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Sample records for pre-clinical neurovirulence assessment

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

    Science.gov (United States)

    Rubin, S A; Afzal, M A

    2011-04-05

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

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

    Science.gov (United States)

    2014-01-01

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

  3. Assessment of clinical reasoning: A Script Concordance test designed for pre-clinical medical students.

    Science.gov (United States)

    Humbert, Aloysius J; Johnson, Mary T; Miech, Edward; Friedberg, Fred; Grackin, Janice A; Seidman, Peggy A

    2011-01-01

    The Script Concordance test (SCT) measures clinical reasoning in the context of uncertainty by comparing the responses of examinees and expert clinicians. It uses the level of agreement with a panel of experts to assign credit for the examinee's answers. This study describes the development and validation of a SCT for pre-clinical medical students. Faculty from two US medical schools developed SCT items in the domains of anatomy, biochemistry, physiology, and histology. Scoring procedures utilized data from a panel of 30 expert physicians. Validation focused on internal reliability and the ability of the SCT to distinguish between different cohorts. The SCT was administered to an aggregate of 411 second-year and 70 fourth-year students from both schools. Internal consistency for the 75 test items was satisfactory (Cronbach's alpha = 0.73). The SCT successfully differentiated second- from fourth-year students and both student groups from the expert panel in a one-way analysis of variance (F(2,508) = 120.4; p students from the two schools were not significantly different (p = 0.20). This SCT successfully differentiated pre-clinical medical students from fourth-year medical students and both cohorts of medical students from expert clinicians across different institutions and geographic areas. The SCT shows promise as an easy-to-administer measure of "problem-solving" performance in competency evaluation even in the beginning years of medical education.

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

    Science.gov (United States)

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

    2018-05-01

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

  5. [Comparative evaluation of Leningrad-3 mumps vaccine virus neurovirulence in a neonatal rat model].

    Science.gov (United States)

    Ignat'ev, G M; Otrashevskaia, E V; Rubin, S A

    2011-01-01

    The neurovirulence and replication potential of several mumps virus strains, including Leningrad-3 mumps vaccine virus (FSUE SIC "Microgen", Russia) and wild type strains isolated in the Novosibirsk Region (Russia), were assessed in rat tests. The mean neurovirulence scores of the Leningrad-3 virus (mumps vaccine strains (usually ranging from 0 to 5). In general, the relative ability of the viruses to replicate in the rat brain tracked with their neurovirulence scores. These results indicate a low neurovirulence potential of the Leningrad-3 mumps vaccine virus for humans.

  6. Performance of two different digital evaluation systems used for assessing pre-clinical dental students' prosthodontic technical skills.

    Science.gov (United States)

    Gratton, D G; Kwon, S R; Blanchette, D R; Aquilino, S A

    2017-11-01

    Proper integration of newly emerging digital assessment tools is a central issue in dental education in an effort to provide more accurate and objective feedback to students. The study examined how the outcomes of students' tooth preparation were correlated when evaluated using traditional faculty assessment and two types of digital assessment approaches. Specifically, incorporation of the Romexis Compare 2.0 (Compare) and Sirona prepCheck 1.1 (prepCheck) systems was evaluated. Additionally, satisfaction of students based on the type of software was evaluated through a survey. Students in a second-year pre-clinical prosthodontics course were allocated to either Compare (n = 42) or prepCheck (n = 37) systems. All students received conventional instruction and used their assigned digital system as an additional evaluation tool to aid in assessing their work. Examinations assessed crown preparations of the maxillary right central incisor (#8) and the mandibular left first molar (#19). All submissions were graded by faculty, Compare and prepCheck. Technical scores did not differ between student groups for any of the assessment approaches. Compare and prepCheck had modest, statistically significant correlations with faculty scores with a minimum correlation of 0.3944 (P = 0.0011) and strong, statistically significant correlations with each other with a minimum correlation of 0.8203 (P < 0.0001). A post-course student survey found that 55.26% of the students felt unfavourably about learning the digital evaluation protocols. A total of 62.31% felt favourably about the integration of these digital tools into the curriculum. Comparison of Compare and prepCheck showed no evidence of significant difference in students' prosthodontics technical performance and perception. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model.

    Science.gov (United States)

    Towner, Rheal A; Ihnat, Michael; Saunders, Debra; Bastian, Anja; Smith, Nataliya; Pavana, Roheeth Kumar; Gangjee, Aleem

    2015-07-17

    High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule. GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively. Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.

  8. A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model

    International Nuclear Information System (INIS)

    Towner, Rheal A.; Ihnat, Michael; Saunders, Debra; Bastian, Anja; Smith, Nataliya; Pavana, Roheeth Kumar; Gangjee, Aleem

    2015-01-01

    High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule. GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively. Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors. Tumor volumes (21–31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls. Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors. It was also found that IC 50 values for AG119 were much lower than those for TMZ in T98G and U251 cells. These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine

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

    Science.gov (United States)

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

    2009-12-01

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

  10. Comparison of a prepCheck-supported self-assessment concept with conventional faculty supervision in a pre-clinical simulation environment.

    Science.gov (United States)

    Wolgin, M; Grabowski, S; Elhadad, S; Frank, W; Kielbassa, A M

    2018-03-25

    This study aimed to evaluate the educational outcome of a digitally based self-assessment concept (prepCheck; DentsplySirona, Wals, Austria) for pre-clinical undergraduates in the context of a regular phantom-laboratory course. A sample of 47 third-year dental students participated in the course. Students were randomly divided into a prepCheck-supervised (self-assessment) intervention group (IG; n = 24); conventionally supervised students constituted the control group (CG; n = 23). During the preparation of three-surface (MOD) class II amalgam cavities, each IG participant could analyse a superimposed 3D image of his/her preparation against the "master preparation" using the prepCheck software. In the CG, several course instructors performed the evaluations according to pre-defined assessment criteria. After completing the course, a mandatory (blinded) practical examination was taken by all course participants (both IG and CG students), and this assessment involved the preparation of a MOD amalgam cavity. Then, optical impressions by means of a CEREC-Omnicam were taken to digitalize all examination preparations, followed by surveying and assessing the latter using prepCheck. The statistical analysis of the digitalized samples (Mann-Whitney U test) revealed no significant differences between the cavity dimensions achieved in the IG and CG (P = .406). Additionally, the sum score of the degree of conformity with the "master preparation" (maximum permissible 10% of plus or minus deviation) was comparable in both groups (P = .259). The implemented interactive digitally based, self-assessment learning tool for undergraduates appears to be equivalent to the conventional form of supervision. Therefore, such digital learning tools could significantly address the ever-increasing student to faculty ratio. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. 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.

  12. Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

    OpenAIRE

    Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

    2013-01-01

    Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dos...

  13. Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations.

    Science.gov (United States)

    Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

    2014-06-01

    Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10(8) , 2 × 10(9) and 2 × 10(10) colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10(9) CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10(10) CFU). The challenge dose, 2 × 10(10) CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. © 2013 The Authors. APMIS published by John Wiley & Sons Ltd.

  14. [Comparative evaluation of neurovirulence of domestic and foreign live mumps vaccine].

    Science.gov (United States)

    Maksimova, O A; Popov, V F; Bektimirov, T A; Grigor'eva, L V; Iunasova, T N; Kaplunova, O P; Sharova, O K

    2001-01-01

    Morphological and immunofluorescent study of changes in the central nervous system of monkeys with mumps was carried out in order to determine the criteria of neurovirulence of different mumps virus strains. Quantitative evaluation showed a lower residual neurovirulence of L-3 strain vs. Jeryl Lynn and Urabe Am9 strains. Use of new methodological approaches to evaluation of mumps vaccine strain neurovirulence will improve the safety control of live mumps vaccines.

  15. Risk factors assessment for nasal colonization of Staphylococcus aureus and its methicillin resistant strains among pre-clinical medical students of Nepal.

    Science.gov (United States)

    Ansari, Shamshul; Gautam, Rajendra; Shrestha, Sony; Ansari, Safiur Rahman; Subedi, Shankar Nanda; Chhetri, Muni Raj

    2016-04-12

    Staphylococcus aureus (S. aureus), a normal flora of nasal cavity, can cause minor to life threatening invasive diseases and nosocomial infections. Methicillin resistant strains of S. aureus are causing a great challenge for treatment options. Therefore, the purpose of this study was to assess the nasal carriage rate of S. aureus, its methicillin resistant strains and risk factors in medical students prior to clinical exposure. The bacterial growth of S. aureus from nasal swab culture was identified by using standard microbiological methods recommended by American Society for Microbiology. Modified Kirby-Bauer disk diffusion method was used for antibiotic susceptibility testing and methicillin resistance was confirmed using cefoxitin and oxacillin disks. D-zone test method was used to determine the inducible clindamycin resistance. Among 200 participants, nasal carriage of S. aureus was detected from 30 (15%) subjects. Upper respiratory tract infections significantly (P aureus and their methicillin resistant strains. All of the isolates were reported to be susceptible to vancomycin and teicoplanin. S. aureus strains detected from 8 (4%) students were confirmed to be methicillin resistant. The result of our study demands for strict policy to screen all the students for nasal carriage of S. aureus and its MRSA strains to minimize the transmission of this organism from community to hospital settings.

  16. 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

  17. 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.

