkiewitz, Katie

    2017-10-01

    Self-efficacy has been associated with smoking cessation outcomes in many correlational research studies, but strong causal inferences are lacking. This study tested whether self-efficacy affects initial smoking cessation in a laboratory experiment, which will allow for stronger causal inferences in this domain of inquiry. Participants (n=103 motivated adult smokers) were provided with brief cessation treatment over three days in preparation for quitting on a target quit day (TQD). In addition, participants were randomized to one of two standard self-efficacy manipulations in the form of bogus feedback about their chances of quitting smoking. Participants in the Average Chances of Quitting (ACQ) condition took a computerized test and were told (falsely) that the test showed that they had the same chances of quitting as everyone else in the study. Participants in the High Chances of Quitting (HCQ) condition took the same computerized test and were told (falsely) that the test showed that they had a greater chance of quitting compared to everyone else in the study. The main outcome was whether participants were able to quit for 24h on the TQD. Results revealed that HCQ participants had a significantly greater chance of quitting smoking compared to ACQ participants. However, these effects were not attributable to changes in self-efficacy brought about by the manipulation. An exploration of other potential mediators showed that the manipulation actually influenced smoking outcome expectancies, and changes in these outcome expectancies influenced initial smoking cessation. The results highlight the conceptual and empirical challenges with manipulating self-efficacy in the smoking literature. Copyright © 2017. Published by Elsevier Ltd.

  16. Efficacy of afoxolaner in a clinical field study in dogs naturally infested with Sarcoptes scabiei.

    Science.gov (United States)

    Beugnet, Frédéric; de Vos, Christa; Liebenberg, Julian; Halos, Lénaïg; Larsen, Diane; Fourie, Josephus

    2016-01-01

    The acaricidal efficacy of afoxolaner (NexGard(®), Merial) was evaluated against Sarcoptes scabiei var. canis in a field efficacy study, when administered orally at a minimum dose of 2.5 mg/kg to dogs naturally infested with the mites. Twenty mixed-breed dogs of either sex (6 males and 14 females), aged over 6 months and weighing 4-18 kg, were studied in this randomised controlled field efficacy trial. Dogs, naturally infested with Sarcoptes scabiei var. canis confirmed by skin scrapings collected prior to allocation, were randomly divided into two equal groups. Dogs in Group 1 were not treated. Dogs in Group 2 were treated on Days 0 and 28. On Days 0 (pre-treatment), 28 (pre-treatment) and 56, five skin scrapings of similar size were taken from different sites with lesions suggestive of sarcoptic mange. The extent of lesions was also recorded on Days 0, 28 and 56, and photographs were taken. Dogs treated orally with afoxolaner had significantly (p dogs at these times (100% efficacy based on mite counts). In addition, dogs treated with NexGard had significantly (p dog showed pruritus compared to 7/10 dogs in the control group, 1/9 treated dogs had crusts compared to 5/10 controls and 8/9 dogs recovered 90% of hairs on lesions compared to 0/10 control dogs. © F. Beugnet et al., published by EDP Sciences, 2016.

  17. The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

    Science.gov (United States)

    Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

    2017-07-01

    Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. The effect of a self-efficacy-based educational programme on maternal breast feeding self-efficacy, breast feeding duration and exclusive breast feeding rates: A longitudinal study.

    Science.gov (United States)

    Chan, Man Yi; Ip, Wan Yim; Choi, Kai Chow

    2016-05-01

    breast feeding has a number of well-documented benefits. Numerous studies have been conducted to investigate an effective approach to increase the breast feeding rate, duration and exclusive breast feeding rate, in which maternal breast feeding self-efficacy was determined as one of the major contributors. Although numerous breast feeding educational programmes have been developed to enhance maternal breastfeeding self-efficacy, results on the effectiveness of these programmes remain inconclusive. this study aims to investigate the effectiven