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Sample records for early preclinical studies

  1. 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

  2. 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.

  3. 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

  4. 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.'

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. Alcohol, psychomotor-stimulants and behaviour: methodological considerations in preclinical models of early-life stress.

    Science.gov (United States)

    McDonnell-Dowling, Kate; Miczek, Klaus A

    2018-04-01

    In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic.

  10. 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.

  11. Impact of a Comprehensive Early Clinical Exposure Program for Preclinical Year Medical Students

    Directory of Open Access Journals (Sweden)

    Sumitra Govindarajan

    2018-06-01

    Full Text Available Purpose: To study the impact of an early clinical exposure program designed to provide a wide variety (cognitive, affective and psychomotor of learning experiences for the preclinical year students. Method: One hundred and fifty preclinical students were posted in small groups to selected departments – Transfusion medicine, Catheterization lab, Simulation lab, Radiology, Neurology, Nephrology, Respiratory medicine and General surgery. Each student had atleast ten hours  of clinical exposure under this program. The program was evaluated through a series of pre and post-test questionnaires, which were designed based on the learning objectives of each session. Students who wished to participate in the program evaluation gave informed consent, took up the pre / post test and were also asked to give their written open comments about the program. Results: There was a significant increase in the post-test scores (ranging from 9.14±2.67 to 36.65±6.62 when compared to the pre-test scores (ranging from 7.94±2.31 to 28.69±6.11 for all the sessions (p value <0.001, n=144. Analysis of the open feedback showed that the program had significant impact on the cognitive, psychomotor and affective domains. “Application of basic sciences in clinical practice”, “motivation to learn”, “got familiar with various specialties”, “insight about what the patient undergoes” were the themes identified from the open comments. Conclusion: The innovative use of early clinical exposure program to teach/learn clinical skills like phlebotomy and Basic Life Support had been well appreciated by the students. The present design involving a variety of learning experiences has been successful in introducing the various dimensions of medical profession like scientific, ethical, interpersonal, professional and social to the new entrants in addition to enhancing their motivation to learn. Keywords: Attitude, Learning, Simulation lab, Medical education, Curriculum

  12. 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

  13. 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)

  14. 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.

  15. Neurosurgery Elective for Preclinical Medical Students: Early Exposure and Changing Attitudes.

    Science.gov (United States)

    Zuckerman, Scott L; Mistry, Akshitkumar M; Hanif, Rimal; Chambless, Lola B; Neimat, Joseph S; Wellons, John C; Mocco, J; Sills, Allen K; McGirt, Matthew J; Thompson, Reid C

    2016-02-01

    Exposure to surgical subspecialties is limited during the preclinical years of medical school. To offset this limitation, the authors created a neurosurgery elective for first- and second-year medical students. The objective was to provide each student with early exposure to neurosurgery by combining clinical experience with faculty discussions about the academic and personal realities of a career in neurosurgery. From 2012 to 2013, the authors offered a neurosurgery elective course to first- and second-year medical students. Each class consisted of the following: 1) peer-reviewed article analysis; 2) student presentation; 3) faculty academic lecture; 4) faculty personal lecture with question and answer period. Thirty-five students were enrolled over a 2-year period. After completing the elective, students were more likely to: consider neurosurgery as a future career (P life to be higher (P life, and family-work balance, while not altering the students' views about the difficulty of training. Adopting a neurosurgery elective geared towards preclinical medical students can significantly change attitudes about the field of neurosurgery and has potential to increase interest in pursuing a career in neurosurgery. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

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

    Science.gov (United States)

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

    2016-10-01

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

  2. 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.

  3. 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.

  4. 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.

  5. 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)

  6. 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.

  7. 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.

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

    Science.gov (United States)

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

    2010-02-01

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

  9. 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.

  10. Preclinical stress research: where are we headed? An early career investigator's perspective.

    Science.gov (United States)

    Gururajan, Anand; Kos, Aron; Lopez, Juan Pablo

    2018-03-07

    Stress is a major risk factor in the development of various psychiatric disorders such as depression, anxiety and post-traumatic stress disorder. The use of stress paradigms in preclinical contexts is essential to advance our understanding of the pathophysiology of these disorders. However, they are not without their limitations and in this commentary, we have examined some of the practical issues associated with their use. We also highlight some of the latest techniques to identify their neuromolecular correlates as well as the potentially important and integrative role of computational neuroscience. Finally, we share our perspective on future directions in the field of preclinical stress research.

  11. 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.

  12. 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.

  13. Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

    Science.gov (United States)

    Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

    2017-02-01

    Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  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. Preclinical Immunomodulation by the Probiotic Bifidobacterium breve M-16V in Early Life.

    Science.gov (United States)

    Rigo-Adrover, Maria Del Mar; Franch, Àngels; Castell, Margarida; Pérez-Cano, Francisco José

    2016-01-01

    This study aimed to investigate the effect of supplementation with the probiotic Bifidobacterium breve M-16V on the maturation of the intestinal and circulating immune system during suckling. In order to achieve this purpose, neonatal Lewis rats were supplemented with the probiotic strain from the 6th to the 18th day of life. The animals were weighed during the study, and faecal samples were obtained and evaluated daily. On day 19, rats were euthanized and intestinal wash samples, mesenteric lymph node (MLN) cells, splenocytes and intraepithelial lymphocytes (IEL) were obtained. The probiotic supplementation in early life did not modify the growth curve and did not enhance the systemic immune maturation. However, it increased the proportion of cells bearing TLR4 in the MLN and IEL, and enhanced the percentage of the integrin αEβ7+ and CD62L+ cells in the MLN and that of the integrin αEβ7+ cells in the IEL, suggesting an enhancement of the homing process of naïve T lymphocytes to the MLN, and the retention of activated lymphocytes in the intraepithelial compartment. Interestingly, B. breve M-16V enhanced the intestinal IgA synthesis. In conclusion, supplementation with the probiotic strain B. breve M-16V during suckling improves the development of mucosal immunity in early life.

  2. Preclinical Immunomodulation by the Probiotic Bifidobacterium breve M-16V in Early Life.

    Directory of Open Access Journals (Sweden)

    Maria Del Mar Rigo-Adrover

    Full Text Available This study aimed to investigate the effect of supplementation with the probiotic Bifidobacterium breve M-16V on the maturation of the intestinal and circulating immune system during suckling. In order to achieve this purpose, neonatal Lewis rats were supplemented with the probiotic strain from the 6th to the 18th day of life. The animals were weighed during the study, and faecal samples were obtained and evaluated daily. On day 19, rats were euthanized and intestinal wash samples, mesenteric lymph node (MLN cells, splenocytes and intraepithelial lymphocytes (IEL were obtained. The probiotic supplementation in early life did not modify the growth curve and did not enhance the systemic immune maturation. However, it increased the proportion of cells bearing TLR4 in the MLN and IEL, and enhanced the percentage of the integrin αEβ7+ and CD62L+ cells in the MLN and that of the integrin αEβ7+ cells in the IEL, suggesting an enhancement of the homing process of naïve T lymphocytes to the MLN, and the retention of activated lymphocytes in the intraepithelial compartment. Interestingly, B. breve M-16V enhanced the intestinal IgA synthesis. In conclusion, supplementation with the probiotic strain B. breve M-16V during suckling improves the development of mucosal immunity in early life.

  3. Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Daniel Rial

    Full Text Available There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/- to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination, anxiety (elevated plus-maze, depressive-like behavior (forced swimming and tail suspension and motor function (rotarod, grasping strength and pole. However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP. These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.

  4. Microbeam evolution: From single cell irradiation to preclinical studies

    DEFF Research Database (Denmark)

    Ghita, Mihaela; Fernandez-Palomo, Cristian; Fukunaga, Hisanori

    2018-01-01

    Purpose: This review follows the development of microbeam technology from the early days of single cell irradiations, to investigations of specific cellular mechanisms and to the development of new treatment modalities in vivo. A number of microbeam applications are discussed with a focus on prec...... to deliver radiotherapy using plane parallel microbeams, in Microbeam Radiotherapy (MRT)....

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Doppler Ultrasound Detection of Preclinical Changes in Foot Arteries in Early Stage of Type 2 Diabetes

    International Nuclear Information System (INIS)

    Leoniuk, Jolanta; Łukasiewicz, Adam; Szorc, Małgorzata; Sackiewicz, Izabela; Janica, Jacek; Łebkowska, Urszula

    2014-01-01

    There are few reports regarding the changes within the vessels in the initial stage of type 2 diabetes. The aim of this study was to estimate the hemodynamic and morphological parameters in foot arteries in type 2 diabetes subjects and to compare these parameters to those obtained in a control group of healthy volunteers. Ultrasound B-mode, color Doppler and pulse wave Doppler imaging of foot arteries was conducted in 37 diabetic patients and 36 non-diabetic subjects to determine their morphological (total vascular diameter and flow lumen diameter) and functional parameters (spectral analysis). In diabetic patients, the overall vascular diameter and wall thickness were statistically significantly larger when compared to the control group in the right dorsalis pedis artery (P=0.01; P=0.001), left dorsalis pedis artery (P=0.007; P=0.006), right posterior tibial artery (P=0.005; P=0.0005), and left posterior tibial artery (P=0.007; P=0.0002). No significant differences were observed in both groups in flow lumen diameters and blood flow parameters (PSV, EDV, PI, RI). In the diabetic group, the level of HbA1c positively correlated with flow resistance index in the right dorsalis pedis artery (r=0.38; P=0.02), right posterior tibial artery (r=0.38; P=0.02) and left posterior tibial artery (r=0.42; P=0.009). The pulsatility index within the dorsalis pedis artery decreased with increased trophic skin changes (r=–0.431, P=0.009). In the diabetic group, overall artery diameters larger than and flow lumina comparable to the control group suggest vessel wall thickening occurring in the early stage of diabetes. Doppler flow parameters are comparable in both groups. In the diabetic group, the level of HbA1c positively correlated with flow resistance index and negative correlation was observed between the intensity of trophic skin changes and the pulsatility index

  14. 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...

  15. 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.

  16. 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)

  17. 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.

  18. Cocoa Diet and Antibody Immune Response in Preclinical Studies

    Directory of Open Access Journals (Sweden)

    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.

  19. 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

  20. 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.

  1. 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.

  2. 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.)

  3. 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...

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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...

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  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. 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.

  16. Content of Diabetes-Associated Autoantibodies against Islet Autoantigens (IA-2A, GADA, IAA and the Level of Different Cytokines in Children and Adolescents on the Pre-Clinical and Early Clinical Stages of Type 1 Diabetes Mellitus Development

    Directory of Open Access Journals (Sweden)

    V.V. Popova

    2015-03-01

    Full Text Available The article provides the data on the immunological mechanisms of type 1 diabetes mellitus (T1DM on the preclinical and early clinical stages of disease formation on the basis of studying the features of T1DM pathogenesis, monitoring the process of autoimmune destruction of insulin-producing β-cells by determining the content of diabetes-associated auto-antibodies (the incidence and titers dynamics, the study of the characteristics of cytokine secretion on the pre-clinical stage of T1DM development in children and adolescents. Introduction of new approaches to pre-clinical diagnosis of T1DM allowed determine the group of marker-positive children with burdened heredity and predictable risk of disease development. The study involved 450 healthy normoglycemic children and adolescents aged from 7 to 15 years old. It was revealed that 94 (26.7 % of 366 children with burdened hereditary by at least two-fold determination of DAAb had an increased DAAb titer, mainly GADA and IA-2A, the clinical debut of T1DM manifested in 49 (52.1 % of them from 6 months to 12 years (30.9 ± 3.2 months. T1DM developed in the same period in a child, that was 0.8 % of the 272 (73.3 % DAAb-negative children. There was determined a formula of combined incidence and values of simultaneously elevated DAAb titers to islet autoantigens, namely IA-2A + GADA, which are predictor of the duration of T1DM pre-clinical stage and debut occurrence. It has been also established a disturbance of cytokine production (increased level of pro-inflammatory cytokines IL-1α, IL-6 and FNO-α, IL-8 and IL-16 while reduced concentration of IL-4 in blood plasma as a key factor in the T1DM pathogenesis that causes the debut occurrence, and aggressiveness of its course.

  17. 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.

  18. 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.

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

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    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.

  20. 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.

  1. 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.

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

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    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.

  3. 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

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

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    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

  5. Horizontal integration of OMIM across the medical school preclinical curriculum for early reinforcement of clinical genetics principles.

    Science.gov (United States)

    Diehl, Adam C; Reader, Lauren; Hamosh, Ada; Bodurtha, Joann N

    2015-02-01

    With the relentless expansion of genetics into every field of medicine, stronger preclinical and clinical medical student education in genetics is needed. The explosion of genetic information cannot be addressed by simply adding content hours. We proposed that students be provided a tool to access accurate clinical information on genetic conditions and, through this tool, build life-long learning habits to carry them through their medical careers. Surveys conducted at the Johns Hopkins University School of Medicine revealed that medical students in all years lacked confidence when approaching genetic conditions and lacked a reliable resource for accurate genetic information. In response, the school created a horizontal thread that stretches across the first-year curriculum and is devoted to teaching students how to use Online Mendelian Inheritance in Man (OMIM) (http://omim.org) and the databases to which it links as a starting point for approaching genetic conditions. The thread improved the first-year students' confidence in clinical genetics concepts and encouraged use of OMIM as a primary source for genetic information. Most students showed confidence in OMIM as a learning tool and wanted to see the thread repeated in subsequent years. Incorporating OMIM into the preclinical curriculum improved students' confidence in clinical genetics concepts.

  6. 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.

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

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    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.

  8. 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

  9. 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

  10. 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

  11. 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?

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Maximilian Richter

    2016-01-01

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

  11. 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.

  12. 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.

  13. 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...

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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)

  20. 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.

  1. 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...

  2. Early Life Stress and Sleep Restriction as Risk Factors in PTSD: An Integrative Pre-Clinical Approach

    Science.gov (United States)

    2012-04-01

    Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats. Brain Res. 922(2):250-60...to SR or SRcont, are exposed to the UWT that serves as an ’ Adult -Stress’. Two hours following the UWT, blood samples are taken from all rats’ tail and...exposure to the ’ Adult -stress’. In order to evaluate the chronic response to an ’ adult -stress’, an additional assessment of the animals’ behavioral

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. Uganda Early Generation Seed Study

    NARCIS (Netherlands)

    Mastenbroek, A.; Ntare, Bonny

    2016-01-01

    One of the major bottlenecks limiting farmers’ access to good quality seed for food crops in Uganda is the shortage of early generation seed (EGS - breeder and foundation) to produce sufficient quantities of certified and/or quality declared) to satisfy the needs of farmers. A national study was

  12. 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

  13. 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)

  14. 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.

  15. [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.

  16. 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

  17. [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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. The importance of being social : preclinical studies on social development, cognitive control and drug addiction

    NARCIS (Netherlands)

    Baarendse, P.J.J.

    2012-01-01

    Marked developmental changes in social behavior take place during youth, including increased complexity of the social repertoire and dramatic increment of peer-directed social interactions. Social experiences early in life are of major importance for proper behavioral development and create valuable

  7. [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

  8. 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

  9. 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/.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

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

    NARCIS (Netherlands)

    Xie, Tianwu; Zaidi, Habib

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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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

  4. 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.

  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. 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

  7. 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.

  8. 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)

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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...

  19. 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.

  20. 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...

  1. 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.

  2. 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

  3. 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)

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. A Preclinical Assessment of Early Continuous Passive Motion and Treadmill Therapeutic Exercises for Generating Chondroprotective Effects After Anterior Cruciate Ligament Rupture.

    Science.gov (United States)

    Chang, Nai-Jen; Lee, Kuan-Wei; Chu, Chih-Jou; Shie, Ming-You; Chou, Pei-Hsi; Lin, Chih-Chan; Liang, Peir-In

    2017-08-01

    Anterior cruciate ligament (ACL) injury is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA). However, whether using continuous passive motion (CPM) with or without additional treadmill exercise (TRE) in early ACL injury might provide chondroprotective effects and further decrease the risk of PTOA has yet to be determined. CPM may offer an enhanced chondroprotective effect, but TRE may attenuate that effect due to the mechanical stress on the joint and inflammatory cytokines in the joint. Controlled laboratory study. Thirty adult New Zealand White male rabbits were randomly allocated to sedentary (SED), CPM, TRE, or CPM+TRE groups. Each rabbit underwent an ACL transection (ACLT) on the right knee, with the contralateral knee used as an internal control (sham). The 4 joint surfaces (ie, medial and lateral femoral condyles and tibial plateaus) were evaluated 4 weeks after surgery for gross appearance, histological characteristics, and quantitative osteoarthritis (OA) scores. Overall, at the end of testing, the CPM group experienced the best protective therapeutic effects in all compartments. In gross appearance, CPM resulted in normal articular surfaces, while the TRE and SED groups exhibited surface abrasion. Histological analysis showed significant differences in articular cartilage status. The CPM group had significantly better histological OA scores ( P CPM+TRE group displayed visible pathological changes in the superficial cartilage, indicating that early loading exercise may contribute to osteoarthritis. The sham treatment showed no difference in the changes in all compartments between groups. Immediate CPM therapy produces a superior in situ microenvironment for reducing the occurrence of PTOA after ACL injury without reconstruction in rabbits. These data suggest that immediate application of CPM therapy may be necessary to create a sound microenvironment in joints and possibly to decrease the risk of PTOA without or while

  7. 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.

  8. 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.

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

    Science.gov (United States)

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

    2018-03-30

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

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

    Science.gov (United States)

    Kim, Soonih

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-01-15

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

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

    Science.gov (United States)

    Xie, Tianwu; Zaidi, Habib

    2016-01-01

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

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

    International Nuclear Information System (INIS)

    Xie, Tianwu; Zaidi, Habib

    2016-01-01

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

  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. 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

  16. 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.