  18. Influence of population diversity on neurovirulence potential of plaque purified L-Zagreb variants.

    Science.gov (United States)

    Ivancic-Jelecki, Jelena; Forcic, Dubravko; Jagusic, Maja; Kosutic-Gulija, Tanja; Mazuran, Renata; Balija, Maja Lang; Isakov, Ofer; Shomron, Noam

    2016-04-29

    Despite continuing research efforts, determinants of mumps virus virulence are still largely unknown. One of consequences of this is difficulty in striking a balance between efficacy and safety of live attenuated mumps vaccines. Among mumps vaccine strains associated with occurrence of postvaccinal aseptic meningitis is L-Zagreb, developed by further attenuation of vaccine strain L-3. Starting from an archived L-Zagreb sample with suboptimal neuroattenuation score, we isolated different viral variants and compared their genetic and phenotypic properties, in investigation of neurovirulence markers. Six different L-Zagreb variants were isolated by plaque purification. Their neurovirulent status was determined by rat-based neurovirulence test; population structure was determined by deep sequencing. We isolated one well neuroattenuated viral variant, two marginally neuroattenuated, and three insufficiently neuroattenuated. No genetic markers of neurovirulence could be identified. None of variants had detectable amounts of defective interfering particles. Two characteristics set insufficiently neuroattenuated variants apart from less-neurovirulent ones: elevated variability level in regions 1293-3314, 5363-7773 and 9382-11657, and/or elevated number of mutations present in frequencies ≥ 1%. The most neurovirulent variants possessed both of these features. Distinctive heterogeneity profiles were obtained for insufficiently neuroattenuated L-Zagreb variants. No markers that would discriminate between marginally and well neuroattenuated variants were identified. The findings of this study may serve as a guideline during development of an improved L3/L-Zagreb vaccine strain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Learning style preferences among pre-clinical medical students

    Directory of Open Access Journals (Sweden)

    Aye Aye Mon

    2014-02-01

    Full Text Available Generally, different students employ different learning styles dur-ing their studies and medical students are exposed to diverse methods of teaching. Therefore, understanding students’ learning style preference is an important consideration for a high quality and effective teaching and learning process.The aim of the study was to study the variation of learning styles among pre-clinical medical students of SEGi University, Malaysia. A cross-sectional study was performed by using VARK (Visual, Audio, Reading and Kinaesthetic questionnaire version 7.2 to assess the learning style preference of 98 (n=98 pre-clinical medical students in SEGi University. The questionnaire consists of 16 items which identify four different learning styles: visual, aural, reading/writing and kin-esthetic. Descriptive statistics were used to identify the learning styles of students. 61 students preferred multimodal as their learning style, out of which 43 (70% of them were female stu-dents and 18 (30% were male students. 37 students preferred unimodal as their learning style out of which 22 (59% of them were female students and 15 (41% were male students. In addi-tion, female students had more diverse preferences than male students by having 10 out of the other 11 possible combinations in multimodal learning style of preference, whereas the male stu-dents only had 5 out of the 11 combinations. In this study, there was no significant gender difference in the percentages of males and female students who preferred unimodal and multimodal styles of information presentation (P= 0.263; α=0.05. To con-clude, the majority of students of both genders had chosen quad-modal as their learning style preference. The results of this study can provide useful information for improving the quality of the teaching and learning experiences of students.

  20. Sequence analysis-based characterization and identification of neurovirulence-associated variants of 36 EV71 strains from China.

    Science.gov (United States)

    Xu, Jun; Wang, Fang; Zhao, Desheng; Liu, Jiang; Su, Hong; Wang, Baolong

    2018-03-30

    Enterovirus 71 (EV71) is the main pathogen of hand-foot-mouth disease (HFMD) and causes several neurological complications. As new strains of EV71 are constantly discovered, it is important to understand the genomic characteristics of the viruses and the mechanism of virulence. Herein, we isolated five strains of EV71 from HFMD patients with or without neurovirulence and sequenced their whole genomes. We then performed whole genome sequence analysis of totally 36 EV71 strains. The phylogenetic analysis of the VP1 region revealed all five isolated strains are clustered into C4a of C4 subgenotype. In addition, by comparing the complete genome sequences of 36 strains, 253 variable amino acid positions were found, 14 of which were identified to be associated with neurovirulence (P < 0.05). Moreover, a similar pattern of amino acid variants combination was identified in four strains without neurovirulence, indicating this type of variant pattern might be associated with avirulence. The strains with neurovirulence appeared to be distinguished from those without neurovirulence by the variants in VP1 and P2 regions, implying VP1 and P2 are the important regions associated with neurovirulence. Indeed, 3-D modeling of VP1 and P2 regions of non-neurovirulent and neurovirulent strains revealed that the different variants resulted in different protein structures and amino acid composition of ligand binding site, which might account for their difference in neurovirulence. In summary, our study reveals 14 variable amino acid positions of VP1, P2 and P3 regions are related to the virulence and that mutations in the capsid proteins of EV71 might contribute to neurovirulence. © 2018 Wiley Periodicals, Inc.

  1. Identification of a consistent pattern of mutations in neurovirulent variants derived from the sabin vaccine strain of poliovirus type 2.

    OpenAIRE

    Equestre, M; Genovese, D; Cavalieri, F; Fiore, L; Santoro, R; Perez Bercoff, R

    1991-01-01

    Complete nucleotide sequencing of the RNAs of two unrelated neurovirulent isolates of Sabin-related poliovirus type 2 revealed that two nucleotides and one amino acid (amino acid 143 in the major capsid protein VP1) consistently departed from the sequences of the nonneurovirulent poliovirus type 2 712 and Sabin vaccine strains. This pattern of mutation appeared to be a feature common to all neurovirulent variants of poliovirus type 2.

  2. Kinetic modeling in pre-clinical positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-07-01

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

  3. Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology

    International Nuclear Information System (INIS)

    Rempel, Julia D.; Murray, Shannon J.; Meisner, Jeffrey; Buchmeier, Michael J.

    2004-01-01

    Differences in disease outcome between the highly neurovirulent MHV-JHM and mildly neurovirulent MHV-A59 have been attributed to variations within the spike (S) glycoprotein. Previously, we found that MHV-JHM neurovirulence was marked by diminished expression of interferon-γ (IFN-γ) mRNA and a reduced presence of CD8 T cells in the CNS concomitant with heightened macrophage inflammatory protein (MIP)-1 transcript levels and greater macrophage infiltration relative to MHV-A59 infection. Here, the ability of the S and non-spike genes to regulate these immune responses was evaluated using chimeric viruses. Chimeric viruses WTR13 and S4R22 were made on MHV-A59 variant backgrounds and, respectively, contained the S gene of MHV-A59 and MHV-JHM. Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival. Unlike unresolving MHV-JHM infections, the clearance of WTR13 and S4R22 infections coincided with strong IFN-γ transcription and an increase in the number of CD8 T cells infiltrating into the CNS. However, despite the absence of detectable viral titers, approximately 40% of S4R22-infected mice succumbed within 3 weeks, indicating that the enhanced mortality following S4R22 infection was not associated with high viral titers. Instead, similar to the MHV-JHM infection, reduced survival following S4R22 infection was observed in the presence of elevated MIP-1α and MIP-1β mRNA accumulation and enhanced macrophage numbers within infected brains. These observations suggest that the S protein of MHV-JHM influences neurovirulence through the induction of MIP-1α- and MIP-1β-driven macrophage immunopathology

  4. 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...

  5. 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.

  6. Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Chad E Mire

    Full Text Available The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV that expresses an individual filovirus glycoprotein (GP in place of the VSV glycoprotein (G. The main concern with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV GP; three animals received rVSV-wild type (wt vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use.

  7. A single mutation in the E2 glycoprotein important for neurovirulence influences binding of Sindbis virus to neuroblastoma cells

    NARCIS (Netherlands)

    Lee, PY; Knight, R; Smit, JM; Wilschut, J; Griffin, DE

    The amino acid at position 55 of the E2 glycoprotein (E2(55)) of Sindbis virus (SV) is a critical determinant of SV neurovirulence in mice. Recombinant virus strain TE (E2(55) = histidine) differs only at this position from virus strain 633 (E2(55) = glutamine), yet TE is considerably more

  8. Pre-clinical MR elastography: Principles, techniques, and applications

    Science.gov (United States)

    Bayly, P. V.; Garbow, J. R.

    2018-06-01

    Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

  9. 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

  10. Neurovirulence of yellow fever 17DD vaccine virus to rhesus monkeys

    International Nuclear Information System (INIS)

    Marchevsky, Renato S.; Freire, Marcos S.; Coutinho, Evandro S.F.; Galler, Ricardo

    2003-01-01

    The yellow fever 17D virus is attenuated and used for human vaccination. Two of its substrains, 17D-204 and 17DD, are used for vaccine production. One of the remarkable properties of this vaccine is limited viral replication in the host but with significant dissemination of the viral mass, yielding a robust and long-lived neutralizing antibody response. The vaccine has excellent records of efficacy and safety and is cheap, used as a single dose, and there are well-established production methodology and quality control procedures which include the monkey neurovirulence test (MNTV). The present study aims at a better understanding of YF 17DD virus attenuation and immunogenicity in the MNVT with special emphasis on viremia, seroconversion, clinical and histological lesions scores, and their intrinsic variability across the tests. Several MNVTs were performed using the secondary seed lot virus 17DD 102/84 totaling 49 rhesus monkeys. Viremia was never higher than the accepted limits established in international requirements, and high levels of neutralizing antibodies were observed in all animals. None of the animals showed visceral lesions. We found that the clinical scores for the same virus varied widely across the tests. There was a direct correlation between the clinical scores in animals with clinical signs of encephalitis and a higher degree of central nervous system (CNS) histological lesions, with an increase of lesions in areas of the CNS such as the substantia nigra, nucleus caudatus, intumescentia cervicalis, and intumescentia ventralis. The histological scores were shown to be less prone to individual variations and had a more homogeneous value distribution among the tests. Since 17DD 102/84 seed virus has been used for human vaccine production and immunization for 16 years with the vaccine being safe and efficacious, it demonstrates that the observed variations across the MNVTs do not influence its effect on humans

  11. Antigenic variants of yellow fever virus with an altered neurovirulence phenotype in mice.

    Science.gov (United States)

    Ryman, K D; Xie, H; Ledger, T N; Campbell, G A; Barrett, A D

    1997-04-14

    The live-attenuated yellow fever (YF) vaccine virus, strain 17D-204, has long been known to consist of a heterologous population of virions. Gould et al. (J. Gen. Virol. 70, 1889-1894 (1989)) previously demonstrated that variant viruses exhibiting a YF wild-type-specific envelope (E) protein epitope are present at low frequency in the vaccine pool and were able to isolate representative virus variants with and without this epitope, designated 17D(+wt) and 17D(-wt), respectively. These variants were employed here in an investigation of YF virus pathogenesis in the mouse model. Both the 17D-204 parent and the 17D(+wt) variant viruses were lethal for adult outbred mice by the intracerebral route of inoculation. However, the 17D(-wt) variant was significantly attenuated (18% mortality rate) and replicated to much lower titer in the brains of infected mice. A single amino acid substitution in the envelope (E) protein at E-240 (Ala-->Val) was identified as responsible for the restricted replication of the 17D(-wt) variant in vivo. The 17D(+wt) variant has an additional second-site mutation, believed to encode a reversion to the neurovirulence phenotype of the 17D-204 parent virus. The amino acid substitution in the E protein at E-173 (Thr-->Ile) of the 17D(+wt) variant which results in the appearance of the wild-type-specific epitope or nucleotide changes in the 5' and 3' noncoding regions of the virus are proposed as a candidates.

  12. 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

  13. 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

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

    African Journals Online (AJOL)

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

  15. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    Science.gov (United States)

    2012-07-01

    will be assessed. Mac- 1 and GFAP immunostaining will be done to gauge inflammation as it relates to HDAC activity. Tyrosine hydroxylase and Nissl ... stained neurons will be counted and complex II histochemistry will be performed. Part II, we will prepare a new set of implanted mice treated with

  16. Neurovirulent vaccine-derived polioviruses in sewage from highly immune populations.

    Directory of Open Access Journals (Sweden)

    Lester M Shulman

    Full Text Available BACKGROUND: Vaccine-derived polioviruses (VDPVs have caused poliomyelitis outbreaks in communities with sub-optimal vaccination. Israeli environmental surveillance of sewage from populations with high (>95% documented vaccine coverage of confirmed efficacy identified two separate evolutionary clusters of VDPVs: Group 1 (1998-2005, one system, population 1.6x10(6 and Group 2 (2006, 2 systems, populations 0.7x10(6 and 5x10(4. PRINCIPAL FINDINGS: Molecular analyses support evolution of nine Group 1 VDPVs along five different lineages, starting from a common ancestral type 2 vaccine-derived Sabin-2/Sabin-1 recombinant strain, and independent evolution of three Group 2 VDPVs along one lineage starting from a different recombinant strain. The primary evidence for two independent origins was based on comparison of unique recombination fingerprints, the number and distribution of identical substitutions, and evolutionary rates. Geometric mean titers of neutralizing antibodies against Group 1 VDPVs were significantly lower than against vaccine strains in all age-group cohorts tested. All individuals had neutralizing titers >1:8 against these VDPVs except 7% of the 20-50 year cohort. Group 1 VDPVs were highly neurovirulent in a transgenic mouse model. Intermediate levels of protective immunity against Group 2 VDPVs correlated with fewer (5.0+1.0 amino acid substitutions in neutralizing antigenic sites than in Group 1 VDPV's (12.1+/-1.5. SIGNIFICANCE: VDPVs that revert from live oral attenuated vaccines and reacquire characteristics of wild-type polioviruses not only threaten populations with poor immune coverage, but are also a potential source for re-introduction of poliomyelitis into highly immune populations through older individuals with waning immunity. The presence of two independently evolved groups of VDPVs in Israel and the growing number of reports of environmental VDPV elsewhere make it imperative to determine the global frequency of

  17. Problem-based learning in pre-clinical medical education: 22 years of outcome research.

    Science.gov (United States)

    Hartling, Lisa; Spooner, Carol; Tjosvold, Lisa; Oswald, Anna

    2010-01-01

    To conduct a systematic review of problem-based learning (PBL) in undergraduate, pre-clinical medical education. A research librarian developed comprehensive search strategies for MEDLINE, PSYCINFO, and ERIC (1985-2007). Two reviewers independently screened search results and applied inclusion criteria. Studies were included if they had a comparison group and reported primary data for evaluative outcomes. One reviewer extracted data and a second reviewer checked data for accuracy. Two reviewers independently assessed methodological quality. Quantitative synthesis was not performed due to heterogeneity. A qualitative review with detailed evidence tables is provided. Thirty unique studies were included. Knowledge acquisition measured by exam scores was the most frequent outcome reported; 12 of 15 studies found no significant differences. Individual studies demonstrated either improved clerkship (N = 3) or residency (N = 1) performance, or benefits on some clinical competencies during internships for PBL (N = 1). Three of four studies found some benefits for PBL when evaluating diagnostic accuracy. Three studies found few differences of clinical (or practical) importance on the impact of PBL on practicing physicians. Twenty-two years of research shows that PBL does not impact knowledge acquisition; evidence for other outcomes does not provide unequivocal support for enhanced learning. Work is needed to determine the most appropriate outcome measures to capture and quantify the effects of PBL. General conclusions are limited by methodological weaknesses and heterogeneity across studies. The critical appraisal of previous studies, conducted as part of this review, provides direction for future research in this area.

  18. Bioluminescent imaging: a critical tool in pre-clinical oncology research.

    LENUS (Irish Health Repository)

    O'Neill, Karen

    2010-02-01

    Bioluminescent imaging (BLI) is a non-invasive imaging modality widely used in the field of pre-clinical oncology research. Imaging of small animal tumour models using BLI involves the generation of light by luciferase-expressing cells in the animal following administration of substrate. This light may be imaged using an external detector. The technique allows a variety of tumour-associated properties to be visualized dynamically in living models. The increasing use of BLI as a small-animal imaging modality has led to advances in the development of xenogeneic, orthotopic, and genetically engineered animal models expressing luciferase genes. This review aims to provide insight into the principles of BLI and its applications in cancer research. Many studies to assess tumour growth and development, as well as efficacy of candidate therapeutics, have been performed using BLI. More recently, advances have also been made using bioluminescent imaging in studies of protein-protein interactions, genetic screening, cell-cycle regulators, and spontaneous cancer development. Such novel studies highlight the versatility and potential of bioluminescent imaging in future oncological research.

  19. Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study.

    Science.gov (United States)

    da Costa, Anaelle; Prehaud, Christophe; Khou, Cecile; Pardigon, Nathalie; Saulnier, Aure; Nougarede, Nolwenn; Lafon, Monique

    2018-05-01

    Live attenuated vaccines have proved to be mostly valuable in the prevention of infectious diseases in humans, especially in developing countries. The safety and potency of vaccine, and the consistency of vaccine batch-to-batch manufacturing, must be proven before being administrated to humans. For now, the tests used to control vaccine safety largely involve animal testing. For live viral vaccines, regulations require suppliers to demonstrate the absence of neurovirulence in animals, principally in non-human primates and mice. In a search to reduce the use of animals and embracing the 3Rs principles (Replacement, Reduction, Refinement in the use of laboratory animals), we developed a new Blood-Brain Barrier Minibrain (BBB-Minibrain) in cellulo device to evaluate the neuroinvasiveness/neurovirulence of live Yellow Fever virus (YFV) vaccines. A pilot study was performed using the features of two distinct YFV strains, with the ultimate goal of proposing a companion test to characterize YFV neurovirulence. Here, we demonstrate that the BBB-Minibrain model is a promising alternative to consider for future replacement of YFV vaccine in vivo neurovirulence testing (see graphical abstract). Copyright © 2018. Published by Elsevier Ltd.

  20. Antiviral activity of 3(2H- and 6-chloro-3(2H-isoflavenes against highly diverged, neurovirulent vaccine-derived, type2 poliovirus sewage isolates.

    Directory of Open Access Journals (Sweden)

    Lester M Shulman

    Full Text Available BACKGROUND: Substituted flavanoids interfere with uncoating of Enteroviruses including Sabin-2 polio vaccine strains. However flavanoid resistant and dependent, type-2 polio vaccine strains (minimally-diverged, emerged during in vitro infections. Between 1998-2009, highly-diverged (8 to >15% type-2, aVDPV(2s, from two unrelated persistent infections were periodically isolated from Israeli sewage. AIM: To determine whether highly evolved aVDPV(2s derived from persistent infections retained sensitivity to isoflavenes. METHODS: Sabin-2 and ten aVDPV(2 isolates from two independent Israeli sources were titered on HEp2C cells in the presence and absence of 3(2H- Isoflavene and 6-chloro-3(2H-Isoflavene. Neurovirulence of nine aVDPV(2s was measured in PVR-Tg-21 transgenic mice. Differences were related to unique amino acid substitutions within capsid proteins. PRINCIPAL FINDINGS: The presence of either flavanoid inhibited viral titers of Sabin-2 and nine of ten aVDPV(2s by one to two log(10. The tenth aVDPV(2, which had unique amino acid substitution distant from the isoflavene-binding pocket but clustered at the three- and five-fold axies of symmetry between capsomeres, was unaffected by both flavanoids. Genotypic neurovirulence attenuation sites in the 5'UTR and VP1 reverted in all aVDPV(2s and all reacquired a full neurovirulent phenotype except one with amino acid substitutions flanking the VP1 site. CONCLUSION: Both isoflavenes worked equally well against Sabin 2 and most of the highly-diverged, Israeli, aVDPV(2s isolates. Thus, functionality of the hydrophobic pocket may be unaffected by selective pressures exerted during persistent poliovirus infections. Amino acid substitutions at sites remote from the drug-binding pocket and adjacent to a neurovirulence attenuation site may influence flavanoid antiviral activity, and neurovirulence, respectively.