  17. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

    Science.gov (United States)

    Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

    2017-10-03

    To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

  18. Dual-energy computed tomography for the assessment of early treatment effects of regorafenib in a preclinical tumor model: comparison with dynamic contrast-enhanced CT and conventional contrast-enhanced single-energy CT

    International Nuclear Information System (INIS)

    Knobloch, Gesine; Hamm, Bernd; Jost, Gregor; Pietsch, Hubertus; Huppertz, Alexander

    2014-01-01

    The potential diagnostic value of dual-energy computed tomography (DE-CT) compared to dynamic contrast-enhanced CT (DCE-CT) and conventional contrast-enhanced CT (CE-CT) in the assessment of early regorafenib treatment effects was evaluated in a preclinical setting. A rat GS9L glioma model was examined with contrast-enhanced dynamic DE-CT measurements (80 kV/140 kV) for 4 min before and on days 1 and 4 after the start of daily regorafenib or placebo treatment. Tumour time-density curves (0-240 s, 80 kV), DE-CT (60 s) derived iodine maps and the DCE-CT (0-30 s, 80 kV) based parameters blood flow (BF), blood volume (BV) and permeability (PMB) were calculated and compared to conventional CE-CT (60 s, 80 kV). The regorafenib group showed a marked decrease in the tumour time-density curve, a significantly lower iodine concentration and a significantly lower PMB on day 1 and 4 compared to baseline, which was not observed for the placebo group. CE-CT showed a significant decrease in tumour density on day 4 but not on day 1. The DE-CT-derived iodine concentrations correlated with PMB and BV but not with BF. DE-CT allows early treatment monitoring, which correlates with DCE-CT. Superior performance was observed compared to single-energy CE-CT. circle Regorafenib treatment response was evaluated by CT in a rat tumour model. (orig.)

  19. A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies.

    Science.gov (United States)

    Ngen, Ethel J; Wang, Lee; Gandhi, Nishant; Kato, Yoshinori; Armour, Michael; Zhu, Wenlian; Wong, John; Gabrielson, Kathleen L; Artemov, Dmitri

    2016-06-01

    Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.

  20. Dual-energy computed tomography for the assessment of early treatment effects of regorafenib in a preclinical tumor model: comparison with dynamic contrast-enhanced CT and conventional contrast-enhanced single-energy CT

    Energy Technology Data Exchange (ETDEWEB)

    Knobloch, Gesine; Hamm, Bernd [Charite - Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany); Jost, Gregor; Pietsch, Hubertus [Bayer Healthcare, MR and CT Contrast Media Research, Berlin (Germany); Huppertz, Alexander [Imaging Science Institute Charite - Siemens, Berlin (Germany)

    2014-08-15

    The potential diagnostic value of dual-energy computed tomography (DE-CT) compared to dynamic contrast-enhanced CT (DCE-CT) and conventional contrast-enhanced CT (CE-CT) in the assessment of early regorafenib treatment effects was evaluated in a preclinical setting. A rat GS9L glioma model was examined with contrast-enhanced dynamic DE-CT measurements (80 kV/140 kV) for 4 min before and on days 1 and 4 after the start of daily regorafenib or placebo treatment. Tumour time-density curves (0-240 s, 80 kV), DE-CT (60 s) derived iodine maps and the DCE-CT (0-30 s, 80 kV) based parameters blood flow (BF), blood volume (BV) and permeability (PMB) were calculated and compared to conventional CE-CT (60 s, 80 kV). The regorafenib group showed a marked decrease in the tumour time-density curve, a significantly lower iodine concentration and a significantly lower PMB on day 1 and 4 compared to baseline, which was not observed for the placebo group. CE-CT showed a significant decrease in tumour density on day 4 but not on day 1. The DE-CT-derived iodine concentrations correlated with PMB and BV but not with BF. DE-CT allows early treatment monitoring, which correlates with DCE-CT. Superior performance was observed compared to single-energy CE-CT. circle Regorafenib treatment response was evaluated by CT in a rat tumour model. (orig.)

  1. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

    Directory of Open Access Journals (Sweden)

    Antonio Gonzalez-Bulnes

    2016-03-01

    Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

  2. [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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. COMPARATIVE STUDY ON SPECIFIC AND EARLY DETECTION ...

    African Journals Online (AJOL)

    The objective of this study was to compare the sensitivity and specificity of smear and culture methods with rapid serological EIA myco kits manufactured by Omega diagnostics, for the early detection of Mycobacterium tuberculosis (MTB) complex. Sera from various categories of smear and culture results were compared ...

  8. 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.

  9. 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

  10. CLINICAL STUDY OF EARLY BREAST CARCINOMA

    Directory of Open Access Journals (Sweden)

    Kiran Kumar

    2016-01-01

    Full Text Available Carcinoma of the breast is one of the commonest cancers occurring in female and accounts for 1/3rd of all the malignant diseases occurring in them. It is mainly a disease of the developed countries and accounts for 1,00,000 deaths annually. Breast carcinoma is classified as Early breast cancer, Locally advanced breast cancer and Metastatic breast cancer. By definition early stage breast cancer constitutes breast tumors of clinical stages I, IIa and T2N1M0. Early breast cancer is the one diagnosed by mammography. Women when approaches at this stage, they can go for breast conservation surgery. Not all women are candidates for this approach, and some require mastectomy as part of their treatment. AIM To observe the incidence of early breast carcinoma with particular reference to the time taken by the patients to seek medical advice after the symptoms have developed i.e. the average time taken by the patients to seek medical advice, their appropriate management and prognosis. MATERIALS AND METHODS This prospective study was conducted over a period of 2 years from Oct-2012 to Oct-2014 in 30 female patients aged between 25-65 years who were presented with lump in breast of size ≤5cms with or without pain, with or without lymph nodes to the outpatient department. All the patients were thoroughly asked about history, examined clinically, investigated, staged and managed by surgery either Breast Conservation Surgery or Modified Radical Mastectomy. Postoperative complications were recorded and followed up regularly. RESULTS The incidence of early breast cancer in this study was 0.98% with peak age incidence between 40-60 years and duration of symptoms <6 months in 18 patients. Breast Conservation Surgery + axillary dissection + Radiotherapy was done in 23%. Prognosis was good in these patients with no local recurrence and death. CONCLUSION The prognosis of early stage breast carcinoma patients in this study was good. To have long term tumor free and

  11. Implications of motivation differences in preclinical-clinical transition of dental students: A one-year follow-up study

    Directory of Open Access Journals (Sweden)

    Cesar Orsini

    2016-10-01

    Discussions: This suggests that while clinical contact supports student self-determination, an abrupt transition might be associated with maladjustment, which could lead to feelings of inadequacy and anxiety. Future research could usefully explore if early and gradual clinical experiences enhance student adaptation to the clinical context, thus increasing relative autonomous motivation and decreasing amotivation in the time.

  12. [Preclinical horizon of depression in adults].

    Science.gov (United States)

    Jiménez-Báez, María Valeria; Márquez-González, Horacio; Monsreal-Góngora, Juan Leonardo; Góngora-González, Gonzalo; Sandoval-Jurado, Luis; Boquer-Hernández, Rubén

    2016-01-01

    Identify factors related to preclinical depression in healthy adults, their risk factors and concordance with family doctor diagnostic. Case-control study in adult from family medicine consulting room. Beck inventory for depression was applied. The correlation between depression and the diagnosis by the family physician was evaluated. Odds ratio (OR) was determined. Involved 138 patients randomly from four family medicine units (FMU) in the Northern Region of Quintana Roo, Mexico. The mean age 34.9 ± 11.4 years, 55.8% women, prevalence for depression was 26.1%. Being male OR: 3.76; 95% CI: 1.69-8.36, under 30 years OR: 2.76; 95% CI: 1.27-5.99, low socioeconomic status (SES) OR: 2.11; 95% CI: 0.97-4.59 and be married OR: 3.22; 95% CI: 1.41.-7.36 had depression risk. Diagnosis by the family physician and inventory Beck. Kappa Index 0.2, 95% CI: -0057-0176; p = 0.05. Almost a third of young adults have some depression degree in family medicine consulting room, it is necessary a depression screening for male patients, low SES, married, and under 30 years old, attending medical consultation familiar, for a early diagnosis and improve prognosis.

  13. 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

  14. 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

  15. 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

  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. 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...

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

    Science.gov (United States)

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

    2007-12-01

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

  19. 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)

  20. 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

  1. Radioecological studies in early period of NIRS

    International Nuclear Information System (INIS)

    Ichikawa, Ryushi

    2004-01-01

    Japanese tuna-fishing boat Fukuryumaru No.5 was exposed to heavy radioactive fallout due to the nuclear test explosion carried out by U.S.A. at Bikini Atoll of Marshal Islands in the central part of Pacific Ocean on March 1, 1954. Following this accident, radioactivity was detected in various environmental samples including rain, marine fishes and agricultural crops. Science Council of Japan organized the new research group of many scientists in the field of fisheries, agricultural, medical and biological studies and radiation protection studies. Government of Japan established National Institute of Radiological Sciences (NIRS) in 1957. In this Institute various radioecological studies have been carried out. In this paper, some of these radioecological studies carried out in early period of NIRS are described. (author)

  2. Early Studies of Binocular and Binaural Directions

    Directory of Open Access Journals (Sweden)

    Nicholas J. Wade

    2018-03-01

    Full Text Available Understanding how the eyes work together to determine the direction of objects provided the impetus for examining integration of signals from the ears to locate sounds. However, the advantages of having two eyes were recorded long before those for two ears were appreciated. In part, this reflects the marked differences in how we can compare perception with one or two organs. It is easier to close one eye and examine monocular vision than to “close” one ear and study monaural hearing. Moreover, we can move our eyes either in the same or in opposite directions, but humans have no equivalent means of moving the ears in unison. Studies of binocular single vision can be traced back over two thousand years and they were implicitly concerned with visual directions from each eye. The location of any point in visual or auditory space can be described by specifying its direction and distance, from the vantage point of an observer. From the late 18th century experiments indicated that binocular direction involved an eye movement component and experimental studies of binaural direction commenced slightly later. However, these early binocular and binaural experiments were not incorporated into theoretical accounts until almost a century later. The early history of research on visual direction with two eyes is contrasted to that on auditory direction with two ears.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    Directory of Open Access Journals (Sweden)

    Amelia Kellar

    2015-01-01

    Full Text Available Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

  10. 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

  11. 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...

  12. 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.

  13. 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)

  14. Study of Early Child Care and Youth Development (SECCYD)

    Science.gov (United States)

    ... Facebook Twitter Pinterest Email Print NICHD Study of Early Child Care and Youth Development (SECCYD) Sunsetted/For Reference ... page is not being updated . The Study of Early Child Care and Youth Development (SECCYD) began as the ...

  15. 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.)

  16. 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)

  17. 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)

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. Early Adolescent Sexual Activity: A Developmental Study.

    Science.gov (United States)

    Whitbeck, Les B.; Yoder, Kevin A.; Hoyt, Dan R.; Conger, Rand D.

    1999-01-01

    Examines predictors of early sexual intercourse for a sample of 457 adolescents in grades 8 through 10, from two-parent and single-mother families. Significant decreases were noted in the effect of mother monitoring by 10th grade. The primary predictors of early intercourse were age, opportunity (steady relationship), sexually permissive attitude,…

  7. 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.

  8. 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)

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. Degenerated human articular cartilage at autopsy represents preclinical osteoarthritic cartilage: comparison with clinically defined osteoarthritic cartilage

    NARCIS (Netherlands)

    van Valburg, A. A.; Wenting, M. J.; Beekman, B.; te Koppele, J. M.; Lafeber, F. P.; Bijlsma, J. W.

    1997-01-01

    To investigate whether macroscopically fibrillated human articular knee cartilage observed at autopsy can be considered an early, preclinical phase of osteoarthritis (OA). Histological and biochemical characteristics of 3 types of articular knee cartilage were compared: macroscopically degenerated

  2. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Directory of Open Access Journals (Sweden)

    Carlo Abbate

    2014-01-01

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

  3. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Science.gov (United States)

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

    2014-01-01

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

  4. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

    Science.gov (United States)

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

    2017-05-09

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

  5. 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

  6. 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

  7. 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

  8. 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

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

    Science.gov (United States)

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

    2015-06-01

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

  10. 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

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

    Directory of Open Access Journals (Sweden)

    Shaun Frost

    2017-01-01

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

  12. Clinical study of early laryngeal cancer

    International Nuclear Information System (INIS)

    Nagatani, Gunji; Mori, Takanori; Udaka, Tsuyoshi; Shiomori, Teruo; Ohbuchi, Toyoaki; Suzuki, Hideaki

    2007-01-01

    We retrospectively analyzed 71 consecutive cases of early laryngeal cancer (stage I or II) that had undergone primary treatment in our department between 1999 and 2004. There were 68 males and 3 females, and their ages ranged from 40 to 85 years of age (average; 67.7 years). Eight patients had the supraglottic type, 61 had the glottic type, and 2 had the subglottic type. Chemoradiotherapy was performed as the primary treatment except in the patients with glottic T1a cancer, who received radiotherapy alone. The 5-year survival rates was 91.1% for glottic cancer (T1a: 100%, T1b: 92.3%, T2: 85.8%) and 75.0% for supraglottic cancer. The local control rate of glottic cancer was 79.6% (T1a: 80.0%, T1b: 74.0%, T2: 85.2%), and significantly higher than that of supraglottic cancer (56.2%, p<0.05). The laryngeal preservation rate was 84.4% in glottic cancer (T1a: 100%, T1b: 76.9%, T2: 77.5%) and 58.3% in supraglottic cancer, and the difference between T1a and T2 glottic cancer was significant (p<0.05). Local recurrence and cervical lymph node metastasis were seen in 9 patients and 6 patients, respectively. Distant metastasis occurred in 4 patients, all of whom had the glottic type. Four patients died of their disease, and distant metastasis was the major cause of death in 3 of them. These results indicate that additional treatment should be performed in cases in which radiotherapy/chemoradiotherapy is ineffective and that both in the early stages glottic and supraglottic cancers can be successfully treated by radiotherapy/chemoradiotherapy. The results also suggested that the survival of patients with early laryngeal cancer depends on whether they develop distant metastasis. Introduction of adjuvant chemotherapy to improve their prognosis remains to be assessed. (author)

  13. 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

  14. Optimization of precursor synthesis, formulation and stability of 1′-[18 F]fluoroethyl-β-D-lactose ([18 F]FEL) for preclinical studies in detection of pancreatic cancer

    International Nuclear Information System (INIS)

    Paolillo, Vincenzo; De Palatis, Louis; Alauddin, Mian M.

    2014-01-01

    Introduction: 1′-[ 18 F]Fluoroethyl-β-D-lactose ([ 18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [ 18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [ 18 F]FEL; we also describe [ 18 F]FEL’s formulation and stability. Methods: Acetylation of D-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-D-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-D-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[ 18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results: Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. Conclusions: A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [ 18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of

  15. Optimization of precursor synthesis, formulation and stability of 1′-[18 F] fluoroethyl-β-d-lactose ([18 F]FEL) for preclinical studies in detection of pancreatic cancer

    Science.gov (United States)

    Paolillo, Vincenzo; De Palatis, Louis; Alauddin, Mian M.

    2014-01-01

    Introduction 1′-[18 F]Fluoroethyl-β-d-lactose ([18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [18 F]FEL; we also describe [18 F]FEL’s formulation and stability. Methods Acetylation of d-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-d-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-d-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. Conclusions A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [18 F]FEL should

  16. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease.

    Science.gov (United States)

    2004-04-01

    Treatment with rasagiline mesylate, an irreversible monoamine oxidase type B inhibitor, improves symptoms of early Parkinson disease (PD). Preclinical studies suggest that this compound may also modify the progression of PD. To compare the effects of early and later initiation of rasagiline on progression of disability in patients with PD. Double-blind, parallel-group, randomized, delayed-start clinical trial. Four hundred four subjects with early PD, not requiring dopaminergic therapy, enrolled at 32 sites in the United States and Canada. Subjects were randomized to receive rasagiline, 1 or 2 mg/d, for 1 year or placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months. Change in total Unified Parkinson's Disease Rating Scale score from baseline to 12 months. Three hundred seventy-one subjects were included in the 1-year efficacy analysis. Subjects treated with rasagiline, 2 mg/d, for 1 year had a 2.29-unit smaller increase in mean adjusted total Unified Parkinson's Disease Rating Scale score compared with subjects treated with placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months (P =.01). The mean adjusted difference between the placebo/rasagiline, 2 mg/d, group and those receiving rasagiline, 1 mg/d, for 1 year was -1.82 unit on the Unified Parkinson's Disease Rating Scale score (P =.05). Subjects treated with rasagiline, 2 and 1 mg/d, for 12 months showed less functional decline than subjects whose treatment was delayed for 6 months.

  17. The Early vs. Late Infantile Strabismus Surgery Study: Monitoring Report

    NARCIS (Netherlands)

    H.J. Simonsz (Huib)

    1995-01-01

    textabstractAbstract: The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists who investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomized, prospective, multi-center trial. Infants between six and 18

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

    Directory of Open Access Journals (Sweden)

    Leila Bond

    2018-01-01

    Full Text Available Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS. In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1 accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70–90% of cell death coincides to inducer exposure equivalent to 30–50% peak concentration (p < 0.05. A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs revealed HSP levels are 30% lower in muscle than spine (p < 0.1. Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05. Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001 but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature

  19. 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)

  20. 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.