  1. Gait analysis and weight bearing in pre-clinical joint pain research.

    Science.gov (United States)

    Ängeby Möller, Kristina; Svärd, Heta; Suominen, Anni; Immonen, Jarmo; Holappa, Johanna; Stenfors, Carina

    2018-04-15

    There is a need for better joint pain treatment, but development of new medication has not been successful. Pre-clinical models with readouts that better reflect the clinical situation are needed. In patients with joint pain, pain at rest and pain at walking are two major complaints. We describe a new way of calculating results from gait analysis using the CatWalk™ setup. Rats with monoarthritis induced by injection of Complete Freund's Adjuvant (CFA) intra-articularly into the ankle joint of one hind limb were used to assess gait and dynamic weight bearing. The results show that dynamic weight bearing was markedly reduced for the injected paw. Gait parameters such as amount of normal step sequences, walking speed and duration of step placement were also affected. Treatment with naproxen (an NSAID commonly used for inflammatory pain) attenuated the CFA-induced effects. Pregabalin, which is used for neuropathic pain, had no effect. Reduced dynamic weight bearing during locomotion, assessed and calculated in the way we present here, showed a dose-dependent and lasting normalization after naproxen treatment. In contrast, static weight bearing while standing (Incapacitance tester) showed a significant effect for a limited time only. Mechanical sensitivity (von Frey Optihairs) was completely normalized by naproxen, and the window for testing pharmacological effect disappeared. Objective and reproducible effects, with an endpoint showing face validity compared to pain while walking in patients with joint pain, are achieved by a new way of calculating dynamic weight bearing in monoarthritic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Neurovirulence of H5N1 infection in ferrets is mediated by multifocal replication in distinct permissive neuronal cell regions.

    Directory of Open Access Journals (Sweden)

    Jennifer R Plourde

    Full Text Available Highly pathogenic avian influenza A (HPAI, subtype H5N1, remains an emergent threat to the human population. While respiratory disease is a hallmark of influenza infection, H5N1 has a high incidence of neurological sequelae in many animal species and sporadically in humans. We elucidate the temporal/spatial infection of H5N1 in the brain of ferrets following a low dose, intranasal infection of two HPAI strains of varying neurovirulence and lethality. A/Vietnam/1203/2004 (VN1203 induced mortality in 100% of infected ferrets while A/Hong Kong/483/1997 (HK483 induced lethality in only 20% of ferrets, with death occurring significantly later following infection. Neurological signs were prominent in VN1203 infection, but not HK483, with seizures observed three days post challenge and torticollis or paresis at later time points. VN1203 and HK483 replication kinetics were similar in primary differentiated ferret nasal turbinate cells, and similar viral titers were measured in the nasal turbinates of infected ferrets. Pulmonary viral titers were not different between strains and pathological findings in the lungs were similar in severity. VN1203 replicated to high titers in the olfactory bulb, cerebral cortex, and brain stem; whereas HK483 was not recovered in these tissues. VN1203 was identified adjacent to and within the olfactory nerve tract, and multifocal infection was observed throughout the frontal cortex and cerebrum. VN1203 was also detected throughout the cerebellum, specifically in Purkinje cells and regions that coordinate voluntary movements. These findings suggest the increased lethality of VN1203 in ferrets is due to increased replication in brain regions important in higher order function and explains the neurological signs observed during H5N1 neurovirulence.

  3. Ethnic and social disparities in different types of examinations in undergraduate pre-clinical training.

    Science.gov (United States)

    Stegers-Jager, K M; Brommet, F N; Themmen, A P N

    2016-12-01

    Medical schools are increasingly faced with a more diverse student population. Generally, ethnic minority students are reported to underperform compared with those from the ethnic majority. However, there are inconsistencies in findings in different types of examinations. Additionally, little is known about the performance of first-generation university students and about performance differences across ethnic minority groups. This study aimed to investigate underperformance across ethnic minority groups and by first-generation university students in different types of written tests and clinical skills examinations during pre-clinical training. A longitudinal prospective cohort study of progress on a 3-year Dutch Bachelor of Medicine course was conducted. Participants included 2432 students who entered the course over a consecutive 6-year period (2008-2013). Compared with Dutch students, the three non-Western ethnic minority groups (Turkish/Moroccan/African, Surinamese/Antillean and Asian) underperformed in the clinical problem solving tests, the language test and the OSCEs. Findings on the theoretical end-of-block tests and writing skills tests, and results for Western minority students were less consistent. Age, gender, pre-university grade point average and additional socio-demographic variables (including first-generation university student, first language, and medical doctor parent) could explain the ethnicity-related differences in theoretical examinations, but not in language, clinical and writing skills examinations. First-generation university students only underperformed in the language test. Apparently, underperformance differs both across ethnic subgroups and between different types of written and clinical examinations. Medical schools should ensure their assessment strategies create a level playing field for all students and explore reasons for underperformance in the clinical and writing skills examinations.

  4. A metabonomic approach for mechanistic exploration of pre-clinical toxicology.

    Science.gov (United States)

    Coen, Muireann

    2010-12-30

    Metabonomics involves the application of advanced analytical tools to profile the diverse metabolic complement of a given biofluid or tissue. Subsequent statistical modelling of the complex multivariate spectral profiles enables discrimination between phenotypes of interest and identifies panels of discriminatory metabolites that represent candidate biomarkers. This review article presents an overview of recent developments in the field of metabonomics with a focus on application to pre-clinical toxicology studies. Recent research investigations carried out as part of the international COMET 2 consortium project on the hepatotoxic action of the aminosugar, galactosamine (galN) are presented. The application of advanced, high-field NMR spectroscopy is demonstrated, together with complementary application of a targeted mass spectrometry platform coupled with ultra-performance liquid chromatography. Much novel mechanistic information has been gleaned on both the mechanism of galN hepatotoxicity in multiple biofluids and tissues, and on the protection afforded by co-administration of glycine and uridine. The simultaneous identification of both the metabolic fate of galN and its associated endogenous consequences in spectral profiles is demonstrated. Furthermore, metabonomic assessment of inter-animal variability in response to galN presents enhanced mechanistic insight on variable response phentoypes and is relevant to understanding wider aspects of individual variability in drug response. This exemplar highlights the analytical and statistical tools commonly applied in metabonomic studies and notably, the approach is applicable to the study of any toxin/drug or intervention of interest. The metabonomic approach holds considerable promise and potential to significantly advance our understanding of the mechanistic bases for adverse drug reactions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

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

    2017-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-07-01

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

  7. A computerized pre-clinical test for cemented hip prostheses based on finite element techniques

    NARCIS (Netherlands)

    Stolk, Jan

    2003-01-01

    Despite the success of cemented total hip replacement (THR), high failure rates are occasionally reported for cemented hip implants that are introduced on the orthopaedic market. Rigorous pre-clinical testing of hip implants could prevent these disasters, by detecting unsafe implant designs at a

  8. 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.

  9. VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

    Science.gov (United States)

    Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

    2016-01-01

    Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

  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. Psychosocial problems of pre-clinical students in the University of Ibadan Medical School.

    Science.gov (United States)

    Omokhodion, F O

    2003-06-01

    Recent changes in the psychosocial environment of the university campus such as the steep rise in student numbers, the high cost of living standards and the increase in violence and cult activities has prompted the need to assess the impact of these changes on the students. A cross sectional study was carried out among pre-clinical medical students to identify their psychosocial problems. A self-administered questionnaire was used to collect information about socio-demographic variables including age, sex, sources of financial support, type of accommodation, smoking and drinking habits and use of recreational facilities. Causes of insecurity and depression among students were also recorded. The General Health Questionnaire GHQ-12 was used to assess their mental health status. One hundred and seventy-six students responded to the enquiry, 94 males (53%) and 80 females (45%). One hundred and thirty-seven (79%) live on the campus while 37 (21%) live off campus. Only 9 of the students (5%) were smokers and 28 (16%) were drinkers. Monthly pocket money ranged from Naira 1,000 to Naira 25,000. Forty-one (23%) thought their pocket money was adequate, 92 (52%) thought it was fair and 39 (22%) thought it was inadequate. Causes of insecurity on the campus were cultism 34 (19%), lack of money 27 (15%), lack of textbooks 13 (7%) and stealing 10 (6%). Causes of depression include fear of failure of examinations, 62 (35%), lack of money, 48 (27%) and family problems 17 (10%). Mental health scores ranged from 1 to 10. Using a cut off point of 3 to delineate those with traits of poor mental health, 35 (21%) fell into the category 15 boys and 20 girls. Mean mental health score were higher for females, those living on campus, smokers and drinkers but this was not statistically significant. Fear of failure of examinations, cultism and lack of money are major concerns among medical students on the main university campus. Counselling services should be provided to assist students with

  12. Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: a pilot study

    OpenAIRE

    Da Costa , Anaelle; Prehaud , Christophe; Khou , Cécile; Pardigon , Nathalie; Saulnier , Aure; Nougarede , Nolwenn; Lafon , Monique

    2018-01-01

    International audience; Live attenuated vaccines have proved to be mostly valuable in the prevention of infectious diseases in humans, especially in developing countries. The safety and potency of vaccine, and the consistency of vaccine batch-to-batch manufacturing, must be proven before being administrated to humans. For now, the tests used to control vaccine safety largely involve animal testing. For live viral vaccines, regulations require suppliers to demonstrate the absence of neurovirul...

  13. Pre-clinical research in small animals using radiotherapy technology. A bidirectional translational approach

    International Nuclear Information System (INIS)

    Tillner, Falk; Buetof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang; Helmholtz-Zentrum Dresden-Rossendorf, Dresden; Technische Univ. Dresden; Helmholtz-Zentrum Dresden-Rossendorf, Dresden

    2014-01-01

    For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

  14. Marker for the pre-clinical development of bone substitute materials

    Directory of Open Access Journals (Sweden)

    de Wild Michael

    2017-09-01

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

  15. Tendinopathies and platelet-rich plasma (PRP: from pre-clinical experiments to therapeutic use

    Directory of Open Access Journals (Sweden)

    Kaux JF

    2015-05-01

    Full Text Available Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed.