  1. Early Tracking or Finally Leaving? Determinants of Early Study Success in First-Year University Students

    Science.gov (United States)

    Brouwer, Jasperina; Jansen, Ellen; Hofman, Adriaan; Flache, Andreas

    2016-01-01

    Two theoretical approaches underlie this investigation of the determinants of early study success among first-year university students. Specifically, to extend Walberg's educational productivity model, this study draws on the expectancy-value theory of achievement motivation in a contemporary university context. The survey data came from 407…

  2. A review of studies on community based early warning systems

    Directory of Open Access Journals (Sweden)

    Margaret Macherera

    2016-04-01

    Full Text Available Community-based early warning systems involve community driven collection and analysis of information that enable warning messages to help a community to react to a hazard and reduce the resulting loss or harm. Most early warning systems are designed at the national or global level. Local communities’ capacity to predict weather conditions using indigenous knowledge has been demonstrated in studies focusing on climate change and agriculture in some African countries. This review was motivated by successes made in non-disease specific community-based early warning systems with a view to identify opportunities for developing similar systems for malaria. This article reviewed the existing community-based early warning systems documented in literature. The types of disasters that are addressed by these systems and the methodologies utilised in the development of the systems were identified. The review showed that most of the documented community-based early warning systems focus on natural disasters such as floods, drought, and landslides. Community-based early warning systems for human diseases are very few, even though such systems exist at national and regional and global levels. There is a clear gap in terms of community-based malaria early warning systems. The methodologies for the development of the community-based early warning systems reviewed mainly derive from the four elements of early warning systems; namely risk knowledge, monitoring, warning communication and response capability. The review indicated the need for the development of community based early warning systems for human diseases. Keywords: community; early warning; disaster; hazards

  3. Noninvasive Multimodality Imaging of the Tumor Microenvironment: Registered Dynamic Magnetic Resonance Imaging and Positron Emission Tomography Studies of a Preclinical Tumor Model of Tumor Hypoxia

    Directory of Open Access Journals (Sweden)

    HyungJoon Cho

    2009-03-01

    Full Text Available In vivo knowledge of the spatial distribution of viable, necrotic, and hypoxic areas can provide prognostic information about the risk of developing metastases and regional radiation sensitivity and may be used potentially for localized dose escalation in radiation treatment. In this study, multimodality in vivo magnetic resonance imaging (MRI and positron emission tomography (PET imaging using stereotactic fiduciary markers in the Dunning R3327AT prostate tumor were performed, focusing on the relationship between dynamic contrast-enhanced (DCE MRI using Magnevist (Gd-DTPA and dynamic 18F-fluoromisonidazole (18F-Fmiso PET. The noninvasive measurements were verified using tumor tissue sections stained for hematoxylin/eosin and pimonidazole. To further validate the relationship between 18F-Fmiso and pimonidazole uptake, 18F digital autoradiography was performed on a selected tumor and compared with the corresponding pimonidazole-stained slices. The comparison of Akep values (kep = rate constant of movement of Gd-DTPA between the interstitial space and plasma and A = amplitude in the two-compartment model (Hoffmann U, Brix G, Knopp MV, Hess T and Lorenz WJ (1995. Magn Reson Med 33, 506– 514 derived from DCE-MRI studies and from early 18F-Fmiso uptake PET studies showed that tumor vasculature is a major determinant of early 18F-Fmiso uptake. A negative correlation between the spatial map of Akep and the slope map of late (last 1 hour of the dynamic PET scan 18F-Fmiso uptake was observed. The relationships between DCE-MRI and hematoxylin/eosin slices and between 18F-Fmiso PET and pimonidazole slices confirm the validity of MRI/PET measurements to image the tumor microenvironment and to identify regions of tumor necrosis, hypoxia, and well-perfused tissue.

  4. Early Onset Malignancies - Genomic Study of Cancer Disparities

    Science.gov (United States)

    The Early Onset Malignancies Initiative studies the genomic basis of six cancers that develop at an earlier age, occur in higher rates, and are typically more aggressive in certain minority populations.

  5. 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

  6. 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

  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. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

    Science.gov (United States)

    Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

    2016-03-01

    During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  9. Diagnostic and prognostic role of semantic processing in preclinical Alzheimer's disease.

    Science.gov (United States)

    Venneri, Annalena; Jahn-Carta, Caroline; Marco, Matteo De; Quaranta, Davide; Marra, Camillo

    2018-06-13

    Relatively spared during most of the timeline of normal aging, semantic memory shows a subtle yet measurable decline even during the pre-clinical stage of Alzheimer's disease. This decline is thought to reflect early neurofibrillary changes and impairment is detectable using tests of language relying on lexical-semantic abilities. A promising approach is the characterization of semantic parameters such as typicality and age of acquisition of words, and propositional density from verbal output. Seminal research like the Nun Study or the analysis of the linguistic decline of famous writers and politicians later diagnosed with Alzheimer's disease supports the early diagnostic value of semantic processing and semantic memory. Moreover, measures of these skills may play an important role for the prognosis of patients with mild cognitive impairment.

  10. The H2 robotic exoskeleton for gait rehabilitation after stroke: early findings from a clinical study.

    Science.gov (United States)

    Bortole, Magdo; Venkatakrishnan, Anusha; Zhu, Fangshi; Moreno, Juan C; Francisco, Gerard E; Pons, Jose L; Contreras-Vidal, Jose L

    2015-06-17

    Stroke significantly affects thousands of individuals annually, leading to considerable physical impairment and functional disability. Gait is one of the most important activities of daily living affected in stroke survivors. Recent technological developments in powered robotics exoskeletons can create powerful adjunctive tools for rehabilitation and potentially accelerate functional recovery. Here, we present the development and evaluation of a novel lower limb robotic exoskeleton, namely H2 (Technaid S.L., Spain), for gait rehabilitation in stroke survivors. H2 has six actuated joints and is designed to allow intensive overground gait training. An assistive gait control algorithm was developed to create a force field along a desired trajectory, only applying torque when patients deviate from the prescribed movement pattern. The device was evaluated in 3 hemiparetic stroke patients across 4 weeks of training per individual (approximately 12 sessions). The study was approved by the Institutional Review Board at the University of Houston. The main objective of this initial pre-clinical study was to evaluate the safety and usability of the exoskeleton. A Likert scale was used to measure patient's perception about the easy of use of the device. Three stroke patients completed the study. The training was well tolerated and no adverse events occurred. Early findings demonstrate that H2 appears to be safe and easy to use in the participants of this study. The overground training environment employed as a means to enhance active patient engagement proved to be challenging and exciting for patients. These results are promising and encourage future rehabilitation training with a larger cohort of patients. The developed exoskeleton enables longitudinal overground training of walking in hemiparetic patients after stroke. The system is robust and safe when applied to assist a stroke patient performing an overground walking task. Such device opens the opportunity to study means

  11. 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

  12. 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.

  13. 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

  14. A review of studies on community based early warning systems

    OpenAIRE

    Margaret Macherera; Moses J. Chimbari

    2016-01-01

    Community-based early warning systems involve community driven collection and analysis of information that enable warning messages to help a community to react to a hazard and reduce the resulting loss or harm. Most early warning systems are designed at the national or global level. Local communities’ capacity to predict weather conditions using indigenous knowledge has been demonstrated in studies focusing on climate change and agriculture in some African countries. This review was motivated...

  15. Unguja Ukuu on Zanzibar : An archaeological study of early urbanism

    OpenAIRE

    Juma, Abdurahman

    2004-01-01

    This study describes archaeological excavations carried out at Unguja Ukuu on the main island of Zanzibar, Tanzania. The site has long remained obscure, oral histories do not mention it and no particular group among the living community of the island describes its origin from the site. A stone well at Unguja Ukuu together with several other early monuments of the east African coast that survive on the site have been attributed to the Wadebuli, suspected by early scholars to be people of Arab ...

  16. Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.

    Science.gov (United States)

    Hovens, Iris B; Schoemaker, Regien G; van der Zee, Eddy A; Heineman, Erik; Izaks, Gerbrand J; van Leeuwen, Barbara L

    2012-10-01

    Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Preclinical Multimodal Molecular Imaging Using 18F-FDG PET/CT and MRI in a Phase I Study of a Knee Osteoarthritis in In Vivo Canine Model

    Directory of Open Access Journals (Sweden)

    Maria I. Menendez DVM, PhD

    2017-03-01

    Full Text Available The aim of this study was to use a multimodal molecular imaging approach to serially assess regional metabolic changes in the knee in an in vivo anterior cruciate ligament transection (ACLT canine model of osteoarthritis (OA. Five canine underwent ACLT in one knee and the contralateral knee served as uninjured control. Prior, 3, 6, and 12 weeks post-ACLT, the dogs underwent 18F-fluoro-d-glucose (18F-FDG positron emission tomography (PET/computed tomography (CT and magnetic resonance imaging (MRI. The MRI was coregistered with the PET/CT, and 3-dimensional regions of interest (ROIs were traced manually and maximum standardized uptake values (SUVmax were evaluated. 18F-fluoro-d-glucose SUVmax in the ACLT knee ROIs was significantly higher compared to the uninjured contralateral knees at 3, 6, and 12 weeks. Higher 18F-FDG uptake observed in ACLT knees compared to the uninjured knees reflects greater metabolic changes in the injured knees over time. Knee 18F-FDG uptake in an in vivo ACLT canine model using combined PET/CT and MRI demonstrated to be highly sensitive in the detection of metabolic alterations in osseous and nonosteochondral structures comprising the knee joint. 18F-fluoro-d-glucose appeared to be a capable potential imaging biomarker for early human knee OA diagnosis, prognosis, and management.

  18. 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

  19. Western gulf culture-density study-early results

    Science.gov (United States)

    Mohd S. Rahman; Michael G. Messina; Richard F. Fisher; Alan B. Wilson; Nick Chappell; Conner Fristoe; Larry Anderson

    2006-01-01

    The Western Gulf Culture-Density Study is a collaborative research effort between Texas A&M University and five forest products companies to examine the effects of early silvicultural treatment intensity and a wide range of both densities and soil types on performance of loblolly pine. The study tests 2 silvicultural intensities, 5 planting densities (200 to 1,200...

  20. EARLY ENTERAL FEEDING AND DELAYED ENTERAL FEEDING- A COMPARATIVE STUDY

    Directory of Open Access Journals (Sweden)

    Alli Muthiah

    2017-03-01

    Full Text Available BACKGROUND Nutrients form the fuel for the body, which comes in the form of carbohydrates, proteins and lipids. The body is intended to burn fuels in order to perform work. Starvation with malnutrition affects the postoperative patients and patients with acute pancreatitis. There is an increased risk of nosocomial infections and a delay in the wound healing may be noted. They are more prone for respiratory tract infections. Enteral Nutrition (EN delivers nutrition to the body through gastrointestinal tract. This also includes the oral feeding. This study will review the administration, rationale and assess the pros and cons associated with the early initiation of enteral feeding. The aim of this study is to evaluate if early commencement of enteral nutrition compared to traditional management (delayed enteral feeding is associated with fewer complications and improved outcome-  In patients undergoing elective/emergency gastrointestinal surgery.  In patients with acute pancreatitis. It is also used to determine whether a period of starvation (nil by mouth after gastrointestinal surgery or in the early days of acute pancreatitis is beneficial in terms of specific outcomes. MATERIALS AND METHODS A prospective cohort interventional study was conducted using 100 patients from July 2012 to November 2012. Patients satisfying the inclusion and exclusion criteria were included in the study. Patients admitted in my unit for GIT surgeries or acute pancreatitis constituted the test group, while patients admitted in other units for similar disease processes constituted the control group. RESULTS Our study concluded that early enteral feeding resulted in reduced incidence of surgical site infections. When the decreased length of stay, shorter convalescent period and the lesser post-interventional fatigue were taken into account, early enteral feeding has a definite cost benefit.CONCLUSION Early enteral feeding was beneficial associated with fewer

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. In vivo evaluation of biofunctionalized implant surfaces with a synthetic peptide (P-15) and its impact on osseointegration. A preclinical animal study.

    Science.gov (United States)

    Schmitt, Christian M; Koepple, Markus; Moest, Tobias; Neumann, Konrad; Weisel, Tamara; Schlegel, Karl Andreas

    2016-11-01

    The overall aim of the study was to investigate a biofunctionalized implant surface with electrochemically deposition of hydroxyapatite and the synthetic peptide (P-15) and its effect on osseointegration. Three modified implant types of ANKYLOS ® C/X implants were used; (1) machined implants used as negative control (M, n = 20), (2) implants with the FRIADENT ® plus surface (grit blasted and acid-etched) used as positive control (P, n = 20), and (3) implants with a biomimetic surface consisting of hydroxyapatite and the synthetic 15 aminoacids containing peptide P-15 (BP, n = 40). The implants were randomly inserted in the mandibles of 10 beagle dogs following 4 months after tooth extraction (P1-P4). Three animals were sacrificed 2 and 7 days after implant insertion, respectively, and four animals were sacrificed 6 months post implant insertion. Bone-to-implant contacts (BICs) were analyzed via histomorphometrical analyses at five different region of interests (ROIs); two at the middle part on either side of the implant (ROI 1/4), two at the apical part of the implant at each side (ROI 2/3), and one at the tip of the implant (ROI 5). All implant surfaces showed a high level of osseointegration and osteoconductivity. The cumulative implant survival rate (CSR) was 93.8%, 100% in the M, 85% in the P, and 95% in the BP group. No statistical difference in BICs at ROI 1/4, 2/3, and 5 could be shown between implant types following 2 and 7 days of healing. BIC values increased in all groups over time. After 6 months of healing the BP group showed superiority in BIC in ROI 2/3 (73.2 ± 15.6%) compared to the P (48.3 ± 10.6%) and M group (66.3 ± 30.2%) with a significant difference between BP and P (P = 0.002). It is hypothesized, that the surface biofunctionalization improves peri-implant bone formation and remodeling, leading to an increased bone-to implant contact. However, within the limitations of the study set-up no benefit in the early phase of

  8. 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.

  9. 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.

  10. Early Discontinuation of Montelukast Treatment; A Danish Nationwide Utilization Study

    DEFF Research Database (Denmark)

    Farah, Rahmo I; Damkier, Per; Christiansen, Anders

    2018-01-01

    Montelukast, a leukotriene receptor antagonist, was marketed in 1998 as an oral supplementary treatment to patients with mild to moderate asthma. The aim of this study was to describe the early discontinuation pattern among montelukast users in Denmark in the period of 1 March 1998 to 31 December....... Early discontinuation was defined as failing to fill a second prescription for montelukast within at least a year after the initial montelukast prescription. Among 135,271 included montelukast users, 47,480 (35%) discontinued the use of montelukast after a single redeemed prescription. The trend...

  11. Gender and teacher training in Early Childhood Education studies

    Directory of Open Access Journals (Sweden)

    Alfonso Romero Díaz

    2008-12-01

    Full Text Available This paper presents the findings of a research study funded by the European Union that aims to improve early childhood teacher training in gender-related topics. Spain has made considerable headway with the inclusion of gender mainstreaming in the political agenda. However, as we point out in this paper, this issue is still not a priority in vocational training for early childhood education. A series of qualitative interviews and a quantitative questionnaire revealed a lack of training, materials and sensitivity, all needed for the introduction of gender and sexual diversity issues.

  12. 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

  13. A Study of Early Learning Services in Museums and Libraries

    Science.gov (United States)

    Sirinides, P.; Fink, R.; DuBois, T.

    2017-01-01

    Museums and libraries can play a role in providing opportunities for early learning, and there is clear momentum and infrastructure already in place to help make this happen. Researchers conducted a mixed-methods descriptive study to generate new evidence about the availability of services for young children in museums and libraries, and the…

  14. Free Play in Early Childhood Education: A Phenomenological Study

    Science.gov (United States)

    Aras, Selda

    2016-01-01

    It is aimed to investigate perceptions and implementations of early childhood teachers on free play and their involvement in children's free play. Recent studies focused on that, although there is an increase in the amount of teacher involvement, the quality of this involvement should be clearly examined. Lev Vygotsky examined play as an…

  15. Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

    Energy Technology Data Exchange (ETDEWEB)

    Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R. [Heidelberg Univ., Mannheim (Germany). Computer Assisted Clinical Medicine

    2014-07-01

    The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

  16. Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

    International Nuclear Information System (INIS)

    Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R.

    2014-01-01

    The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

  17. Identifying early indicators in bipolar disorder: a qualitative study.

    Science.gov (United States)

    Benti, Liliane; Manicavasagar, Vijaya; Proudfoot, Judy; Parker, Gordon

    2014-06-01

    The identification of early markers has become a focus for early intervention in bipolar disorder. Using a retrospective, qualitative methodology, the present study compares the early experiences of participants with bipolar disorder to those with unipolar depression up until their first diagnosed episode. The study focuses on differences in early home and school environments as well as putative differences in personality characteristics between the two groups. Finally we a compare and contrast prodromal symptoms in these two populations. Thirty-nine participants, 20 diagnosed with unipolar depression and 19 diagnosed with bipolar disorder, took part in the study. A semi-structured interview was developed to elicit information about participants' experiences prior to their first episode. Participants with bipolar disorder reported disruptive home environments, driven personality features, greater emotion dysregulation and adverse experiences during the school years, whereas participants with depression tended to describe more supportive home environments, and more compliant and introvert personality traits. Retrospective data collection and no corroborative evidence from other family members. No distinction was made between bipolar I and bipolar II disorder nor between melancholic and non-melancholic depression in the sample. Finally the study spanned over a 12-month period which does not allow for the possibility of diagnostic reassignment of some of the bipolar participants to the unipolar condition. These findings indicate that there may be benefits in combining both proximal and distal indicators in identifying a bipolar disorder phenotype which, in turn, may be relevant to the development of early intervention programs for young people with bipolar disorder.

  18. The Porto Alegre Early Life Nutrition and Health Study.

    Science.gov (United States)

    Chaffee, Benjamin Wilk; Vítolo, Márcia Regina; Feldens, Carlos Alberto

    2014-12-01

    Early childhood caries is a persistent worldwide problem. The etiologic contribution of feeding practices has been less frequently investigated in prospective studies of young children. The Porto Alegre Early Life Nutrition and Health Study has followed a birth cohort of 715 mother-child pairs, recruited from municipal health centers, originally involved in a cluster-randomized controlled trial of healthcare worker training. The birth cohort links prospectively collected socio-demographic, infant feeding, and general and oral health information. To date, oral health data, including caries status and oral health-related quality of life, have been collected for 458 children at the age of 2-3 years. Studies are underway to investigate possible determinants and consequences of oral health among these children.

  19. The Porto Alegre Early Life Nutrition and Health Study

    Directory of Open Access Journals (Sweden)

    Benjamin Wilk Chaffee

    2014-12-01

    Full Text Available Early childhood caries is a persistent worldwide problem. The etiologic contribution of feeding practices has been less frequently investigated in prospective studies of young children. The Porto Alegre Early Life Nutrition and Health Study has followed a birth cohort of 715 mother-child pairs, recruited from municipal health centers, originally involved in a cluster-randomized controlled trial of healthcare worker training. The birth cohort links prospectively collected socio-demographic, infant feeding, and general and oral health information. To date, oral health data, including caries status and oral health-related quality of life, have been collected for 458 children at the age of 2-3 years. Studies are underway to investigate possible determinants and consequences of oral health among these children.

  20. A study of the impact of technology in early education

    OpenAIRE

    Wajszczyk, Rafal

    2014-01-01

    The purpose of this study is to analyse the current state of the use of Information and communication technology (ICT) and its impact on pupils in their early stages of education. The aim is to find out how, when and in what context ICT is used in the work with students. The overall objective is to study teachers views on ICT and their opinion on how ICT does affects pupils - positively or negatively. The results of this study are based on both a literature review and a qualitative study. The...

  1. Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.

    Science.gov (United States)

    Rea, Domenica; Coppola, Carmela; Barbieri, Antonio; Monti, Maria Gaia; Misso, Gabriella; Palma, Giuseppe; Bimonte, Sabrina; Zarone, Mayra Rachele; Luciano, Antonio; Liccardo, Davide; Maiolino, Piera; Cittadini, Antonio; Ciliberto, Gennaro; Arra, Claudio; Maurea, Nicola

    2016-01-01

    In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography. We generated a mouse model of cardiotoxicity induced by doxorubicin. C57BL 6 mice were divided into two groups, treated for 7 days by intraperitoneal injections of placebo (vehicle) or doxorubicin (2.17 mg/kg), in order to characterize the cardiac phenotype in vivo. We demonstrated that doxorubicin caused ealy remodeling of the left ventricle: after two days of therapy, the radial, circumferential and strain rates were reduced respectively by 35%, 34%, and 39% (p-value ≤0.001). Moreover, histological analysis revealed that doxorubicin treatment increased fibrosis, cardiomyocyte diameter and apoptosis. In a murine model of doxorubicin-induced cardiac injury, we detected left ventricular dysfunction followed by alterations in conventional echocardiographic indices. Our study suggests that a change in strain could be an effective early marker of myocardial dysfunction for new anticancer treatments and, in preclinical studies, it might also be a valuable indicator for the assessment of activity of cardioprotective agents. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. 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.

  3. Imaging tissue hypoxia: clinical and pre-clinical experience with {sup 123}IAZA

    Energy Technology Data Exchange (ETDEWEB)

    Wiebe, L.I. [University of Alberta, Edmonton (Canada). Noujaim Institute for Pharmaceutical Oncology Research, Faculty of Pharmacy and Pharmaceutical Sciences

    1997-10-01

    The molecular mechanisms that underline the selective binding of iodazomycin arabinoside, IAZA, and related nitromidazoles are reviewed as a basis for interpretation of preclinical and clinical data for hypoxic binding of radioiodinated IAZA. Clinical data are presented for {sup 123}IAZA uptake in a number of pathologies including metastatic tumours, peripheral vascular disease in diabetes, muscle stress and rheumatoid arthritis. The results of studies to determine the influence of tumour type on uptake of {sup 123} I-IAZA in patients with a variety of deep-seated solid tumours will be presented. Correlations of hypoxia-dependent binding with {sup 99m}Tc-HMPAO perfusion images will be reviewed and early correlations of uptake to treatment response in cancer will be presented. Unusual features of {sup 123}I-IAZA biodistribution will also be discussed together with detailed pharmacokinetic and radiation dosimetry data for `2{sup 123}I- IAZA in normal volunteers 27 refs., 1 fig.

  4. Imaging tissue hypoxia: clinical and pre-clinical experience with 123IAZA

    International Nuclear Information System (INIS)

    Wiebe, L.I.

    1997-01-01

    The molecular mechanisms that underline the selective binding of iodazomycin arabinoside, IAZA, and related nitromidazoles are reviewed as a basis for interpretation of preclinical and clinical data for hypoxic binding of radioiodinated IAZA. Clinical data are presented for 123 IAZA uptake in a number of pathologies including metastatic tumours, peripheral vascular disease in diabetes, muscle stress and rheumatoid arthritis. The results of studies to determine the influence of tumour type on uptake of 123 I-IAZA in patients with a variety of deep-seated solid tumours will be presented. Correlations of hypoxia-dependent binding with 99m Tc-HMPAO perfusion images will be reviewed and early correlations of uptake to treatment response in cancer will be presented. Unusual features of 123 I-IAZA biodistribution will also be discussed together with detailed pharmacokinetic and radiation dosimetry data for '2 123 I- IAZA in normal volunteers

  5. Early studies of placental ultrastructure by electron microscopy

    DEFF Research Database (Denmark)

    Carter, A M; Enders, A C

    2016-01-01

    many other scientists to Washington University in St. Louis. Work on human placental ultrastructure was initiated at Cambridge and Kyoto whilst domestic animals were initially studied by Björkman in Stockholm and electron micrographs of bat placenta were published by Wimsatt of Cornell University......BACKGROUND: Transmission electron microscopy (TEM) was first applied to study placental ultrastructure in the 1950's. We review those early studies and mention the scientists that employed or encouraged the use of TEM. FINDINGS: Among the pioneers Edward W. Dempsey was a key figure who attracted...

  6. In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

    OpenAIRE

    Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

    2017-01-01

    Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

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

    Science.gov (United States)

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

    2017-11-01

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

  8. Preclinical Alzheimer disease and risk of falls.

    Science.gov (United States)

    Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

    2013-07-30

    We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

  9. Micro-dosing for early biokinetic studies in humans

    International Nuclear Information System (INIS)

    Stenstroem, K.; Sydoff, M.; Mattsson, S.

    2010-01-01

    Micro-dosing is a new concept in drug development that-if implemented in the pharmaceutical industry-would mean that new drugs can be tested earlier in humans than done today. The human micro-dosing concept-or 'Phase 0'-may offer improved candidate selection, reduced failure rates in the drug development line and a reduction in the use of laboratory animals in early drug development, factors which will help to speed up drug development and also reduce the costs. Micro-dosing utilises sub-pharmacological amounts of the substance to open opportunities for early studies in man. Three technologies are used for micro-dosing: accelerator mass spectrometry (AMS), positron emission tomography and liquid chromatography-tandem mass spectrometry. This paper focuses on the principle of AMS and discusses the current status of micro-dosing with AMS. (authors)

  10. Evolution of strategies to improve preclinical cardiac safety testing.

    Science.gov (United States)

    Gintant, Gary; Sager, Philip T; Stockbridge, Norman

    2016-07-01

    The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

  11. Is medical students' moral orientation changeable after preclinical medical education?

    Science.gov (United States)

    Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

    2012-03-01

    Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

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

    Science.gov (United States)

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

    2003-06-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Marc T Avey

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

  15. 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.

  16. Preclinical animal anxiety research - flaws and prejudices.

    Science.gov (United States)

    Ennaceur, Abdelkader; Chazot, Paul L

    2016-04-01

    The current tests of anxiety in mice and rats used in preclinical research include the elevated plus-maze (EPM) or zero-maze (EZM), the light/dark box (LDB), and the open-field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a source of their inconsistent and contradictory results. These constraints are very costly, and they are in most cases useless as they originate from flawed methodologies. In the present report, we argue that the EPM or EZM, LDB, and OF do not provide unequivocal measures of anxiety; that there is no evidence of motivation conflict involved in these tests. They can be considered at best, tests of natural preference for unlit and/or enclosed spaces. We also argued that pharmacological validation of a behavioral test is an inappropriate approach; it stems from the confusion of animal models of human behavior with animal models of pathophysiology. A behavioral test is developed to detect not to produce symptoms, and a drug is used to validate an identified physiological target. In order to overcome the major methodological flaws in animal anxiety studies, we proposed an open space anxiety test, a 3D maze, which is described here with highlights of its various advantages over to the traditional tests.

  17. A Flexible, Preclinical, Medical School Curriculum Increases Student Academic Productivity and the Desire to Conduct Future Research

    Science.gov (United States)

    Peacock, Justin G.; Grande, Joseph P.

    2015-01-01

    In 2006, small blocks of flexible curriculum time, termed selectives, were implemented in the Mayo Medical School preclinical curriculum. Selectives permitted students to pursue professional endeavors, such as research, service, and career exploration, in the preclinical years. The purpose of this study was to survey current and former Mayo…

  18. 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

  19. 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.

  20. Early failure analysis of machining centers: a case study

    International Nuclear Information System (INIS)

    Wang Yiqiang; Jia Yazhou; Jiang Weiwei

    2001-01-01

    To eliminate the early failures and improve the reliability, nine ex-factory machining centers are traced under field conditions in workshops. Their early failure information throughout the ex-factory run-in test is collected. The field early failure database is constructed based on the collection of field early failure data and the codification of data. Early failure mode and effects analysis is performed to indicate the weak subsystem of a machining center or the troublemaker. The distribution of the time between early failures is analyzed and the optimal ex-factory run-in test time for machining center that may expose sufficiently the early failures and cost minimum is discussed. Suggestions how to arrange ex-factory run-in test and how to take actions to reduce early failures for machining center is proposed

  1. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [18F]FPS

    International Nuclear Information System (INIS)

    Waterhouse, Rikki N.; Stabin, Michael G.; Page, John G.

    2003-01-01

    [ 18 F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18 F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [ 18 F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [ 18 F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [ 18 F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [ 18 F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 μg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m 2 ) in these species. These data support the expectation that [ 18 F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 μg FPS per injection

  2. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [(18)F]FPS.

    Science.gov (United States)

    Waterhouse, Rikki N; Stabin, Michael G; Page, John G

    2003-07-01

    [(18)F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [(18)F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [(18)F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [(18)F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 microg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m(2)) in these species. These data support the expectation that [(18)F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 microg FPS per injection.

  3. Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs

    International Nuclear Information System (INIS)

    Choi, Jin Woo; Lee, Jae Young; Hwang, Eui Jin; Hwang, In Pyeong; Woo, Sung Min; Lee, Chang Joo; Park, Eun Joo; Choi, Byung Ihn

    2014-01-01

    The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs.

  4. Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jin Woo; Lee, Jae Young; Hwang, Eui Jin; Hwang, In Pyeong; Woo, Sung Min; Lee, Chang Joo; Park, Eun Joo; Choi, Byung Ihn [Dept. of Radiology and Institute of Radiation Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2014-10-15

    The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs.

  5. Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [{sup 18}F]FPS

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. E-mail: rn27@columbia.edu; Stabin, Michael G.; Page, John G

    2003-05-01

    [{sup 18}F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [{sup 18}F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [{sup 18}F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [{sup 18}F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [{sup 18}F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 {mu}g per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m{sup 2}) in these species. These data support the expectation that [{sup 18}F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 {mu}g FPS per injection.

  6. B Physics and Quarkonia studies with early ATLAS data

    CERN Document Server

    Etzion, Erez

    2010-01-01

    Quarkonia and B-Physics are among the first areas to be investigated with the first data collected by ATLAS. The ATLAS detector at CERN's LHC is preparing to take data from proton-proton collisions expected to start by the end of 2009. Investigation of the decay of B-hadrons represents a complementary approach to direct searches for Physics beyond the Standard Model. Early B-physics data will provide valuable information on the detector performance, as well as allow calibration studies in support of new Physics searches. Meaningful quarkonia studies performed with early data are expected to have the reach to make authoritative statements about the underlying production mechanism and provide cross-sections in this new energy regime. We review various aspects of prompt quarkonium production at the LHC: the accessible ranges in transverse momentum and pseudo-rapidity, spin alignment of vector states, separation of color octet and color singlet production mechanism and feasibility of observing radiative chi_c dec...

  7. [Dental caries and early childhood development: a pilot study].

    Science.gov (United States)

    Núñez, F Loreto; Sanz, B Javier; Mejía, L Gloria

    2015-01-01

    To investigate the association between dental caries and early childhood development in 3-year-olds from Talca, Chile. A pilot study with a convenience sample of 3-year-olds from Talca (n = 39) who attend public healthcare centers. Child development was measured by the Psychomotor Development Index (PDI), a screening tool used nationally among pre-school children to assess language development, fine motor skills and coordination areas. Dental caries prevalence was evaluated by decayed, missing, filled teeth (DFMT) and decayed, missing, filled tooth surfaces (DFMS) ceo-d and ceo-s indexes. The children were divided into two groups according to the PDIscore: those with a score of 40 or more were considered developmentally normal (n = 32), and those with a score below 40 were considered as having impaired development (n = 7). The severity of caries (DMFT) was negatively correlated with PDI (r = -0.82), and children with the lowest TEPSI score had the highest DFMT values. The average DMFT in children with normal development was 1.31, and 3.57 for those with impaired development. This pilot study indicates that the severity of dental caries is correlated with early childhood development. Copyright © 2015. Publicado por Elsevier España, S.L.U.

  8. Pharmacokinetics and tumor targeting of 131I-labeled F(ab')2 fragments of the chimeric monoclonal antibody G250: preclinical and clinical pilot studies.

    NARCIS (Netherlands)

    Brouwers, A.H.; Mulders, P.F.A.; Oosterwijk, E.; Buijs, W.C.A.M.; Corstens, F.H.M.; Boerman, O.C.; Oyen, W.J.G.

    2004-01-01

    INTRODUCTION: Clinical and animal studies of chimeric monoclonal antibody G250 (moAb cG250) for the targeting of clear-cell renal cell carcinoma (RCC), to date, have been with the intact IgG form. To determine whether F(ab')2 fragments are more suited for radioimmunotherapy (RIT) than intact IgG,

  9. Assessing brain immune activation in psychiatric disorders : Clinical and preclinical PET imaging studies of the 18-kDa translocator protein

    NARCIS (Netherlands)

    van der Doef, Thalia F; Doorduin, Janine; van Berckel, Bart N M; Cervenka, Simon

    2015-01-01

    Accumulating evidence from different lines of research suggests an involvement of the immune system in the pathophysiology of several psychiatric disorders. During recent years, a series of positron emission tomography (PET) studies have been published using radioligands for the translocator protein

  10. Preclinical evaluation and test-retest studies of [{sup 18}F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu{sub 5})

    Energy Technology Data Exchange (ETDEWEB)

    Milicevic Sephton, Selena; Mueller Herde, Adrienne; Keller, Claudia; Ruedisuehli, Sonja; Schibli, Roger; Kraemer, Stefanie D.; Ametamey, Simon M. [Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Zurich (Switzerland); Mu, Linjing [University Hospital Zuerich, Department of Nuclear Medicine, Zuerich (Switzerland); Auberson, Yves [Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel (Switzerland)

    2015-01-15

    A novel, {sup 18}F-labelled metabotropic glutamate receptor subtype 5 (mGlu{sub 5}) derivative of [{sup 11}C]ABP688 ([{sup 11}C]1), [{sup 18}F]PSS232 ([{sup 18}F]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test-retest reliability studies The radiosynthesis of [{sup 18}F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu{sub 5} and mGlu{sub 1}, respectively. Small-animal PET, biodistribution, and test-retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7. [{sup 18}F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 - 400 GBq/μmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu{sub 5} with high binding to hippocampal and cortical regions, and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with 6, reduced [{sup 18}F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. Test-retest studies were reproducible with a variability ranging from 6.8 % to 8.2 %. An extended single-dose toxicity study in Wistar rats showed no compound-related adverse effects. The new mGlu{sub 5} radiotracer, [{sup 18}F]5, showed specific and selective in vitro and in vivo

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

    Science.gov (United States)

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

    2015-05-20

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

  12. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

    Science.gov (United States)

    Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

    2012-03-01

    Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Archaeomagnetic Study performed on Early Medieval Buildings from western France

    Science.gov (United States)

    Chauvin, A.; Lanos, P.; Dufresne, P.; Blain, S.; Guibert, P.; Oberlin, C.; Sapin, C.