  16. Pre-clinical research in small animals using radiotherapy technology--a bidirectional translational approach.

    Science.gov (United States)

    Tillner, Falk; Thute, Prasad; Bütof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang

    2014-12-01

    For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained. Copyright © 2014. Published by Elsevier GmbH.

  17. Pre-clinical research in small animals using radiotherapy technology. A bidirectional translational approach

    Energy Technology Data Exchange (ETDEWEB)

    Tillner, Falk; Buetof, Rebecca [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Thute, Prasad [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Krause, Mechthild [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; German Cancer Consortium (DKTK), Dresden (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); Enghardt, Wolfgang [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany). Inst. of Radiooncology

    2014-07-01

    For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

  18. Nitric oxide nanoparticles: Pre-clinical utility as a therapeutic for intramuscular abscesses

    OpenAIRE

    Schairer, David O.; Martinez, Luis R.; Blecher, Karin; Chouake, Jason S.; Nacharaju, Parimala; Gialanella, Philip; Friedman, Joel M.; Nosanchuk, Joshua D.; Friedman, Adam J.

    2012-01-01

    Nitric oxide (NO) is a critical component of host defense against invading pathogens; however, its therapeutic utility is limited due to a lack of practical delivery systems. Recently, a NO-releasing nanoparticulate platform (NO-np) was shown to have in vitro broad-spectrum antimicrobial activity and in vivo pre-clinical efficacy in a dermal abscess model. To extend these findings, both topical (TP) and intralesional (IL) NO-np administration was evaluated in a MRSA intramuscular murine absce...

  19. 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.

  20. Enhancing translation: guidelines for standard pre-clinical experiments in mdx mice.

    Science.gov (United States)

    Willmann, Raffaella; De Luca, Annamaria; Benatar, Michael; Grounds, Miranda; Dubach, Judith; Raymackers, Jean-Marc; Nagaraju, Kanneboyina

    2012-01-01

    Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. The predictive validity of the BioMedical Admissions Test for pre-clinical examination performance.

    Science.gov (United States)

    Emery, Joanne L; Bell, John F

    2009-06-01

    Some medical courses in the UK have many more applicants than places and almost all applicants have the highest possible previous and predicted examination grades. The BioMedical Admissions Test (BMAT) was designed to assist in the student selection process specifically for a number of 'traditional' medical courses with clear pre-clinical and clinical phases and a strong focus on science teaching in the early years. It is intended to supplement the information provided by examination results, interviews and personal statements. This paper reports on the predictive validity of the BMAT and its predecessor, the Medical and Veterinary Admissions Test. Results from the earliest 4 years of the test (2000-2003) were matched to the pre-clinical examination results of those accepted onto the medical course at the University of Cambridge. Correlation and logistic regression analyses were performed for each cohort. Section 2 of the test ('Scientific Knowledge') correlated more strongly with examination marks than did Section 1 ('Aptitude and Skills'). It also had a stronger relationship with the probability of achieving the highest examination class. The BMAT and its predecessor demonstrate predictive validity for the pre-clinical years of the medical course at the University of Cambridge. The test identifies important differences in skills and knowledge between candidates, not shown by their previous attainment, which predict their examination performance. It is thus a valid source of additional admissions information for medical courses with a strong scientific emphasis when previous attainment is very high.

  2. Non-invasive pre-clinical MR imaging of prostate tumor hypoxia for radiation therapy prognosis

    Directory of Open Access Journals (Sweden)

    Derek White

    2014-03-01

    patient stratification for clinical implementation.------------------------------Cite this article as: White DA, Mason RP. Non-invasive pre-clinical MR imaging of prostate tumor hypoxia for radiation therapy prognosis. Int J Cancer Ther Oncol 2014; 2(2:020243. DOI: 10.14319/ijcto.0202.43

  3. Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir.

    Science.gov (United States)

    Murphy, Diarmaid J; Desjardins, Delphine; Dereuddre-Bosquet, Nathalie; Brochard, Patricia; Perrot, Ludivine; Pruvost, Alain; Le Grand, Roger; Lagatie, Ole; Vanhooren, Leen; Feyaerts, Maxim; van Roey, Jens; Malcolm, R Karl

    2014-09-01

    Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the pre-clinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir. Macaque rings containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir or 100 mg dapivirine+300 mg darunavir were manufactured and characterized by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28 day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values were calculated. Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present and the release medium. In macaques, serum concentrations of both microbicides were maintained between 10(1) and 10(2) pg/mL. Vaginal fluid levels ranged between 10(3) and 10(4) ng/g and between 10(4) and 10(5) ng/g for dapivirine and darunavir, respectively. Both dapivirine and darunavir showed very similar concentrations in each tissue type; the range of drug tissue concentrations followed the general rank order: vagina (1.8 × 10(3)-3.8 × 10(3) ng/g)  > cervix (9.4 × 10(1)-3.9 × 10(2) ng/g)  > uterus (0-108 ng/g)  > rectum (0-40 ng/g). Measured IC50 values were >2 ng/mL for both compounds. Based on these results, and in light of recent clinical progress of the 25 mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate. © The Author 2014. Published by Oxford University Press on behalf of the British Society for

  4. EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer.

    Science.gov (United States)

    van Driel, Pieter B A A; Boonstra, Martin C; Slooter, Maxime D; Heukers, Raimond; Stammes, Marieke A; Snoeks, Thomas J A; de Bruijn, Henriette S; van Diest, Paul J; Vahrmeijer, Alexander L; van Bergen En Henegouwen, Paul M P; van de Velde, Cornelis J H; Löwik, Clemens W G M; Robinson, Dominic J; Oliveira, Sabrina

    2016-05-10

    Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre-clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro, the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo, PDT was applied on an orthotopic mouse tumor model with illumination at 1h post-injection of the nanobody-PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody-PS conjugate, with illumination performed 24h post-injection. Importantly, EGFR targeted nanobody-PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24h after PDT. Overall, results show that these EGFR targeted nanobody-PS conjugates are selective and able to induce tumor cell death in vivo. Additional studies are now needed to assess the full potential of this approach to improving PDT. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. The relationship between learning preferences (styles and approaches) and learning outcomes among pre-clinical undergraduate medical students.

    Science.gov (United States)

    Liew, Siaw-Cheok; Sidhu, Jagmohni; Barua, Ankur

    2015-03-11

    Learning styles and approaches of individual undergraduate medical students vary considerably and as a consequence, their learning needs also differ from one student to another. This study was conducted to identify different learning styles and approaches of pre-clinical, undergraduate medical students and also to determine the relationships of learning preferences with performances in the summative examinations. A cross-sectional study was conducted among randomly selected 419 pre-clinical, undergraduate medical students of the International Medical University (IMU) in Kuala Lumpur. The number of students from Year 2 was 217 while that from Year 3 was 202. The Visual, Auditory, Read/Write, Kinesthetic (VARK) and the Approaches and Study Skills Inventory for Students (ASSIST) questionnaires were used for data collection. This study revealed that 343 students (81.9%) had unimodal learning style, while the remaining 76 (18.1%) used a multimodal learning style. Among the unimodal learners, a majority (30.1%) were of Kinesthetic (K) type. Among the middle and high achievers in summative examinations, a majority had unimodal (Kinaesthetic) learning style (30.5%) and were also strategic/deep learners (79.4%). However, the learning styles and approaches did not contribute significantly towards the learning outcomes in summative examinations. A majority of the students in this study had Unimodal (Kinesthetic) learning style. The learning preferences (styles and approaches) did not contribute significantly to the learning outcomes. Future work to re-assess the viability of these learning preferences (styles and approaches) after the incorporation of teaching-learning instructions tailored specifically to the students will be beneficial to help medical teachers in facilitating students to become more capable learners.

  6. Psychosocial impact, perceived stress and learning effect in undergraduate dental students during transition from pre-clinical to clinical education.

    Science.gov (United States)

    Frese, C; Wolff, D; Saure, D; Staehle, H J; Schulte, A

    2018-04-10

    This study aimed to develop a suitable instrument for a comprehensive quantitative and qualitative assessment of perceived psychosocial impact, levels of stress and learning effect in undergraduate dental students during the transition from pre-clinical to clinical education. These findings might improve curricular structures and didactic organisation during this period. At the beginning of their first clinical year, undergraduate dental students were asked to complete an anonymous forty-item questionnaire. Two hundred and seventy-six undergraduate dental students were willing to participate and completed the questionnaire and participated during the years 2011-2016. The response rate was between 45% and 96%. Correlational analysis (Spearman-Rho) in the field of psychosocial impact showed the dental teacher to be the most important multiplier of students' feelings. If the students feel that their teacher acts cooperatively, positive items increase and negative items decrease significantly (P < .0001). Also, students who report high levels of stress are affected significantly in their psychosocial interaction (P < .0001). Wilcoxon test yielded highest levels of stress in endodontology during the first weeks (P < .0001). During the same period, the greatest learning increment was seen for diagnostics and caries excavation. In conclusion, teaching of undergraduate dental students during the transition period from pre-clinical to clinical education can be positively influenced by a supportive learning environment and by specific chronological modifications in the curriculum. Students should start their clinical training with diagnostics, preventive dentistry and initial periodontal treatment. Due to high levels of perceived stress, endodontology should be introduced later in the clinical curriculum. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

    Science.gov (United States)

    Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

    2014-11-01

    Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  8. The detection, diagnosis, therapy, and pre-clinical biology of breast cancer

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram covers clinical aspects of cancers of the mammary glands, the fat pads and the supporting tissues. Abstracts included concern certain specific types of neoplasms which occur in the breast, and in ancillary tissues related to the breast (axillary lymph nodes, etc.). Also included are selected studies on receptors and the physiological aspects of lactation, pregnancy, and ontogeny related to cancer of the breast. The topic includes clinically relevant aspects of the prevention, detection, diagnosis, evaluation, and therapy of breast cancer. With certain exceptions, pre-clinical studies of tissue culture systems or animal model studies which are not directly related to primary human disease are excluded

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  10. Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

    Science.gov (United States)

    2014-05-16

    FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Cheng eWang

    2012-10-01

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

  13. Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.