    2009-05-01

    A multiple dating study, involving a collaboration between specialists of dating techniques (thermoluminescence (TL) and radiocarbon), historians of art and archaeologists, has been carried out on several early medieval buildings from western France. The early medieval period is not well known especially in France where there is a lack of visible evidence that identifies pre-Romanesque architecture. The majority of buildings to have survived from this period are religious ones, considered important enough to be made of strong, non-perishable material such as stone or brick, as for example the churches of Notre-Dame-sous- Terre in the Mont-Saint-Michel or St Martin in Angers. Due to their significance in architectural history, it is imperative to position them accurately in the chronology of the history of art. Bricks are often used to build up round-headed arches or to reinforce the frame of a wall with bonding courses in those churches. TL dating and archeomagnetic analysis were performed on cores drilled within bricks while radiocarbon dating were undertaken on coals found within mortars. In order to increase the number of data during the early Middle Ages, archeointensity determinations using the classical Thellier technique with anisotropy of thermal remanence and cooling rate corrections were performed. Archaeomagnetic directions were used to recognize the firing position of bricsk during manufacture. Reliable and precise ages were obtained on the church Notre-Dame-sous-Terre; they indicate two phases of building in 950±50AD and 990±50AD. Mean archeointensities obtained on 17 (21) samples from the first (second) phases appears very closed 69.1±1.2 and 68.3±1.6 microTesla. Ages and archeomagnetic results obtained on 4 other sites will be presented and compared to the available data in western Europe.

  14. Investigating the Usability and Acute Effects of a Bedside Video Console to Prefrontal Cortical Activity Alterations: A Preclinical Study in Healthy Elderly.

    Science.gov (United States)

    Knols, Ruud H; Swanenburg, Jaap; De Bon, Dino; Gennaro, Federico; Wolf, Martin; Krüger, Bernard; Bettex, Dominique; de Bruin, Eling D

    2017-01-01

    Elderly people at risk of developing cognitive decline; e.g., following surgery, may benefit from structured, challenging, and repetitive cognitive video training. This study assessed usability and acute effects of a newly developed bedside console (COPHYCON). Fifteen healthy elderly individuals performed a one-time 80-min intervention, including cognitive video games aimed at improving awareness and selective attention. Perceived usefulness and perceived ease of use (Technology Acceptance Model) were assessed together with measures of the achieved game level, reaction times, (in-) correct responses during ALERT and SELECT game play. Further, prefrontal cortical involvement of the regional cerebral hemoglobin saturation (rS02%) assessed with functional near infrared spectroscopy (fNIRS) ( n = 5) and EEG power ( n = 10) was analyzed. All participants completed the study without any adverse events. Perceived usefulness and perceived ease of use (TAM scores range 1-7) of the system varied between 3.9 and 6.3. The game levels reached for awareness varied between 9 and 11 (initial score 8-10), for reaction speed between 439 and 469 ms, and for correct responses between 74.1 and 78.8%. The highest level for the selective attention games was 2 (initial score 1), where reaction speed varied between 439 and 469 ms, correct responses between 96.2 and 98.5%, respectively. The decrease of rS02% in the right prefrontal cortex during gameplay was significantly ( p games ( p games. EEG recordings of theta power significantly decreased in the averaged ~0.25-0.75 time interval for the left prefrontal cortex sensor across the cognitive game levels between the ALERT 1 and SELECT 1, as well as between SELECT 1 and 2 games. Participants rated the usability of the COPHYCON training positively. Further results indicate that video gaming may be an effective measure to affect prefrontal cortical functioning in elderly. The results warrant a clinical explorative study investigating the

  15. Endoscopic ultrasound-guided biliary drainage using a newly designed metal stent with a thin delivery system: a preclinical study in phantom and porcine models.

    Science.gov (United States)

    Minaga, Kosuke; Kitano, Masayuki; Itonaga, Masahiro; Imai, Hajime; Miyata, Takeshi; Yamao, Kentaro; Tamura, Takashi; Nuta, Junya; Warigaya, Kenji; Kudo, Masatoshi

    2017-12-08

    This study was designed to evaluate the feasibility and safety of a newly designed self-expandable metal stent for endoscopic ultrasound-guided biliary drainage (EUS-BD) when it was delivered via three different stent delivery systems: a 7.5Fr delivery catheter with a bullet-shaped tip (7.5Fr-bullet), a 7Fr catheter with a bullet-shaped tip (7Fr-bullet), or a 7Fr catheter with a tee-shaped tip (7Fr-tee). This experimental study utilized a porcine model of biliary dilatation involving ten pigs. In the animal study, technical feasibility and clinical outcomes of the stent when placed with each of the delivery systems were examined. In addition, a phantom model was used to measure the resistance of these delivery systems to advancement. Phantom experiments showed that, compared with 7Fr-bullet, 7Fr-tee had less resistance force to the advancement of the stent delivery system. EUS-BD was technically successful in all ten pigs. Fistulous tract dilation was necessary in 100% (2/2), 75% (3/4), and 0% (0/4) of the pigs that underwent EUS-BD using 7.5Fr-bullet, 7Fr-bullet, and 7Fr-tee, respectively. There were no procedure-related complications. Our newly designed metal stent may be feasible and safe for EUS-BD, particularly when delivered by 7Fr-tee, because it eliminates the need for fistulous tract dilation.

  16. Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition

    Directory of Open Access Journals (Sweden)

    Jayanthan Aarthi

    2011-12-01

    Full Text Available Abstract Background Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines. Results AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination. Conclusions In addition to previously described involvement of insulin like growth factor (IGF family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

  17. Distribution of Glutathione-Stabilized Gold Nanoparticles in Feline Fibrosarcomas and Their Role as a Drug Delivery System for Doxorubicin—Preclinical Studies in a Murine Model

    Directory of Open Access Journals (Sweden)

    Katarzyna Zabielska-Koczywąs

    2018-03-01

    Full Text Available Feline injection site sarcomas (FISS are malignant skin tumors with high recurrence rates despite the primary treatment of radical surgical resections. Adjunctive radiotherapy or chemotherapy with doxorubicin is mostly ineffective. Cellular and molecular causes of multidrug resistance, specific physio-chemical properties of solid tumors impairing drug transport, and the tumor microenvironment have been indicated for causing standard chemotherapy failure. Gold nanoparticles are promising imaging tools, nanotherapeutics, and drug delivery systems (DDS for chemotherapeutics, improving drug transport within solid tumors. This study was conducted to assess the distribution of 4-nm glutathione-stabilized gold nanoparticles in FISS and their influence on kidney and liver parameters in nude mice. The role of gold nanoparticles as a doxorubicin DDS in FISS was examined to determine the potential reasons for failure to translate results from in vitro to in vivo studies. Grade III tumors characterized by a large area of necrosis at their core displayed positive immuneexpression of tumor-associated macrophages (TAM at both the periphery and within the tumor core near the area of necrosis. Gold nanoparticles did not cause necrosis at the injection site and had no negative effect on liver and kidney parameters in nude mice. Gold nanoparticles accumulated in the tumor core and at the periphery and co-internalized with TAM—an important observation and potential therapeutic target warranting further investigation. The large area of necrosis and high immunoexpression of TAM, indicating “pro-tumor macrophages”, may be responsible for FISS tumor progression and therapeutic failure. However, further studies are required to test this hypothesis.

  18. Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE KPT-335 in spontaneous canine cancer: results of a phase I study.

    Directory of Open Access Journals (Sweden)

    Cheryl A London

    Full Text Available The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1 against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL, mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed, mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday although biologic activity was observed at 1 mg/kg. Clinical benefit (CB including partial response to therapy (PR, n = 2 and stable disease (SD, n = 7 was observed in 9/14 dogs with NHL with a median time to progression (TTP for responders of 66 days (range 35-256 days. A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days. Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

  19. Tumour T1 changes in vivo are highly predictive of response to chemotherapy and reflect the number of viable tumour cells – a preclinical MR study in mice

    International Nuclear Information System (INIS)

    Weidensteiner, Claudia; Allegrini, Peter R; Sticker-Jantscheff, Melanie; Romanet, Vincent; Ferretti, Stephane; McSheehy, Paul MJ

    2014-01-01

    Effective chemotherapy rapidly reduces the spin–lattice relaxation of water protons (T 1 ) in solid tumours and this change (ΔT 1 ) often precedes and strongly correlates with the eventual change in tumour volume (TVol). To understand the biological nature of ΔT 1 , we have performed studies in vivo and ex vivo with the allosteric mTOR inhibitor, everolimus. Mice bearing RIF-1 tumours were studied by magnetic resonance imaging (MRI) to determine TVol and T 1 , and MR spectroscopy (MRS) to determine levels of the proliferation marker choline and levels of lipid apoptosis markers, prior to and 5 days (endpoint) after daily treatment with vehicle or everolimus (10 mg/kg). At the endpoint, tumours were ablated and an entire section analysed for cellular and necrotic quantification and staining for the proliferation antigen Ki67 and cleaved-caspase-3 as a measure of apoptosis. The number of blood-vessels (BV) was evaluated by CD31 staining. Mice bearing B16/BL6 melanoma tumours were studied by MRI to determine T 1 under similar everolimus treatment. At the endpoint, cell bioluminescence of the tumours was measured ex vivo. Everolimus blocked RIF-1 tumour growth and significantly reduced tumour T 1 and total choline (Cho) levels, and increased polyunsaturated fatty-acids which are markers of apoptosis. Immunohistochemistry showed that everolimus reduced the %Ki67 + cells but did not affect caspase-3 apoptosis, necrosis, BV-number or cell density. The change in T 1 (ΔT 1 ) correlated strongly with the changes in TVol and Cho and %Ki67 + . In B16/BL6 tumours, everolimus also decreased T 1 and this correlated with cell bioluminescence; another marker of cell viability. Receiver-operating-characteristic curves (ROC) for everolimus on RIF-1 tumours showed that ΔT 1 had very high levels of sensitivity and specificity (ROC AUC = 0.84) and this was confirmed for the cytotoxic patupilone in the same tumour model (ROC AUC = 0.97). These studies suggest that ΔT 1 is not a

  20. The development of functional network organization in early childhood and early adolescence: A resting-state fNIRS study

    OpenAIRE

    Lin Cai; Qi Dong; Haijing Niu

    2018-01-01

    Early childhood (7–8 years old) and early adolescence (11–12 years old) constitute two landmark developmental stages that comprise considerable changes in neural cognition. However, very limited information from functional neuroimaging studies exists on the functional topological configuration of the human brain during specific developmental periods. In the present study, we utilized continuous resting-state functional near-infrared spectroscopy (rs-fNIRS) imaging data to examine topological ...

  1. MiR-221 and -222-based therapeutic approach in melanoma and GIST (Gastrointestinal Stromal Tumor): in vitro and in vivo preclinical studies

    Energy Technology Data Exchange (ETDEWEB)

    Care, A; Bonci, D [Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome (Italy); Peschle, C [IRCCS MultiMedica, Milan (Italy)

    2009-07-01

    Micro RNAs (miRs) are small ({approx}22 nucleotides) non coding RNAs involved in gene expression, as negative regulators of specific mRNA targets. Growing evidences indicated miR functional roles in all the main biological processes, including cancer where they can act as oncogenes as well as tumor suppressor genes. Several studies reported the involvement of miR- 221 and -222 in the induction and/or progression of different neoplasias. We have analyzed miR-221/-222 functional role in a panel of differently staged melanoma cell lines and primary bioptic samples, showing their capabilities to regulate two distinct, but functionally convergent pathways of melanocyte transformation through the cell cycle inhibitor p27Kip and c-kit receptor. We also demonstrated the lack of the tumor suppressor gene PLZF as a direct cause of miR-221/-222 up regulation in melanoma cells. In vitro and, more important, in vivo studies confirmed that suppression of miR-221/-222 strongly reduced melanoma growth and dissemination.

  2. MiR-221 and -222-based therapeutic approach in melanoma and GIST (Gastrointestinal Stromal Tumor): in vitro and in vivo preclinical studies

    International Nuclear Information System (INIS)

    Care, A.; Bonci, D.; Peschle, C.

    2009-01-01

    Micro RNAs (miRs) are small (∼22 nucleotides) non coding RNAs involved in gene expression, as negative regulators of specific mRNA targets. Growing evidences indicated miR functional roles in all the main biological processes, including cancer where they can act as oncogenes as well as tumor suppressor genes. Several studies reported the involvement of miR- 221 and -222 in the induction and/or progression of different neoplasias. We have analyzed miR-221/-222 functional role in a panel of differently staged melanoma cell lines and primary bioptic samples, showing their capabilities to regulate two distinct, but functionally convergent pathways of melanocyte transformation through the cell cycle inhibitor p27Kip and c-kit receptor. We also demonstrated the lack of the tumor suppressor gene PLZF as a direct cause of miR-221/-222 up regulation in melanoma cells. In vitro and, more important, in vivo studies confirmed that suppression of miR-221/-222 strongly reduced melanoma growth and dissemination

  3. Early development of executive functions: a differential study

    Directory of Open Access Journals (Sweden)

    Sylvia Sastre-Riba

    2015-05-01

    Full Text Available The ontogeny of executive functions is essential in explaining differential and normative developmental trends. Executive functions must be studied from an early age given their consequential effects on mental flexibility, monitoring information, planning, and cognitive control. We propose a differential study in alternative developmental courses through observing typical babies, Down syndrome babies, and babies with risk-factors at birth (due to low weight or to congenital hypothyroidism. Applymg Systematic Observational Methodology, spontaneous babies' activity was registered. The results indicated that: a Typical babies showed better shifting and action flexibility in order to obtain a goal, thus better results; b Among the higher risk-babies, the lower efficacy in executive functioning was observed in underweight babies. Those with hypothyroidism were more in line with the typical babies; c Underweight babies showed a good level of combining actions but they obtained inferior results; d Down syndrome babies displayed more executive functioning difficulty, lower flexibility, high perseveration and less error detection.

  4. Preclinical pharmacokinetics, biodistribution, radiation dosimetry and acute toxicity studies required for regulatory approval of a Clinical Trial Application for a Phase I/II clinical trial of 111In-BzDTPA-pertuzumab

    International Nuclear Information System (INIS)

    Lam, Karen; Chan, Conrad; Done, Susan J.; Levine, Mark N.; Reilly, Raymond M.

    2015-01-01

    administration of multiples of the human dose in healthy Balb/c mice but no histopathological abnormalities were noted in any tissues. There were no significant differences in body mass between mice injected with 111 In-BzDTPA-pertuzumab or control mice. Conclusion: Preclinical studies predicted that 111 In-BzDTPA-pertuzumab is safe to administer to humans at a dose of 111 MBq (5 mg). The radiopharmaceutical exhibited preclinical pharmacokinetic, biodistribution and radiation dosimetry properties suitable for advancement to a first-in-humans clinical trial. Advances in knowledge and implications for patient care: The results of these studies supported the regulatory approval by Health Canada of 111 In-BzDTPA-pertuzumab for a Phase I/II clinical trial of for imaging the response of patients with metastatic BC to treatment with trastuzumab combined with chemotherapy (PETRA trial; ClinicalTrials.gov identifier: NCT01805908)

  5. Investigating the Usability and Acute Effects of a Bedside Video Console to Prefrontal Cortical Activity Alterations: A Preclinical Study in Healthy Elderly

    Directory of Open Access Journals (Sweden)

    Ruud H. Knols

    2017-11-01

    Full Text Available Elderly people at risk of developing cognitive decline; e.g., following surgery, may benefit from structured, challenging, and repetitive cognitive video training. This study assessed usability and acute effects of a newly developed bedside console (COPHYCON. Fifteen healthy elderly individuals performed a one-time 80-min intervention, including cognitive video games aimed at improving awareness and selective attention. Perceived usefulness and perceived ease of use (Technology Acceptance Model were assessed together with measures of the achieved game level, reaction times, (in- correct responses during ALERT and SELECT game play. Further, prefrontal cortical involvement of the regional cerebral hemoglobin saturation (rS02% assessed with functional near infrared spectroscopy (fNIRS (n = 5 and EEG power (n = 10 was analyzed. All participants completed the study without any adverse events. Perceived usefulness and perceived ease of use (TAM scores range 1–7 of the system varied between 3.9 and 6.3. The game levels reached for awareness varied between 9 and 11 (initial score 8–10, for reaction speed between 439 and 469 ms, and for correct responses between 74.1 and 78.8%. The highest level for the selective attention games was 2 (initial score 1, where reaction speed varied between 439 and 469 ms, correct responses between 96.2 and 98.5%, respectively. The decrease of rS02% in the right prefrontal cortex during gameplay was significantly (p < 0.001 lower, compared to the left prefrontal cortex. Four participants yielded significant lower rS02% measures after exergaming with the ALERT games (p < 0.000, but not with the SELECT games. EEG recordings of theta power significantly decreased in the averaged ~0.25–0.75 time interval for the left prefrontal cortex sensor across the cognitive game levels between the ALERT 1 and SELECT 1, as well as between SELECT 1 and 2 games. Participants rated the usability of the COPHYCON training positively

  6. Early parenting styles and sexual offending behavior: A comparative study.

    Science.gov (United States)

    Sigre-Leirós, Vera; Carvalho, Joana; Nobre, Pedro J

    2016-01-01

    Sexual offenders, in general, report problematic rearing practices from their parents, lacking however more empirical research on this topic regarding particular subtypes of offenders. The current study examined the relationship between early parenting styles and different types of sexual offending. A total of 113 sexual offenders (rapists, pedophilic and nonpedophilic child molesters), and 51 nonsexual offenders completed the EMBU (My Memories of Upbringing), the Brief Symptom Inventory, and the Socially Desirable Response Set Measure. Results showed that rapists were less likely to remember their fathers as being emotionally warm compared with nonsexual offenders and pedophilic child molesters. In addition, compared with rapists, pedophilic offenders perceived their mothers as having been less emotionally warm to them. Overall, results showed that certain developmental experiences with parents were able to distinguish between subtypes of offenders supporting an association between distal interpersonal factors and sexual offending. These findings may have important implications for early intervention and prevention of sexual crimes. Further research using larger samples of pedophilic child molesters is recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Early breastfeeding experiences of adolescent mothers: a qualitative prospective study