    Science.gov (United States)

    Iglesias, Ainhoa; García-Nimo, Laura; Cocho de Juan, José A; Moreno, José C

    2014-03-01

    DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Pre-clinical medical student experience in a pediatric pulmonary clinic

    Directory of Open Access Journals (Sweden)

    Thomas G. Saba

    2015-11-01

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

  15. A generalizable pre-clinical research approach for orphan disease therapy

    Directory of Open Access Journals (Sweden)

    Beaulieu Chandree L

    2012-06-01

    Full Text Available Abstract With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.

  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. Pre-clinical assessment of A-674563 as an anti-melanoma agent

    International Nuclear Information System (INIS)

    Zou, Ying; Fan, Guobiao; Wang, Xuemin

    2016-01-01

    The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. - Highlights: • A-674563 inhibits human melanoma cell survival and proliferation. • A-674563 induces melanoma cell apoptotic death, inhibited by caspase inhibitors. • A-674563 inhibits melanoma cells via Akt-dependent and -independent mechanisms. • A-674563 induces ceramide production in melanoma cells, independent of Akt inhibition. • A-674563 oral administration potently inhibits A375 xenograft growth in mice.

  18. Pre-clinical assessment of A-674563 as an anti-melanoma agent

    Energy Technology Data Exchange (ETDEWEB)

    Zou, Ying; Fan, Guobiao; Wang, Xuemin, E-mail: wangxuemeidr@yeah.net

    2016-08-12

    The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A-674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A-674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A-674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms. - Highlights: • A-674563 inhibits human melanoma cell survival and proliferation. • A-674563 induces melanoma cell apoptotic death, inhibited by caspase inhibitors. • A-674563 inhibits melanoma cells via Akt-dependent and -independent mechanisms. • A-674563 induces ceramide production in melanoma cells, independent of Akt inhibition. • A-674563 oral administration potently inhibits A375 xenograft growth in mice.

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

    Science.gov (United States)

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

    2017-09-01

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

  20. Possible repurposing of pyrvinium pamoate for the treatment of mesothelioma: A pre-clinical assessment.

    Science.gov (United States)

    Barbarino, Marcella; Cesari, Daniele; Intruglio, Riccardo; Indovina, Paola; Namagerdi, Asadoor; Bertolino, Franca Maria; Bottaro, Maria; Rahamani, Delaram; Bellan, Cristiana; Giordano, Antonio

    2018-04-16

    Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, whose incidence is increasing worldwide. Unfortunately, no effective therapies are currently available and the prognosis is extremely poor. Recently, the anti-helminthic drug pyrvinium pamoate has attracted a strong interest for its anti-cancer activity, which has been demonstrated in many cancer models. Considering the previously established inhibitory effect of pyrvinium pamoate on the Wnt/β-catenin pathway and given the important role of this pathway in MM, we investigated the potential anti-tumor activity of this drug in MM cell lines. We observed that pyrvinium pamoate significantly impairs MM cell proliferation, cloning efficiency, migration, and tumor spheroid formation. At the molecular level, our data show that pyrvinium pamoate down-regulates the expression of β-catenin and Wnt-regulates genes. Overall, our study suggests that the repurposing of pyrvinium pamoate for MM treatment could represent a new promising therapeutic approach. © 2018 Wiley Periodicals, Inc.

  1. Extending the theoretical framework for curriculum integration in pre-clinical medical education

    DEFF Research Database (Denmark)

    Vergel, John; Stentoft, Diana; Montoya, Juny

    2017-01-01

    students' knowledge integration. Therefore, we aimed to uncover how curriculum integration is manifested through context. METHODS: We collected data from the official curriculum and interviewed ten participants (including curriculum designers, facilitators, and students) in the bachelor's medical program......INTRODUCTION: Curriculum integration is widely discussed in medical education but remains ill defined. Although there is plenty of information on logistical aspects of curriculum integration, little attention has been paid to the contextual issues that emerge from its practice and may complicate...... at Aalborg University. We observed various learning activities focused on pre-clinical education. Inspired by grounded theory, we analyzed the information we gathered. RESULTS: The following theoretical constructs emerged after the inductive analysis: 1) curriculum integration complexity is embedded...

  2. 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.

  3. A highly invasive human glioblastoma pre-clinical model for testing therapeutics

    Directory of Open Access Journals (Sweden)

    Cao Brian

    2008-12-01

    Full Text Available Abstract Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino-17-demethoxy geldanamycin (17AAG. Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2. These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.

  4. Yellow fever vaccine: comparison of the neurovirulence of new 17D-204 Stamaril™ seed lots and RK 168-73 strain.

    Science.gov (United States)

    Moulin, Jean-Claude; Silvano, Jérémy; Barban, Véronique; Riou, Patrice; Allain, Caroline

    2013-07-01

    The neurovirulence of two new candidate 17D-204 Stamaril™ working seed lots and that of two reference preparations were compared. The Stamaril™ working seed lots have been used for more than twenty years for the manufacturing of vaccines of acceptable safety and efficacy. The preparation designated RK 168-73 and provided by the Robert Koch Institute was used as a reference. It was confirmed that RK 168-73 strain was not a good virus control in our study because it has a very low neurovirulence regarding both the clinical and histopathological scores in comparison with Stamaril™ strain and is not representative of a vaccine known to be satisfactory in use. The results were reinforced by the phenotypic characterization by plaque assay demonstrating that RK 168-73 was very different from the Stamaril™ vaccine, and by sequencing results showing 4 mutations between Stamaril™ and RK 168-73 viruses leading to amino acid differences in the NS4B and envelop proteins. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2016-11-30

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

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

    Science.gov (United States)

    Tucker, Laura B.; Fu, Amanda H.

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Diego Ronaldo Thomaz Sampaio

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

  8. Transparency in the reporting of in vivo pre-clinical pain research: The relevance and implications of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.

    Science.gov (United States)

    Rice, Andrew S C; Morland, Rosemary; Huang, Wenlong; Currie, Gillian L; Sena, Emily S; Macleod, Malcolm R

    2017-12-29

    Clear reporting of research is crucial to the scientific process. Poorly designed and reported studies are damaging not only to the efforts of individual researchers, but also to science as a whole. Standardised reporting methods, such as those already established for reporting randomised clinical trials, have led to improved study design and facilitated the processes of clinical systematic review and meta-analysis. Such standards were lacking in the pre-clinical field until the development of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. These were prompted following a survey which highlighted a widespread lack of robust and consistent reporting of pre-clinical in vivo research, with reports frequently omitting basic information required for study replication and quality assessment. The resulting twenty item checklist in ARRIVE covers all aspects of experimental design with particular emphasis on bias reduction and methodological transparency. Influential publishers and research funders have already adopted ARRIVE. Further dissemination and acknowledgement of the importance of these guidelines is vital to their widespread implementation. Conclusions and implications Wide implementation of the ARRIVE guidelines for reporting of in vivo preclinical research, especially pain research, are essential for a much needed increased transparency and quality in publishing such research. ARRIVE will also positively influence improvements in experimental design and quality, assist the conduct of accurate replication studies of important new findings and facilitate meta-analyses of preclinical research.

  9. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

    Science.gov (United States)

    Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

    2010-09-01

    Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

  10. Targeting NK cells for anti-cancer immunotherapy: clinical and pre-clinical approaches

    Directory of Open Access Journals (Sweden)

    Sebastian eCarotta

    2016-04-01

    Full Text Available The recent success of checkpoint blockade has highlighted the potential of immunotherapy approaches for cancer treatment. While the majority of approved immunotherapy drugs target T cell subsets, it is appreciated that other components of the immune system have important roles in tumor immune-surveillance as well and thus represent promising additional targets for immunotherapy. Natural killer cells are the body’s first line of defense against infected or transformed cells as they kill target cells in an antigen-independent manner. Although several studies have clearly demonstrated the active role of NK cells in cancer-immune surveillance, only few clinically approved therapies currently exist that harness their potential. Our increased understanding of NK cell biology over the past few years has renewed the interest in NK cell based anti-cancer therapies, which has lead to a steady increase of NK cell based clinical and pre-clinical trials. Here, the role of NK cells in cancer immunesurveillance is summarized and several novel approaches to enhance NK cell cytotoxicity against cancer are discussed.

  11. Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery.

    Science.gov (United States)

    Brothers, John F; Ung, Matthew; Escalante-Chong, Renan; Ross, Jermaine; Zhang, Jenny; Cha, Yoonjeong; Lysaght, Andrew; Funt, Jason; Kusko, Rebecca

    2018-06-01

    The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Zhisheng Her

    2017-10-01

    Full Text Available Abstract Background Xenotransplantation of patient-derived AML (acute myeloid leukemia cells in NOD-scid Il2rγ null (NSG mice is the method of choice for evaluating this human hematologic malignancy. However, existing models constructed using intravenous injection in adult or newborn NSG mice have inferior engraftment efficiency, poor peripheral blood engraftment, or are difficult to construct. Methods Here, we describe an improved AML xenograft model where primary human AML cells were injected into NSG newborn pups intrahepatically. Results Introduction of primary cells from AML patients resulted in high levels of engraftment in peripheral blood, spleen, and bone marrow (BM of recipient mice. The phenotype of engrafted AML cells remained unaltered during serial transplantation. The mice developed features that are consistent with human AML including spleen enlargement and infiltration of AML cells into multiple organs. Importantly, we demonstrated that although leukemic stem cell activity is enriched and mediated by CD34+CD117+ subpopulation, CD34+CD117− subpopulation can acquire CD34+CD117+ phenotype through de-differentiation. Lastly, we evaluated the therapeutic potential of Sorafenib and Regorafenib in this AML model and found that periphery and spleen AML cells are sensitive to these treatments, whereas BM provides a protective environment to AML. Conclusions Collectively, our improved model is robust, easy-to-construct, and reliable for pre-clinical AML studies.