    Directory of Open Access Journals (Sweden)

    Smith Paige Hall

    2012-09-01

    Full Text Available Abstract Background Teen mothers face many challenges to successful breastfeeding and are less likely to breastfeed than any other population group in the U.S. Few studies have investigated this population; all prior studies are cross-sectional and collect breastfeeding data retrospectively. The purpose of our qualitative prospective study was to understand the factors that contribute to the breastfeeding decisions and practices of teen mothers. Methods This prospective study took place from January through December 2009 in Greensboro, North Carolina in the U.S. We followed the cohort from pregnancy until two weeks after they ceased all breastfeeding and milk expression. We conducted semi-structured interviews at baseline and follow-up, and tracked infant feeding weekly by phone. We analyzed the data to create individual life and breastfeeding journeys and then identified themes that cut across the individual journeys. Results Four of the five teenagers breastfed at the breast for nine days: in contrast, one teen breastfed exclusively for five months. Milk expression by pumping was associated with significantly longer provision of human milk. Breastfeeding practices and cessation were closely connected with their experiences as new mothers in the context of ongoing multiple roles, complex living situations, youth and dependency, and poor knowledge of the fundamentals of breastfeeding and infant development. Breastfeeding cessation was influenced by inadequate breastfeeding skill, physically unpleasant and painful early experiences they were unprepared to manage, and inadequate health care response to real problems. Conclusions Continued breastfeeding depends on a complex interplay of multiple factors, including having made an informed choice and having the skills, support and experiences needed to sustain the belief that breastfeeding is the best choice for them and their baby given their life situation. Teenagers in the US context need to have

  8. [{sup 11}C]S.L.(25.1188), a new radioligand to study the monoamine oxidase type B with PET: preclinical characterisation

    Energy Technology Data Exchange (ETDEWEB)

    Saba, W.; Valette, H.; Peyronneau, M.A.; Bramoulle, Y.; Coulon, C.; Dolle, F.; Bottlaender, M. [Service Hospitalier Frederic Joliot, IIBM/DSV, 91 - Orsay (France); Curet, O.; George, P. [Sanofi-Aventis, 92 - Bagneux (France)

    2008-02-15

    Introduction. - Monoamine oxidase (M.A.O.) is a flavin containing enzyme, that catalyzes the oxidative deamination of various amines and neurotransmitters. Two isoforms exist, M.A.O.-A and M.A.O.-B. Variations in M.A.O. activity may be associated to human disease such as Parkinson and Alzheimer disease. Few radiotracers have been developed for M.A.O. PET studies such as [{sup 11}C]deprenyl, an irreversible M.A.O.-B inhibitor. Recently an oxazolidinone derivative, S.L.- 25.1188 ((S)-5-methoxy-methyl-3-[6-(4,4,4-tri-fluoro butoxy)- benzo[d]isoxazol-3-yl]-oxazolidin-2-one), belonging to a new generation of selective and reversible M.A.O.-B inhibitors was developed and showed in vitro a high selectivity for M.A.O.B. [1]. The aim of this study was to characterize [{sup 11}C]S.L.- 25.1188 as radioligand for in vivo PET examination of M.A.O.-B. Materials and methods. - PET studies of the brain distribution were carried out in male Papio anubis baboons. Selectivity and reversibility of [{sup 11}C]S.L.-25.1188 binding for M.A.O.-B was assessed by pre-treatment or displacement experiments (30 min before and after tracer injection, respectively) using reference ligands for M.A.O.-B (deprenyl: 2 mg/kg i.v. and lazabemide: 0.5 mg/kg i.v.) or by displacement experiments using unlabelled S.L.-25.1188 (1 mg/kg, i.v., 30 min after tracer injection). Distribution volume (D.V.) was calculated using 2-tissue-compartment model. The saturable binding following pre-treatment with deprenyl was considered as the specific binding. Results. - After injection, [1{sup 1C}]S.L.-25.1188 presents a rapid phase of distribution in blood (about 5 min), followed by a elimination with T1/2 of 75 min. The Blood to plasma concentration ratio was constant during the experimentation (0.9 {+-} .04) consistent with a similar kinetic of [{sup 11}C]S.L.- 25.1188 in both blood and plasma. Metabolism analysis showed that [{sup 11}C]S.L.-25.1188 is stable in vivo. In the brain, uptake in different areas was

  9. Quantification of triacontanol and its PEGylated prodrug in rat plasma by GC-MS/MS: Application to a pre-clinical pharmacokinetic study.

    Science.gov (United States)

    Lu, Xiaoyu; Fang, Min; Dai, Yu; Yang, Yue; Fan, Ali; Xu, Jiaqiu; Qin, Zhiying; Lu, Yang; Zhao, Di; Chen, Xijing; Li, Ning

    2018-04-24

    PEGylation techniques have been increasingly employed in drug delivery system and chemical modification of compounds with low aqueous solubility. Triacontanol (TA) is a natural product with several pharmacological activities, but its low aqueous solubility significantly limited its application. PEGylated triacontanol (PEG-TA) was designed as the prodrug to improve the aqueous solubility and pharmacokinetic properties of TA. On the basis of salting-out assisted liquid-liquid extraction (SALLE) and saponification sample preparation procedure, a reliable gas chromatography tandem mass spectrometric (GC-MS/MS) method was developed and validated for the quantification of PEG-TA and its metabolite TA in rat plasma after separation and transformation. Acetonitrile-methanol (9:1, v/v) and ammonium acetate (10 M) were utilized to separate PEG-TA and TA (including conjugated TA with fatty acid). Saponification facilitated the complete conversion of PEG-TA into TA, so PEG-TA could be indirectly quantified. The results revealed that the GC-MS/MS method had excellent selectivity, accuracy and linearity. Calibration curves were linear (R 2 >0.99) within the range of 20.0-1000.0 ng/mL for TA and 100.0-10,000.0 ng/mL for PEG-TA. The intra- and inter-day precision of quality control samples were within 15%, and their accuracy values varied from 93.54% to 113.38%. This analytical method has been successfully applied to pharmacokinetic study of PEG-TA. This study can facilitate the further exploration and quantification of PEGylated prodrugs. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. 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.

  11. NGAL (Neutrophil Gelatinase-associated Lipocalin) is an Early Predictor of Acute Kidney Injury after Cardiac Surgery and Variation of NGAL Values in Homogenous Study Subject.

    Science.gov (United States)

    Miah, O F; Dowel, F A; Latif, A; Hai, A N; Mahmud, M A; Razzak, M A; Ahammod, T

    2018-01-01

    Isolated CABG (coronary artery bypass grafting) has the lowest incidence of AKI (Acute Kidney Injury), followed by valvular surgery and then, combined CABG with valvular surgery. Due to the difference in baseline characteristics and in surgery type, the range of incidence is between 8.9 and 39% based on RIFLE (Risk Injury failure loss end stage kidney disease) or AKIN (Acute Kidney Injury Network) criteria. The advent of novel biomarkers of kidney injury has opened a new era of early detection and prognosis prediction for AKI. NGAL is a small molecule of 178 amino acids that belongs to the super family of lipocalins, which are proteins specialized in binding and transporting small hydrophobic molecules. The expression of NGAL raises 1000 fold in humans and rodents in response to renal tubular injury and it appears so rapidly in the urine and serum that it is useful as an early biomarker of renal failure. The role of plasma NGAL to classify AKI severity and predict the need for RRT (renal replacement therapy) after cardiac surgery has been suggested. Although study subjects were more or less from same cohort (All undergone cardiac surgery), previous studies showed that NGAL raised differently in different proportion. NGAL as an early AKI marker has successfully passed through the pre-clinical, assay development and initial clinical testing stages. It is badly need to enter in a consensus about the cutoff value of NGAL which should help the physician about leveling a case as AKI or non AKI and their consequence management.

  12. Development of {sup 18}F-FDG ([F-18]-2-fluoro-2-deoxy-D-glucose) injection for imaging of tumor reflecting glucose metabolism. Results of preclinical studies

    Energy Technology Data Exchange (ETDEWEB)

    Ino, Sento; Shimada, Takayuki; Kanagawa, Masaru; Suzuki, Noriaki; Kondo, Susumu; Shirakami, Yoshifumi; Ito, Osamu; Kato-Azuma, Makoto [Nihon Medi-Physics Co., Ltd., Sodegaura, Chiba (Japan). Research Center

    1999-07-01

    Fluorine-18-2-fluoro-2-deoxy-D-glucose ({sup 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 {sup 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 {sup 18}F-FDG injection is expected to be useful for further clinical application. (author)

  13. Noninvasive assessment of preclinical atherosclerosis

    Directory of Open Access Journals (Sweden)

    Helen A Lane

    2006-03-01

    Full Text Available Helen A Lane, Jamie C Smith, J Stephen DaviesDepartment of Endocrinology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UKAbstract: Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk.Keywords: endothelial function, vascular risk, vascular stiffness

  14. Ridge augmentation using recombinant human fibroblast growth factor-2 with biodegradable gelatin sponges incorporating β-tricalcium phosphate: a preclinical study in dogs.

    Science.gov (United States)

    Hoshi, S; Akizuki, T; Matsuura, T; Ikawa, T; Kinoshita, A; Oda, S; Tabata, Y; Matsui, M; Izumi, Y

    2016-02-01

    Fibroblast growth factor-2 (FGF-2) regulates the proliferation and differentiation of osteogenic cells, resulting in the promotion of bone formation. Biodegradable gelatin sponges incorporating β-tricalcium phosphate (β-TCP) have been reported as a scaffold, which has the ability to control growth factor release, offering sufficient mechanical strength and efficient migration of mesenchymal cells. In this study, we evaluated the effects of the combined use of recombinant human FGF-2 (rhFGF-2) and gelatin/β-TCP sponge on ridge augmentation in dogs. Six male beagle dogs were used in this study. Twelve wk after tooth extraction, bilateral 10 × 5 mm (width × depth) saddle-type defects were created 3 mm apart from the mesial side of the maxillary canine. At the experimental sites, the defects were filled with gelatin/β-TCP sponge infiltrated with 0.3% rhFGF-2, whereas gelatin/β-TCP sponge infiltrated with saline was applied to the control sites. Eight wk after surgery, qualitative and quantitative analyses were performed. There were no signs of clinical inflammation at 8 wk after surgery. Histometric measurements revealed that new bone height at the experimental sites (2.98 ± 0.65 mm) was significantly greater than that at the control sites (1.56 ± 0.66 mm; p = 0.004). The total tissue height was greater at the experimental sites (6.62 ± 0.66 mm) than that at the control sites (5.95 ± 0.74 mm), although there was no statistical significant difference (p = 0.051). Cast model measurements revealed that the residual defect height at the experimental sites (2.31 ± 0.50 mm) was significantly smaller than that at the control sites (3.51 ± 0.78 mm; p = 0.012). The combined use of rhFGF-2 and gelatin/β-TCP sponge promotes ridge augmentation in canine saddle-type bone defects. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. 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

  16. Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

    Energy Technology Data Exchange (ETDEWEB)

    Cao-Pham, Thanh-Trang; Tran, Ly-Binh-An; Colliez, Florence; Joudiou, Nicolas [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); El Bachiri, Sabrina [Université Catholique de Louvain, IMMAQ Technological Platform, Methodology and Statistical Support, Louvain-la-Neuve (Belgium); Grégoire, Vincent [Université Catholique de Louvain, Institute of Experimental and Clinical Research, Center for Molecular Imaging, Radiotherapy and Oncology, Brussels (Belgium); Levêque, Philippe; Gallez, Bernard [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium); Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be [Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium)

    2016-09-01

    Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}*. R{sub 1} is sensitive to dissolved molecular oxygen, whereas R{sub 2}* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}* with pO{sub 2} assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R{sub 1}, R{sub 2}*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O{sub 2}, 5% CO{sub 2}). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO{sub 2}. Global and lipids R{sub 1} were found to be correlated to pO{sub 2} in the rhabdomyosarcoma model, whereas R{sub 2}* was found to be inversely correlated to pO{sub 2} in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R{sub 2}* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. {sup 18}F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R{sub 1} and R{sub 2}* parameters to changes in tumor oxygenation. However, R{sub 1

  17. Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

    International Nuclear Information System (INIS)

    Cao-Pham, Thanh-Trang; Tran, Ly-Binh-An; Colliez, Florence; Joudiou, Nicolas; El Bachiri, Sabrina; Grégoire, Vincent; Levêque, Philippe; Gallez, Bernard; Jordan, Bénédicte F.

    2016-01-01

    Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R_1, water R_1, lipids R_1, and R_2*. R_1 is sensitive to dissolved molecular oxygen, whereas R_2* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R_1, water R_1, lipids R_1, and R_2* with pO_2 assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R_1, R_2*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O_2, 5% CO_2). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO_2. Global and lipids R_1 were found to be correlated to pO_2 in the rhabdomyosarcoma model, whereas R_2* was found to be inversely correlated to pO_2 in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R_2* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. "1"8F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R_1 and R_2* parameters to changes in tumor oxygenation. However, R_1 parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R_2* was found to be

  18. 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

    Full Text Available Many patients undergoing cardiac surgery have risk factors for both atrial fibrillation (AF and stroke. The left atrial appendage (LAA is the primary site for thrombi formation. The most severe complication of emboli derived from LAA is stroke, which is associated with a 12-month mortality rate of 38% and a 12-month recurrence rate of 17%. The most common form of treatment for atrial fibrillation and stroke prevention is the pharmacological therapy with anticoagulants. Nonetheless this form of therapy is associated with high risk of major bleeding. Therefore LAA occlusion devices should be tested for their ability to reduce future cerebral ischemic events in patients with high-risk of haemorrhage.The aim of this study was to evaluate the safety and feasibility of a novel left atrial appendage exclusion device with a minimally invasive introducer in a swine model.A completely novel LAA device, which is composed of two tubes connected together using a specially created bail, was designed using finite element modelling (FEM to obtain an optimal support force of 36 N at the closure line. The monolithic form of the occluder was obtained by using additive manufacturing of granular PA2200 powder with the technology of selective laser sintering (SLS. Fifteen swine were included in the feasibility tests, with 10 animals undergoing fourteen days of follow-up and 5 animals undergoing long-term observation of 3 months. For one animal, the follow-up was further prolonged to 6 months. The device was placed via minithoracotomy. After the observation period, all of the animals were euthanized, and their hearts were tested for LAA closure and local inflammatory and tissue response.After the defined observation period, all fifteen hearts were explanted. In all cases the full closure of the LAA was achieved. The macroscopic and microscopic evaluation of the explanted hearts showed that all devices were securely integrated in the surrounding tissues. No

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

    Science.gov (United States)

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

    2013-03-01

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

  20. Brain morphometry and the neurobiology of levodopa-induced dyskinesias: current knowledge and future potential for translational pre-clinical neuroimaging studies.

    Directory of Open Access Journals (Sweden)

    Clare eFinlay

    2014-06-01

    Full Text Available Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson's disease (PD developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater understanding of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID is therefore crucial to develop new treatments to prevent or mitigate LID. Such investigations in humans are largely confined to assessment of neurochemical and cerebrovascular blood flow changes using positron emission tomography (PET and functional magnetic resonance imaging (fMRI. However, recent evidence suggests that LID is associated with specific morphological changes in the frontal cortex and midbrain, detectable by structural MRI and voxel-based morphometry (VBM. Current human neuroimaging methods however lack sufficient resolution to reveal the biological mechanism driving these morphological changes at the cellular level. In contrast, there is a wealth of literature from well-established rodent models of LID documenting detailed post-mortem cellular and molecular measurements. The combination therefore of advanced neuroimaging methods and rodent LID models offers an exciting opportunity to bridge these currently disparate areas of research. To highlight this opportunity, in this mini-review, we provide an overview of the current clinical evidence for morphological changes in the brain associated with LID and identify potential cellular mechanisms as suggested from human and animal studies. We then suggest a framework for combining small animal MRI imaging with rodent models of LID, which may provide important mechanistic insights into the neurobiology of LID.

  1. Determination of lansoprazole enantiomers in dog plasma by column-switching liquid chromatography with tandem mass spectrometry and its application to a preclinical pharmacokinetic study.

    Science.gov (United States)

    Wang, Hao; Sun, Yantong; Meng, Xiangjun; Yang, Bo; Wang, Jian; Yang, Yan; Gu, Jingkai

    2015-09-01

    Lansoprazole, a selective proton pump inhibitor, has a chiral benzimidazole sulfoxide structure and is used for the treatment of gastric acid hypersecretory related diseases. To investigate its stereoselective pharmacokinetics, a column-switching liquid chromatography with tandem mass spectrometry method was developed for the determination of lansoprazole enantiomers in dog plasma using (+)-pantoprazole as an internal standard. After a simple protein precipitation procedure with acetonitrile, matrix components left behind after sample preparation were further eliminated from the sample by reversed-phase chromatography on a C18 column. The fluent was fed to a chiral column for the separation of lansoprazole enantiomers. Baseline separation of lansoprazole enantiomers was achieved on a Chiralcel OZ-RH column using acetonitrile/0.1% formic acid in water (35:65, v/v) as the mobile phase at 40°C. The linearity of the calibration curves ranged from 3 to 800 ng/mL for each enantiomer. Intra- and inter-day precisions ranged from 2.1 to 7.3% with an accuracy of ±1.7% for (+)-lansoprazole, and from 1.6 to 6.9% with an accuracy of ±3.5% for (-)-lansoprazole, respectively. The validated method was successfully applied for the stereoselective pharmacokinetic study of lansoprazole in beagle dog after intravenous infusion. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Relationship of pass/fail grading and curriculum structure with well-being among preclinical medical students: a multi-institutional study.