  13. Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

    Directory of Open Access Journals (Sweden)

    Chiang Po-Chang

    2009-01-01

    Full Text Available Abstract Asthma and chronic obstructive pulmonary disease (COPD are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT, intranasal (IN, or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN dosing, and was able to achieve dose dependent lung deposition.

  14. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses.

    Science.gov (United States)

    Schairer, David; Martinez, Luis R; Blecher, Karin; Chouake, Jason; Nacharaju, Parimala; Gialanella, Philip; Friedman, Joel M; Nosanchuk, Joshua D; Friedman, Adam

    2012-01-01

    Nitric oxide (NO) is a critical component of host defense against invading pathogens; however, its therapeutic utility is limited due to a lack of practical delivery systems. Recently, a NO-releasing nanoparticulate platform (NO-np) was shown to have in vitro broad-spectrum antimicrobial activity and in vivo pre-clinical efficacy in a dermal abscess model. To extend these findings, both topical (TP) and intralesional (IL) NO-np administration was evaluated in a MRSA intramuscular murine abscess model and compared with vancomycin. All treatment arms accelerated abscess clearance clinically, histologically, and by microbiological assays on both days 4 and 7 following infection. However, abscesses treated with NO-np via either route demonstrated a more substantial, statistically significant decrease in bacterial survival based on colony forming unit assays and histologically revealed less inflammatory cell infiltration and preserved muscular architecture. These data suggest that the NO-np may be an effective addition to our armament for deep soft tissue infections.

  15. Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

    Directory of Open Access Journals (Sweden)

    Julia L. Hurwitz

    2010-02-01

    Full Text Available Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans.

  16. Characterization of a switchable chimeric antigen receptor platform in a pre-clinical solid tumor model.

    Science.gov (United States)

    Pishali Bejestani, Elham; Cartellieri, Marc; Bergmann, Ralf; Ehninger, Armin; Loff, Simon; Kramer, Michael; Spehr, Johannes; Dietrich, Antje; Feldmann, Anja; Albert, Susann; Wermke, Martin; Baumann, Michael; Krause, Mechthild; Bornhäuser, Martin; Ehninger, Gerhard; Bachmann, Michael; von Bonin, Malte

    2017-01-01

    The universal modular chimeric antigen receptor (UniCAR) platform redirects CAR-T cells using a separated, soluble targeting module with a short half-life. This segregation allows precise controllability and flexibility. Herein we show that the UniCAR platform can be used to efficiently target solid cancers in vitro and in vivo using a pre-clinical prostate cancer model which overexpresses prostate stem cell antigen (PSCA). Short-term administration of the targeting module to tumor bearing immunocompromised mice engrafted with human UniCAR-T cells significantly delayed tumor growth and prolonged survival of recipient mice both in a low and high tumor burden model. In addition, we analyzed phenotypic and functional changes of cancer cells and UniCAR-T cells in association with the administration of the targeting module to reveal potential immunoevasive mechanisms. Most notably, UniCAR-T cell activation induced upregulation of immune-inhibitory molecules such as programmed death ligands. In conclusion, this work illustrates that the UniCAR platform mediates potent anti-tumor activity in a relevant in vitro and in vivo solid tumor model.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    Girija Madhavanprabhakaran

    2015-01-01

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

  19. Quantitative pre-clinical screening of therapeutics for joint diseases using contrast enhanced micro-computed tomography.

    Science.gov (United States)

    Willett, N J; Thote, T; Hart, M; Moran, S; Guldberg, R E; Kamath, R V

    2016-09-01

    The development of effective therapies for cartilage protection has been limited by a lack of efficient quantitative cartilage imaging modalities in pre-clinical in vivo models. Our objectives were two-fold: first, to validate a new contrast-enhanced 3D imaging analysis technique, equilibrium partitioning of an ionic contrast agent-micro computed tomography (EPIC-μCT), in a rat medial meniscal transection (MMT) osteoarthritis (OA) model; and second, to quantitatively assess the sensitivity of EPIC-μCT to detect the effects of matrix metalloproteinase inhibitor (MMPi) therapy on cartilage degeneration. Rats underwent MMT surgery and tissues were harvested at 1, 2, and 3 weeks post-surgery or rats received an MMPi or vehicle treatment and tissues harvested 3 weeks post-surgery. Parameters of disease progression were evaluated using histopathology and EPIC-μCT. Correlations and power analyses were performed to compare the techniques. EPIC-μCT was shown to provide simultaneous 3D quantification of multiple parameters, including cartilage degeneration and osteophyte formation. In MMT animals treated with MMPi, OA progression was attenuated, as measured by 3D parameters such as lesion volume and osteophyte size. A post-hoc power analysis showed that 3D parameters for EPIC-μCT were more sensitive than 2D parameters requiring fewer animals to detect a therapeutic effect of MMPi. 2D parameters were comparable between EPIC-μCT and histopathology. This study demonstrated that EPIC-μCT has high sensitivity to provide 3D structural and compositional measurements of cartilage and bone in the joint. EPIC-μCT can be used in combination with histology to provide a comprehensive analysis to screen new potential therapies. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  20. 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

  1. Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.

    Directory of Open Access Journals (Sweden)

    Alain Le Coupanec

    Full Text Available Human coronaviruses (HCoV are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43. In an attempt to study the role of this protein in virus spread within the central nervous system (CNS and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758, which introduces a putative furin-like cleavage (↓ site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies.

  2. VARK learning preferences and mobile anatomy software application use in pre-clinical chiropractic students.

    Science.gov (United States)

    Meyer, Amanda J; Stomski, Norman J; Innes, Stanley I; Armson, Anthony J

    2016-05-06

    Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists between preferred learning styles as determined by the validated VARK(©) questionnaire and use of mobile anatomy apps. The majority of the students who completed the VARK questionnaire were multimodal learners with kinesthetic and visual preferences. Sixty-seven percent (73/109) of students owned one or more mobile anatomy apps which were used by 57 students. Most of these students owned one to five apps and spent less than 30 minutes per week using them. Six of the top eight mobile anatomy apps owned and recommended by the students were developed by 3D4Medical. Visual learning preferences were not associated with time spent using mobile anatomy apps (OR = 0.40, 95% CI 0.12-1.40). Similarly, kinesthetic learning preferences (OR = 1.88, 95% CI 0.18-20.2), quadmodal preferences (OR = 0.71, 95% CI 0.06-9.25), or gender (OR = 1.51, 95% CI 0.48-4.81) did not affect the time students' spent using mobile anatomy apps. Learning preferences do not appear to influence students' time spent using mobile anatomy apps. Anat Sci Educ 9: 247-254. © 2015 American Association of Anatomists. © 2015 American Association of Anatomists.

  3. Pre-clinical evaluation of an inverse planning module for segmental MLC based IMRT delivery

    International Nuclear Information System (INIS)

    Georg, Dietmar; Kroupa, Bernhard

    2002-01-01

    Phantom tests are performed for pre-clinical evaluation of a commercial inverse planning system (HELAX TMS, V 6.0) for segmented multileaf collimator (MLC) intensity modulated radiotherapy (IMRT) delivery. The optimization module has available two optimization algorithms: the target primary feasibility and the weighted feasibility algorithm, only the latter allows the user to specify weights for structures. In the first series, single beam tests are performed to evaluate the outcome of inverse planning in terms of plausibility for the following situations: oblique incidence, presence of inhomogeneities, multiple targets at different depths and multiple targets with different desired doses. Additionally, for these tests a manual plan is made for comparison. In the absence of organs at risk, both the optimization algorithms are found to assign the highest priority to low dose constraints for targets. In the second series, tests resembling clinical relevant configurations (simultaneous boost and concave target with critical organ) are performed with multiple beam arrangements in order to determine the impact of the system's configuration on inverse planning. It is found that the definition of certain segment number and segment size limitations does not largely compromise treatment plans when using multiple beams. On the other hand, these limitations are important for delivery efficiency and dosimetry. For the number of iterations and voxels per volume of interest, standard values in the system's configuration are considered to be sufficient. Additionally, it is demonstrated that precautions must be taken to precisely define treatment goals when using computerized treatment optimization. Similar phantom tests could be used for a direct dosimetric verification of all steps from inverse treatment planning to IMRT delivery. (note)

  4. A pneumatic Bionic Voice prosthesis-Pre-clinical trials of controlling the voice onset and offset.

    Directory of Open Access Journals (Sweden)

    Farzaneh Ahmadi

    Full Text Available Despite emergent progress in many fields of bionics, a functional Bionic Voice prosthesis for laryngectomy patients (larynx amputees has not yet been achieved, leading to a lifetime of vocal disability for these patients. This study introduces a novel framework of Pneumatic Bionic Voice Prostheses as an electronic adaptation of the Pneumatic Artificial Larynx (PAL device. The PAL is a non-invasive mechanical voice source, driven exclusively by respiration with an exceptionally high voice quality, comparable to the existing gold standard of Tracheoesophageal (TE voice prosthesis. Following PAL design closely as the reference, Pneumatic Bionic Voice Prostheses seem to have a strong potential to substitute the existing gold standard by generating a similar voice quality while remaining non-invasive and non-surgical. This paper designs the first Pneumatic Bionic Voice prosthesis and evaluates its onset and offset control against the PAL device through pre-clinical trials on one laryngectomy patient. The evaluation on a database of more than five hours of continuous/isolated speech recordings shows a close match between the onset/offset control of the Pneumatic Bionic Voice and the PAL with an accuracy of 98.45 ±0.54%. When implemented in real-time, the Pneumatic Bionic Voice prosthesis controller has an average onset/offset delay of 10 milliseconds compared to the PAL. Hence it addresses a major disadvantage of previous electronic voice prostheses, including myoelectric Bionic Voice, in meeting the short time-frames of controlling the onset/offset of the voice in continuous speech.