    Science.gov (United States)

    Reed, Darcy A; Shanafelt, Tait D; Satele, Daniel W; Power, David V; Eacker, Anne; Harper, William; Moutier, Christine; Durning, Steven; Massie, F Stanford; Thomas, Matthew R; Sloan, Jeff A; Dyrbye, Liselotte N

    2011-11-01

    Psychological distress is common among medical students. Curriculum structure and grading scales are modifiable learning environment factors that may influence student well-being. The authors sought to examine relationships among curriculum structures, grading scales, and student well-being. The authors surveyed 2,056 first- and second-year medical students at seven U.S. medical schools in 2007. They used the Perceived Stress Scale, Maslach Burnout Inventory, and Medical Outcomes Study Short Form (SF-8) to measure stress, burnout, and quality of life, respectively. They measured curriculum structure using hours spent in didactic, clinical, and testing experiences. Grading scales were categorized as two categories (pass/fail) versus three or more categories (e.g., honors/pass/fail). Of the 2,056 students, 1,192 (58%) responded. In multivariate analyses, students in schools using grading scales with three or more categories had higher levels of stress (beta 2.65; 95% CI 1.54-3.76, Pstudents in schools using pass/fail grading. There were no relationships between time spent in didactic and clinical experiences and well-being. How students are evaluated has a greater impact than other aspects of curriculum structure on their well-being. Curricular reform intended to enhance student well-being should incorporate pass/fail grading.

  3. Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

    Science.gov (United States)

    Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; Jolesz, Ferenc A; Zadicario, Eyal; Killiany, Ron; Moore, Tara; Rosen, Douglas

    2006-08-01

    MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used.

  4. Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.

    Science.gov (United States)

    Woitek, Felix; Zentilin, Lorena; Hoffman, Nicholas E; Powers, Jeffery C; Ottiger, Isabel; Parikh, Suraj; Kulczycki, Anna M; Hurst, Marykathryn; Ring, Nadja; Wang, Tao; Shaikh, Farah; Gross, Polina; Singh, Harinder; Kolpakov, Mikhail A; Linke, Axel; Houser, Steven R; Rizzo, Victor; Sabri, Abdelkarim; Madesh, Muniswamy; Giacca, Mauro; Recchia, Fabio A

    2015-07-14

    Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor promoter. Compared with control subjects, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B167 expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions. Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and effective new therapy for nonischemic heart failure. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  5. Vitamin D for combination photodynamic therapy of skin cancer in individuals with vitamin D deficiency: Insights from a preclinical study in a mouse model of squamous cell carcinoma

    Science.gov (United States)

    Anand, Sanjay; Thomas, Erik; Hasan, Tayyaba; Maytin, Edward V.

    2016-03-01

    Combination photodynamic therapy (cPDT) in which vitamin D (VD) is given prior to aminolevulinate, a precursor (pro-drug) for protoporphyrin IX (PpIX), is an approach developed in our laboratory. We previously showed that 1α,25- dihydroxyvitamin D3 (calcitriol), given prior to PDT, enhances accumulation of PpIX and improves cell death post-PDT in a mouse skin cancer model. However, since calcitriol poses a risk for hypercalcemia, we replaced systemic calcitriol with oral cholecalciferol (D3), administered as a high (tenfold, "10K") diet over a ten-day period. Here, we ask whether VD deficiency might alter the response to cPDT. Nude mice were fed a VD-deficient diet for at least 4 weeks ("deficient"); controls were fed a normal 1,000 IU/kg diet ("1K"). Human A431 cells were implanted subcutaneously and mice were switched to the 10K diet or continued on their baseline diets (controls). In other experiments, mice received a human equivalent dose of 50,000 IU D3 by oral gavage, to simulate administration of a single, high-dose VD pill. At various times, tumors were harvested and serum was collected to measure levels of VD metabolic intermediates. A significant increase in PpIX levels and in the expression of differentiation and proliferation markers in tumor tissue was observed after VD supplementation of both the deficient and 1K mice. Further results describing mechanistic details of PpIX enhancement through alteration of heme- and VD-metabolic enzyme levels will be presented. Based on these results, a clinical study using oral vitamin D prior to PDT for human skin cancer should be performed.

  6. Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

    Science.gov (United States)

    Lee, Karla C L; Baker, Luisa A; Stanzani, Giacomo; Alibhai, Hatim; Chang, Yu Mei; Jimenez Palacios, Carolina; Leckie, Pamela J; Giordano, Paola; Priestnall, Simon L; Antoine, Daniel J; Jenkins, Rosalind E; Goldring, Christopher E; Park, B Kevin; Andreola, Fausto; Agarwal, Banwari; Mookerjee, Rajeshwar P; Davies, Nathan A; Jalan, Rajiv

    2015-09-01

    In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  7. Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies

    Directory of Open Access Journals (Sweden)

    Laith Altaweel

    2009-09-01

    Full Text Available Laith Altaweel, Daniel Sweeney, Xizhong Cui, Amisha Barochia, Charles Natanson, Peter Q EichackerCritical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USAAbstract: Recombinant human activated protein C (rhAPC was developed to reduce excessive coagulant and inflammatory activity during sepsis. Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC. Based in large part on the results of a single multicenter randomized controlled trial, rhAPC was first approved in 2001 by the US Food and Drug Administration (FDA as adjunctive therapy in septic patients with a high risk of death. This was followed closely by approval in Europe, Australia, and New Zealand. At the original FDA review of rhAPC, concerns were raised as to whether a confirmatory trial should be done before final regulatory approval because of concerns that rhAPCs bleeding risk might outweigh its potential benefit during clinical use. Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis. Moreover, subsequent controlled trials in other types of septic patients and observational studies appear to support earlier concerns that the benefit-to-risk ratio of rhAPC may not support its clinical use. This experience has prompted additional trials presently underway, to define whether treatment with rhAPC as it was originally indicated in septic patients with persistent shock, is safe and effective. Until such trials are complete, physicians employing this agent must carefully consider which patients may be appropriate candidates for rhAPC administration.Keywords: rhAPC, treatment, sepsis

  8. Preclinical pharmacological study of 99mTcN(NOET)2 and comparison with 201Tl in redistribution of ischemia myocardium

    International Nuclear Information System (INIS)

    Wang, J.C.; Zhang, J.B.; Wang, Q.; Mi, H.Z.; Wang, X.B.

    2002-01-01

    Aim: To study the biological properties of the myocardial imaging agent 99m TcN(NOET) 2 and compare with 201 Tl in redistribution of ischemia myocardium. Materials and Methods: To prepared the 99m TcN(NOET) 2 complex, the intermediate [ 99m TcN] 2+ and ligand NOET were synthesized. In the presence of reducer and the doner of N, the [ 99m Tc=N] 2+ could be synthesized at 100, then NOET was added, 99m TcN(NOET) 2 was formed at room temperature. 201 Tl was provided by the Department of Isotope, China Institute of Atomic Energy. Five dogs were from the Fu Wai experimental animal feeding center, two of them were made into ischemia myocardium models by ligating some coronary artery branches were demonstrated by X-ray coronary angiography, the extent of stenosis of those blood vessels was over 90%. Dynamic imaging of rest was performed respectively in three normal dogs after injecting a dose of 555MBq (15mCi) of 99m TcN(NOET) 2 complex up to two hours. The whole body imaging planar and tomography imaging was carried out respectively at fixed time intervals during two hours in order to obtain the time-activity curves of heart, lung and liver, in vivo biodistribution and quality analysis of myocardial images. Moreover, intravenous blood samples were collected at different times to gain the kinetics of blood clearance. Stress and redistribution imaging underwent in two dogs with ischemia myocardium. Dipyridamol was given intravenously at a dose of 0.6mg/Kg in 4 mins. Stress :9 9m TcN(NOET) 2 myocardial SPECT imaging was performed at 30, 70 and 110 min after injection of 99m TcN(NOET) 2 complex, stress 201 Tl myocardial SPECT imaging was carried out 10 min and redistribution imaging 4 hr after injection of 55.5MBq (1.5mCi) 201 Tl chloride. The tests of 99m TcN(NOET) 2 and 201 Tl were performed respectively in the same dog within 10 days, in order to obtain a comparison between two myocardial redistribution imaging. Results: Radiochemical purity of 99m TcN(NOET) 2 was 98.41%

  9. A case study of early British Sherlockian fandom

    Directory of Open Access Journals (Sweden)

    Katharine Brombley

    2017-03-01

    Full Text Available Previous studies of Sherlock Holmes fandom have concentrated on fan letters as being exemplary of the early beginnings of the Great Game: a fantasy played by fans that acts upon the belief that Sherlock Holmes exists. Fans, while fully comprehending that it is indeed a fantasy or a game, perform fan activities such as historical and literary analysis as if Holmes were real. This paper shifts the focus away from letter writing as the central means of the expression of this ironic belief and looks at the example of collecting autographs as a means of celebration of the canon. It places the autograph in its historical context of being the meeting point between the remnants of the Romantic theory of genius, the development of pseudosciences such as the interpretation of handwriting, and the literary, cultural, and commercial landscape in which Holmes appeared.

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

    Directory of Open Access Journals (Sweden)

    Nicole Rafai

    2016-11-01

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

  11. Eradication of early P. aeruginosa infection in children age with cystic fibrosis: The early study.

    Science.gov (United States)

    Ratjen, Felix; Moeller, Alexander; McKinney, Martha L; Asherova, Irina; Alon, Nipa; Maykut, Robert; Angyalosi, Gerhild

    2018-04-20

    Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. This double-blind, placebo-controlled trial randomised CF patients early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29. On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p early Pa-infection with a favourable safety profile in young CF patients. NCT01082367. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  12. Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Cacciamani, Federica; Tandetnik, Caroline; Gagliardi, Geoffroy; Bertin, Hugo; Habert, Marie-Odile; Hampel, Harald; Boukadida, Laurie; Révillon, Marie; Epelbaum, Stéphane; Dubois, Bruno

    2017-01-01

    Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD). In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group. This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

  13. preclinical toxicity study of the phytomedicine

    African Journals Online (AJOL)

    2014-01-31

    Jan 31, 2014 ... The animals were observed continuously for the first 4 hours and then for each hour the next 12 hours and at 6 hourly interval for the next 56 hours after administering of the drug to observe any death or changes in general behavior and other physiological activities (Bürger et al., 2005; Shah et al., 1997).

  14. The early growth and development study: a prospective adoption design.

    Science.gov (United States)

    Leve, Leslie D; Neiderhiser, Jenae M; Ge, Xiaojia; Scaramella, Laura V; Conger, Rand D; Reid, John B; Shaw, Daniel S; Reiss, David

    2007-02-01

    The Early Growth and Development Study is a prospective adoption study of birth parents, adoptive parents, and adopted children (N=359 triads) that was initiated in 2003. The primary study aims are to examine how family processes mediate or moderate the expression of genetic influences in order to aid in the identification of specific family processes that could serve as malleable targets for intervention. Participants in the study are recruited through adoption agencies located throughout the United States, following the birth of a child. Assessments occur at 6-month intervals until the child reaches 3 years of age. Data collection includes the following primary constructs: infant and toddler temperament, social behavior, and health; birth and adoptive parent personality characteristics, psychopathology, competence, stress, and substance use; adoptive parenting and marital relations; and prenatal exposure to drugs and maternal stress. Preliminary analyses suggest the representativeness of the sample and minimal confounding effects of current trends in adoption practices, including openness and selective placement. Future plans are described.

  15. Study of early pregnancy factor (EPF) in equine (Equus caballus).

    Science.gov (United States)

    Ohnuma, K; Yokoo, M; Ito, K; Nambo, Y; Miyake, Y I; Komatsu, M; Takahashi, J

    2000-03-01

    Early pregnancy factor (EPF) is an immunosuppressive protein detected in the early pregnancy serum. We have already reported that we developed the rosette inhibition test for mare EPF and detected EPF in thoroughbreds. The aim of this study was to determine whether or not our method could be used clinically. The rosette inhibition test for equine EPF was carried out on serum from six nonpregnant and six pregnant Shetland ponies, a female and a male Chinese pony, and four nonpregnant and 13 pregnant thoroughbred mares. In the thoroughbreds sera were collected during the pregnancy period. Furthermore, we measured progesterone and detected pregnant mare serum gonadotrophin (PMSG) in order to confirm pregnancy of the Chinese pony 3 and 6 months after mating. In the nonpregnant Shetland ponies, the rosette inhibition titre (RIT) was 6.0+/-1.0 and EPF was negative. In contrast, in the pregnant ponies, the RIT was 9.2+/-0.4 and EPF was positive. Based on these results, we diagnosed pregnancy of the Chinese pony. The RIT of the female Chinese pony (3 months after mating) was above 10 and EPF was positive. Furthermore, we detected PMSG and progesterone in the serum of this pony. EPF appeared in the maternal blood circulation at 24-72 hr after mating, it was detected until the second trimester, and after that it disappeared from the maternal serum. The pony's EPF was detected by using the same rosette inhibition test as in the thoroughbred and was present from 24 to 72 hr after mating until the second trimester. The results indicated that our method was useful for pregnancy diagnosis of Equine.

  16. The Progression and Early detection of Subclinical Atherosclerosis (PESA) study

    DEFF Research Database (Denmark)

    Fernández-Ortiz, Antonio; Jiménez-Borreguero, L Jesús; Peñalvo, José L

    2013-01-01

    The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly defined.......The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly defined....

  17. [Early Intervention and Cognitive Development: A Longitudinal Study with Psychologically Stressed Mother-Child-Dyad during Early Childhood].

    Science.gov (United States)

    Zwönitzer, Annabel; Ziegenhain, Ute; Bovenschen, Ina; Pillhofer, Melanie; Spangler, Gottfried; Gerlach, Jennifer; Gabler, Sandra; Kindler, Heinz; Fegert, Jörg M; Künster, Anne Katrin

    2016-01-01

    Early intervention programs aiming at developing parents’ relationship and parenting skills and supporting young families have become increasingly established in Germany throughout the last decade. The present longitudinal study analyzed 53 children and their mothers receiving early intervention due to their psychosocially highly challenging life situations and personal circumstances. The children were examined at birth and at an age of twelve months as well as between ages two and four. The results revealed that the child’s cognitive development could be predicted by both maternal sensitivity and mother’s psychosocial stress. However, the amount, type, and intensity of early intervention did not have any effect on the child’s development. In terms of the effectiveness of early interventions the results implicate that interventions seems to be offered in an unspecific manner and does not contribute to an improvement of the child’s developmental status.

  18. Retaining early career registered nurses: a case study.

    Science.gov (United States)

    Mills, Jane; Chamberlain-Salaun, Jennifer; Harrison, Helena; Yates, Karen; O'Shea, Andrea

    2016-01-01

    A core objective of the Australian health system is to provide high quality, safe health care that meets the needs of all Australians. To achieve this, an adequate and effective workforce must support the delivery of care. With rapidly changing health care systems and consumer demographics, demand for care is increasing and retention of sufficient numbers of skilled staff is now a critical priority to meet current and future health care demands. Nurses are the largest cohort of professionals within the health workforce. Reducing the rates at which nurses leave the profession and supporting nurses to practice in their profession longer will have beneficial implications for the sustainability of a nursing workforce and, ultimately, to patient outcomes. The aim of the study was to describe and explain early career registered nurses' (ECRNs) experiences and support requirements during the first five years of practice for the purposes of identifying strategies that would support greater retention of ECRNs. A single case study design focused on early career registered nurses (ECRNs) working in a hospital and health service in northern Australia. The research team adopted Djukic et al's definition of ECRNs as "RNs who have practiced for less than 5 years". Data was collected via three individual interviews and two focus groups. Thirty-five ECRNs participated in the study. Qualitative analysis of data generated during interviews and focus groups, identified the key themes of receiving career advice and choice or no choice . Analysis of study data in the context of the broader literature resulted in the researchers identifying six areas of focus for ECRN retention: 1) well-planned, supported and structured transition periods; 2) consideration of rotation through different areas with a six month minimum for skills development; 3) empowering decision making; 4) placement opportunities and choice in decisions of where to work; 5) career advice and support that considers ECRNs

  19. The development of functional network organization in early childhood and early adolescence: A resting-state fNIRS study.

    Science.gov (United States)

    Cai, Lin; Dong, Qi; Niu, Haijing

    2018-04-01

    Early childhood (7-8 years old) and early adolescence (11-12 years old) constitute two landmark developmental stages that comprise considerable changes in neural cognition. However, very limited information from functional neuroimaging studies exists on the functional topological configuration of the human brain during specific developmental periods. In the present study, we utilized continuous resting-state functional near-infrared spectroscopy (rs-fNIRS) imaging data to examine topological changes in network organization during development from early childhood and early adolescence to adulthood. Our results showed that the properties of small-worldness and modularity were not significantly different across development, demonstrating the developmental maturity of important functional brain organization in early childhood. Intriguingly, young children had a significantly lower global efficiency than early adolescents and adults, which revealed that the integration of the distributed networks strengthens across the developmental stages underlying cognitive development. Moreover, local efficiency of young children and adolescents was significantly lower than that of adults, while there was no difference between these two younger groups. This finding demonstrated that functional segregation remained relatively steady from early childhood to early adolescence, and the brain in these developmental periods possesses no optimal network configuration. Furthermore, we found heterogeneous developmental patterns in the regional nodal properties in various brain regions, such as linear increased nodal properties in the frontal cortex, indicating increasing cognitive capacity over development. Collectively, our results demonstrated that significant topological changes in functional network organization occurred during these two critical developmental stages, and provided a novel insight into elucidating subtle changes in brain functional networks across development. Copyright

  20. The development of functional network organization in early childhood and early adolescence: A resting-state fNIRS study

    Directory of Open Access Journals (Sweden)

    Lin Cai

    2018-04-01

    Full Text Available Early childhood (7–8 years old and early adolescence (11–12 years old constitute two landmark developmental stages that comprise considerable changes in neural cognition. However, very limited information from functional neuroimaging studies exists on the functional topological configuration of the human brain during specific developmental periods. In the present study, we utilized continuous resting-state functional near-infrared spectroscopy (rs-fNIRS imaging data to examine topological changes in network organization during development from early childhood and early adolescence to adulthood. Our results showed that the properties of small-worldness and modularity were not significantly different across development, demonstrating the developmental maturity of important functional brain organization in early childhood. Intriguingly, young children had a significantly lower global efficiency than early adolescents and adults, which revealed that the integration of the distributed networks strengthens across the developmental stages underlying cognitive development. Moreover, local efficiency of young children and adolescents was significantly lower than that of adults, while there was no difference between these two younger groups. This finding demonstrated that functional segregation remained relatively steady from early childhood to early adolescence, and the brain in these developmental periods possesses no optimal network configuration. Furthermore, we found heterogeneous developmental patterns in the regional nodal properties in various brain regions, such as linear increased nodal properties in the frontal cortex, indicating increasing cognitive capacity over development. Collectively, our results demonstrated that significant topological changes in functional network organization occurred during these two critical developmental stages, and provided a novel insight into elucidating subtle changes in brain functional networks across

  1. 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.

  2. Accuracy of a clinical PET/CT vs. a preclinical μPET system for monitoring treatment effects in tumour xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Palmowski, Karin [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Department of Pneumology and Critical Care Medicine, Thoraxklinik Heidelberg, University of Heidelberg, Heidelberg (Germany); Winz, Oliver [Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Rix, Anne; Bzyl, Jessica [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Behrendt, Florian F.; Verburg, Frederic A.; Mottaghy, Felix M. [Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Palmowski, Moritz, E-mail: mpalmowski@ukaachen.de [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Academic Radiology Baden Baden, Diagnostic and Interventional Radiology, University Medical Center Heidelberg, Heidelberg (Germany)

    2013-08-15

    Purpose: Small animal imaging is of growing importance for preclinical research and drug development. Tumour xenografts implanted in mice can be visualized with a clinical PET/CT (cPET); however, it is unclear whether early treatment effects can be monitored. Thus, we investigated the accuracy of a cPET versus a preclinical μPET using {sup 18}F-FDG for assessing early treatment effects. Materials and methods: The spatial resolution and the quantitative accuracy of a clinical and preclinical PET were evaluated in phantom experiments. To investigate the sensitivity for assessing treatment response, A431 tumour xenografts were implanted in nude mice. Glucose metabolism was measured in untreated controls and in two therapy groups (either one or four days of antiangiogenic treatment). Data was validated by γ-counting of explanted tissues. Results: In phantom experiments, cPET enabled reliable separation of boreholes ≥ 5 mm whereas μPET visualized boreholes ≥ 2 mm. In animal studies, μPET provided significantly higher tumour-to-muscle ratios for untreated control tumours than cPET (3.41 ± 0.87 vs. 1.60 ± .0.28, respectively; p < 0.01). During treatment, cPET detected significant therapy effects at day 4 (p < 0.05) whereas μPET revealed highly significant therapy effects even at day one (p < 0.01). Correspondingly, γ-counting of explanted tumours indicated significant therapy effects at day one and highly significant treatment response at day 4. Correlation with γ-counting was good for cPET (r = 0.74; p < 0.01) and excellent for μPET (r = 0.85; p < 0.01). Conclusion: Clinical PET is suited to investigate tumour xenografts ≥ 5 mm at an advanced time-point of treatment. For imaging smaller tumours or for the sensitive assessment of very early therapy effects, μPET should be preferred.

  3. Equity and Quality? Challenges for Early Childhood and Primary Education in Ethiopia, India and Peru. Working Papers in Early Childhood Development, No. 55. Studies in Early Childhood Transitions

    Science.gov (United States)

    Woodhead, Martin; Ames, Patricia; Vennam, Uma; Abebe, Workneh; Streuli, Natalia

    2009-01-01

    Part of the "Studies in Early Transitions" series, this Working Paper draws on interviews and observations carried out as part of "Young Lives", a 15-year longitudinal study of childhood poverty in Ethiopia, India, Peru and Vietnam based at the University of Oxford's Department of International Development. This paper focuses…

  4. Increasing Choice or Inequality? Pathways through Early Education in Andhra Pradesh, India. Working Papers in Early Childhood Development, No. 58. Studies in Early Childhood Transitions

    Science.gov (United States)

    Streuli, Natalia; Vennam, Uma; Woodhead, Martin

    2011-01-01

    This working paper is part of the Studies in Early Transitions series emerging from "Young Lives", a 15-year longitudinal study of childhood poverty in Ethiopia, India, Peru and Vietnam. It explores recent trends for children growing up in Andhra Pradesh, one of India's most populous states, based on Young Lives survey data collected for…

  5. Continuity and Respect for Diversity: Strengthening Early Transitions in Peru. Working Papers in Early Childhood Development, No. 56. Studies in Early Childhood Transitions

    Science.gov (United States)

    Ames, Patricia; Rojas, Vanessa; Portugal, Tamia

    2010-01-01

    This working paper is part of a series on early transitions from "Young Lives," a 15-year longitudinal study of childhood poverty in Ethiopia, India, Peru and Vietnam. It explores the diverse experiences of 28 children from four contrasting communities in Peru as they start school. These detailed case studies highlight common problems:…

  6. Community based study of sleep bruxism during early childhood

    Science.gov (United States)

    Insana, Salvatore P.; Gozal, David; McNeil, Daniel W.; Montgomery-Downs, Hawley E.

    2012-01-01

    Objectives The aims for this study were to determine the prevalence of sleep-bruxism among young children, explore child behavior problems that may be associated with sleep-bruxism, and identify relations among sleep-bruxism, health problems, and neurocognitive performance. Methods The current study was a retrospective analysis of parent report surveys, and behavioral and neurocognitive assessments. Parents of 1953 preschool and 2888 first grade children indicated their child’s frequency of bruxism during sleep. A subsample of preschool children (n = 249) had additional behavioral, as well as neurocognitive assessments. Among the subsample, parents also reported on their child’s health, and completed the Child Behavioral Checklist; children were administered the Differential Ability Scales, and Pre-Reading Abilities subtests of the Developmental Neuropsychological Assessment. Results 36.8% of preschoolers and 49.6% of first graders were reported to brux ≥ 1 time per week. Among the preschool subsample, bruxing was independently associated with increased internalizing behaviors (β = .17). Bruxism was also associated with increased health problems (β = .19), and increased health problems were associated with decreased neurocognitive performance (β = .22). Conclusions The prevalence of sleep-bruxism was high. A dynamic and potentially clinically relevant relation exists among sleep-bruxism, internalizing behaviors, health, and neurocognition. Pediatric sleep-bruxism may serve as a sentinel marker for possible adverse health conditions, and signal a need for early intervention. These results support the need for an interdisciplinary approach to pediatric sleep medicine, dentistry, and psychology. PMID:23219144

  7. Birds flush early and avoid the rush: an interspecific study.

    Directory of Open Access Journals (Sweden)

    Diogo S M Samia

    Full Text Available Since 1986, studies about the escape decisions made by prey are grounded in optimal escape theory (OET which states that prey will initiate escape when the risk of remaining and the costs of leaving are equal. However, a recent hypothesis, Flush Early and Avoid the Rush (FEAR, acknowledged that the cost of monitoring approaching predators might be a ubiquitous cost. The FEAR hypothesis predicts that prey will generally flee soon after they detect a predator so as to minimize the costs incurred by monitoring the predator. Knowing whether animals flee to reduce monitoring costs is of applied interest because wildlife managers use escape behavior to create set-back zones to reduce human-wildlife conflict. Here we provide the most comprehensive assessment of the FEAR hypothesis using data collected from 178 bird species representing 67 families from two continents. The FEAR hypothesis explains escape behavior in 79% of studied species. Because the FEAR hypothesis is a widespread phenomenon that drives escape behavior in birds, alert distance must be systematically incorporated into the design of set-back zones to protect vulnerable species.

  8. Preclinical evaluation of strontium-containing bioactive bone cement

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-01

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

  9. Preclinical evaluation of strontium-containing bioactive bone cement

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  10. 78 FR 44553 - Agency Information Collection Activities; Comment Request; Early Childhood Longitudinal Study...

    Science.gov (United States)

    2013-07-24

    ...) of the U.S. Department of Education (ED), is a survey that focuses on children's early school... child assessments. Like its sister study, the Early Childhood Longitudinal Study, Kindergarten Class of..., early learning, and school progress, drawing together information from multiple sources to provide rich...

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

    Directory of Open Access Journals (Sweden)

    Schofield Peter W

    2012-05-01

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

  12. 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.

  13. 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.

  14. Forensic Study of Early Failures with Unbonded Concrete Overlays

    Science.gov (United States)

    2017-11-01

    A forensic investigation was conducted to identify failure mechanisms responsible for early failures of unbonded concrete overlays on selected projects in Ohio, including I-70 in Madison County, I-77 in Washington and Noble Counties, and I-90 in Lake...

  15. Social Strategies during University Studies Predict Early Career Work Burnout and Engagement: 18-Year Longitudinal Study

    Science.gov (United States)

    Salmela-Aro, Katariina; Tolvanen, Asko; Nurmi, Jari-Erik

    2011-01-01

    This longitudinal study spanning 18 years examined the role of social strategies in early career adaptation. The aim was to find out whether individuals' social strategies measured during their university studies had an impact on work burnout and work engagement measured 10-18 years later. A sample of 292 university students completed the SAQ…

  16. Reirradiation of normal tissues: Preclinical radiobiological data; Reirradiation des tissus sains: donnees radiobiologiques precliniques

    Energy Technology Data Exchange (ETDEWEB)

    Bourgier, C.; Vozenin, M.C.; Deutsch, E. [Departement de radiotherapie et laboratoire Upres EA2710, institut Gustave-Roussy, 94 - Villejuif (France)

    2010-10-15

    Reirradiation represent an unfrequent particular clinical situation. The risk/benefit ratio assessment must be taken into account, considering both clinical and dosimetric aspects. There is a relatively limited amount of preclinical data available to date and clinicians should cautiously perform re-irradiations in selected indications. This review summarizes the experimental data available on reirradiation of normal tissues, the consequences on early and late toxicities as well as the intrinsic limitations of these models. (authors)

  17. The Flipped Classroom for pre-clinical dental skills teaching - a reflective commentary.

    Science.gov (United States)

    Crothers, A J; Bagg, J; McKerlie, R

    2017-05-12

    A Flipped Classroom method for teaching of adult practical pre-clinical dental skills was introduced to the BDS curriculum in Glasgow during the 2015/2016 academic session. This report provides a commentary of the first year of employing this method - from the identification of the need to optimise teaching resources, through the planning, implementation and development of the method, with an early indication of performance.

  18. Collaborative learning in pre-clinical dental hygiene education.

    Science.gov (United States)

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

    2013-04-01

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

  19. A review of targeted therapies evaluated by the Pediatric Preclinical Testing Program for osteosarcoma

    Directory of Open Access Journals (Sweden)

    Valerie eSampson

    2013-05-01

    Full Text Available Osteosarcoma, the most common malignant bone tumor of childhood, is a high grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical end points for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

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

    Directory of Open Access Journals (Sweden)

    Simon Turner

    2012-04-01

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

  1. Increased cost of motor activity and heat transfer between non-shivering thermogenesis, motor activity and thermic effect of feeding in mice housed at room temperature – Implications in pre-clinical studies.

    Directory of Open Access Journals (Sweden)

    Patrick Christian Even

    2016-10-01

    Full Text Available The components of energy expenditure, total metabolic rate (TMR, resting metabolic rate (RMR, thermogenic response to feeding (TEF, activity and cost of activity were measured in fed and fasted mice housed at 22°C and 30° C. Mice housed at 22°C had more than 2 times larger TMR and RMR. Mice at 22°C were less active when fasted but more active when fed. Cost of activity was nearly doubled in the fasted and in the fed state. Analysis of the short-term relation between TMR, RMR and bouts of activity showed that, at 22°C, the bouts of activity induced a decrease in the intensity of RMR that reflected the reduced need for thermal regulation induced by the heat released from muscular contraction. This phenomenon induced a considerable underestimation of TEF and prevented its reliable measurement when mice were housed at 22°C. Correlation between TMR and activity measured across time in individual mice was very strong at both 22°C and 30°C, but the correlation measured across mice was much weaker at 30°C and no longer significant at 22°C. We suspect that this phenomenon was due to the fact that RMR is a much more reliable predictor of TMR than activity. RMR is more variable at 22°C than at 30°C because of heat-transfers between thermal regulation and heat released by other discontinuous processes such as activity and TEF. Therefore more noise is introduced into the correlations performed across multiple mice between TMR and activity at 22°C. On the other hand it should be kept in mind that the doubling of TMR and RMR at 22°C is fueled by an increased non-shivering thermogenesis that can obviously modify how the mouse responds to pharmacological and nutritional challenges. Taken together these results suggest that in pre-clinical studies, mice should be housed in conditions where thermal regulation is limited as is generally the case in humans. However, the increased sensitivity of mice to small changes in ambient temperature can also be

  2. [Clinical study of induced abortion of early-early pregnancy: an analysis of 10, 404 cases].

    Science.gov (United States)

    Kang, Jian; Wang, Xue-fen; Zhang, Li; Liu, Jian-hua

    2012-01-03

    To evaluate the advantages and disadvantages of early-early pregnancy induced abortion (EPIA). A total of 10 404 cases of EPIA performed at our hospital from January 1993 to December 2003 were retrospectively analyzed and compared with 9434 cases of common induced abortion (CIA). The amount of hemorrhage and operative duration, degree of pain, rate of induced-abortion syndrome, rate of incomplete abortion, menstrual changes and post-operative onset of Asherman's syndrome were observed and compared between 2 groups. The average age, ratio of parous cases, ratio of the cases of first-pregnancy induced abortion were not different between 2 groups (P > 0.05). The amount of hemorrhage bleeding ((4.9 ± 3.2) ml), operative duration ((90.3 ± 12.4) s), degree of pain, rate of induced-abortion syndrome, menstrual changes and the rate of Asherman's syndrome in the EPIA group were all significantly less than those in the CIA group (P abortion (0.44%) in the EPIA group was significantly higher than that (0.21%) in the CIA group (P abortion stays high.

  3. Cued memory decline in biomarker-defined preclinical Alzheimer disease.

    Science.gov (United States)

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

    2017-04-11

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

  4. Functional network integrity presages cognitive decline in preclinical Alzheimer disease.

    Science.gov (United States)

    Buckley, Rachel F; Schultz, Aaron P; Hedden, Trey; Papp, Kathryn V; Hanseeuw, Bernard J; Marshall, Gad; Sepulcre, Jorge; Smith, Emily E; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Chhatwal, Jasmeer P

    2017-07-04

    To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD). A total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years. Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance. In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings. © 2017 American Academy of Neurology.

  5. The recruitment of early retirees: a vignette study of the factors that affect managers' decisions

    NARCIS (Netherlands)

    Karpinska, K.; Henkens, C.J.I.M.; Schippers, J.

    2011-01-01

    Retirement is characterised as a dynamic process that has several different outcomes, from early retirement to re-entry to the labour force. Recent studies of the Dutch population show that a substantial number of early retirees re-enter the workforce after early retirement, but others do not

  6. Early studies of instant-fMRI for routine examination

    International Nuclear Information System (INIS)

    Sakurai, Yuuki; Harada, Kuniaki; Nagahama, Hiroshi; Akatsuka, Yoshihiro; Shinozaki, Jun

    2010-01-01

    Authors are developing a low-burden, short-time acquisition method of functional magnetic resonance imaging (fMRI) with 3T machine, named ''Instant-fMRI'', aiming for its application to routine examinations, of which results of early studies on identification of the language hemisphere are reported. Subjects were 10 healthy volunteers (8 males, 2 females, mean age 34.2 y, 8 right-handers) and 5 right-hander patients with brain tumor (4 males, 1 female, mean age 50 y). The machine was GE Signa HDx 3.0T ver. 14, using 8 channel head coil. For Instant-fMRI, T1-weighted imaging sequence for mapping was in fast spoiled gradient recalled acquisition in the steady state (fSPGR) mode (scan time: 1 min 44 sec) and fMRI sequence, in GRE-EPI (scan time: 1 min), which thus required only about 3 min in total. Reference was defined to be the anterior-posterior commissure line, to which parallel sections involving centriciput and cerebellum were acquired. Rest (30 sec)-task (shiritori language game, 30 sec) cycle was to be one in instant-fMRI in contrast to three in the conventional fMRI. Volunteers received both instant-fMRI and conventional fMRI and patients, the former alone. Data were analyzed by GE Brain Wave PA. Right and left hemisphere of the left and right hander, respectively, was identified to be activated by instant-fMRI in 9 of 10 volunteers and in all patients, and by the conventional fMRI, in all volunteers. The instant-fMRI can be a useful examination of other brain functions as well as identifying the language field when acquisition parameters for desired diagnostic purpose are optimized. (T.T.)

  7. The importance of clinical pharmacokinetic–pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes

    OpenAIRE

    McCallum, Andrew; Sloan, Derek

    2017-01-01

    Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK–PD) tools, are based on incomplete understanding of exposure–response relationships in drug susceptible and multidrug re