  5. A pneumatic Bionic Voice prosthesis-Pre-clinical trials of controlling the voice onset and offset.

    Science.gov (United States)

    Ahmadi, Farzaneh; Noorian, Farzad; Novakovic, Daniel; van Schaik, André

    2018-01-01

    Despite emergent progress in many fields of bionics, a functional Bionic Voice prosthesis for laryngectomy patients (larynx amputees) has not yet been achieved, leading to a lifetime of vocal disability for these patients. This study introduces a novel framework of Pneumatic Bionic Voice Prostheses as an electronic adaptation of the Pneumatic Artificial Larynx (PAL) device. The PAL is a non-invasive mechanical voice source, driven exclusively by respiration with an exceptionally high voice quality, comparable to the existing gold standard of Tracheoesophageal (TE) voice prosthesis. Following PAL design closely as the reference, Pneumatic Bionic Voice Prostheses seem to have a strong potential to substitute the existing gold standard by generating a similar voice quality while remaining non-invasive and non-surgical. This paper designs the first Pneumatic Bionic Voice prosthesis and evaluates its onset and offset control against the PAL device through pre-clinical trials on one laryngectomy patient. The evaluation on a database of more than five hours of continuous/isolated speech recordings shows a close match between the onset/offset control of the Pneumatic Bionic Voice and the PAL with an accuracy of 98.45 ±0.54%. When implemented in real-time, the Pneumatic Bionic Voice prosthesis controller has an average onset/offset delay of 10 milliseconds compared to the PAL. Hence it addresses a major disadvantage of previous electronic voice prostheses, including myoelectric Bionic Voice, in meeting the short time-frames of controlling the onset/offset of the voice in continuous speech.

  6. A pneumatic Bionic Voice prosthesis—Pre-clinical trials of controlling the voice onset and offset

    Science.gov (United States)

    Noorian, Farzad; Novakovic, Daniel; van Schaik, André

    2018-01-01

    Despite emergent progress in many fields of bionics, a functional Bionic Voice prosthesis for laryngectomy patients (larynx amputees) has not yet been achieved, leading to a lifetime of vocal disability for these patients. This study introduces a novel framework of Pneumatic Bionic Voice Prostheses as an electronic adaptation of the Pneumatic Artificial Larynx (PAL) device. The PAL is a non-invasive mechanical voice source, driven exclusively by respiration with an exceptionally high voice quality, comparable to the existing gold standard of Tracheoesophageal (TE) voice prosthesis. Following PAL design closely as the reference, Pneumatic Bionic Voice Prostheses seem to have a strong potential to substitute the existing gold standard by generating a similar voice quality while remaining non-invasive and non-surgical. This paper designs the first Pneumatic Bionic Voice prosthesis and evaluates its onset and offset control against the PAL device through pre-clinical trials on one laryngectomy patient. The evaluation on a database of more than five hours of continuous/isolated speech recordings shows a close match between the onset/offset control of the Pneumatic Bionic Voice and the PAL with an accuracy of 98.45 ±0.54%. When implemented in real-time, the Pneumatic Bionic Voice prosthesis controller has an average onset/offset delay of 10 milliseconds compared to the PAL. Hence it addresses a major disadvantage of previous electronic voice prostheses, including myoelectric Bionic Voice, in meeting the short time-frames of controlling the onset/offset of the voice in continuous speech. PMID:29466455

  7. Pre-clinical evaluation of a novel nanoemulsion-based hepatitis B mucosal vaccine.

    Directory of Open Access Journals (Sweden)

    Paul E Makidon

    2008-08-01

    Full Text Available Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg in a novel nanoemulsion (NE adjuvant (HBsAg-NE could be effective with fewer administrations.Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/-17 nm associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached > or = 10(6 titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu. Normalization showed that HBsAg-NE vaccination correlates with a protective immunity equivalent or greater than 1000 IU/ml. Th1 polarized immune response was indicated by IFN-gamma and TNF-alpha cytokine production and elevated levels of IgG(2 subclass of HBsAg-specific antibodies. The vaccine retains full immunogenicity for a year at 4 degrees C, 6 months at 25 degrees C and 6 weeks at 40 degrees C. Comprehensive pre-clinical toxicology evaluation demonstrated that HBsAg-NE vaccine is safe and well tolerated in multiple animal models.Our results suggest that needle-free nasal immunization with HBsAg-NE could be a safe and effective hepatitis B vaccine, or provide an alternative booster administration for the parenteral hepatitis B vaccines. This vaccine induces a Th1 associated cellular immunity and also may provide therapeutic benefit to patients with chronic hepatitis B infection who lack cellular immune responses to adequately control viral replication. Long-term stability

  8. Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

    Science.gov (United States)

    Abicht, Jan-Michael; Mayr, Tanja; Reichart, Bruno; Buchholz, Stefan; Werner, Fabian; Lutzmann, Isabelle; Schmoeckel, Michael; Bauer, Andreas; Thormann, Michael; Langenmayer, Martin; Herbach, Nadja; Pohla, Heike; Herzog, Rudolf; McGregor, Christopher G A; Ayares, David; Wolf, Eckhard; Klymiuk, Nikolai; Baehr, Andrea; Kind, Alexander; Hagl, Christian; Ganswindt, Ute; Belka, Claus; Guethoff, Sonja; Brenner, Paolo

    2015-01-01

    As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical

  9. Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

    Science.gov (United States)

    Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

    2013-03-01

    Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted

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

    Directory of Open Access Journals (Sweden)

    Ghosh Anamitra

    2012-10-01

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

  11. The relationship between learning preferences (styles and approaches) and learning outcomes among pre-clinical undergraduate medical students

    OpenAIRE

    Liew, Siaw-Cheok; Sidhu, Jagmohni; Barua, Ankur

    2015-01-01

    Background Learning styles and approaches of individual undergraduate medical students vary considerably and as a consequence, their learning needs also differ from one student to another. This study was conducted to identify different learning styles and approaches of pre-clinical, undergraduate medical students and also to determine the relationships of learning preferences with performances in the summative examinations. Methods A cross-sectional study was conducted among randomly selected...

  12. Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

    2016-12-01

    Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

  13. 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.

  14. High-resolution mutational profiling suggests the genetic validity of glioblastoma patient-derived pre-clinical models.

    Directory of Open Access Journals (Sweden)

    Shawn E Yost

    Full Text Available Recent advances in the ability to efficiently characterize tumor genomes is enabling targeted drug development, which requires rigorous biomarker-based patient selection to increase effectiveness. Consequently, representative DNA biomarkers become equally important in pre-clinical studies. However, it is still unclear how well these markers are maintained between the primary tumor and the patient-derived tumor models. Here, we report the comprehensive identification of somatic coding mutations and copy number aberrations in four glioblastoma (GBM primary tumors and their matched pre-clinical models: serum-free neurospheres, adherent cell cultures, and mouse xenografts. We developed innovative methods to improve the data quality and allow a strict comparison of matched tumor samples. Our analysis identifies known GBM mutations altering PTEN and TP53 genes, and new actionable mutations such as the loss of PIK3R1, and reveals clear patient-to-patient differences. In contrast, for each patient, we do not observe any significant remodeling of the mutational profile between primary to model tumors and the few discrepancies can be attributed to stochastic errors or differences in sample purity. Similarly, we observe ∼96% primary-to-model concordance in copy number calls in the high-cellularity samples. In contrast to previous reports based on gene expression profiles, we do not observe significant differences at the DNA level between in vitro compared to in vivo models. This study suggests, at a remarkable resolution, the genome-wide conservation of a patient's tumor genetics in various pre-clinical models, and therefore supports their use for the development and testing of personalized targeted therapies.

  15. Growth/differentiation factor-5: pre-clinical and clinical evaluations of periodontal regeneration and alveolar augmentation--review.

    Science.gov (United States)

    Lee, Jaebum; Wikesjö, Ulf M E

    2014-08-01

    Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Growth/differentiation factor-5: a candidate therapeutic agent for periodontal regeneration? A review of pre-clinical data.

    Science.gov (United States)

    Moore, Yolanda R; Dickinson, Douglas P; Wikesjö, Ulf M E

    2010-03-01

    Therapeutic concepts involving the application of matrix, growth and differentiation factors have been advocated in support of periodontal wound healing/regeneration. Growth/differentiation factor-5 (GDF-5), a member of the bone morphogenetic protein family, represents one such factor. The purpose of this review is to provide a background of the therapeutic effects of GDF-5 expressed in various musculoskeletal settings using small and large animal platforms. A comprehensive literature search was conducted to identify all reports in the English language evaluating GDF-5 using the PubMed and Google search engines, and a manual search of the reference lists from the electronically retrieved reports. Two reviewers independently screened the titles and abstracts from a total of 69 reports, 22 of which were identified as pre-clinical (in vivo) evaluations of GDF-5. The full-length article of the 22 pre-clinical reports was then reviewed. Various applications including cranial and craniofacial bone formation, spine fusion, long bone fracture healing, cartilage, and tendon/ligament repair using a variety of small and large animal platforms evaluating GDF-5 as a therapeutic agent were identified. A majority of studies, using biomechanical, radiographic, and histological analysis, demonstrated significant dose-dependent effects of GDF-5. These include increased/enhanced local bone formation, fracture healing/repair, and cartilage and tendon/ligament formation. GDF-5 frequently was shown to accelerate wound maturation. Several studies demonstrated GDF-5 to be a realistic alternative to autograft bone. Studies using pre-clinical models and human histology suggest GDF-5 may also increase/enhance periodontal wound healing/regeneration. GDF-5 appears a promising therapeutic agent for periodontal wound healing/regeneration as GDF-5 supports/accelerates bone and tendon/ligament formation in several musculoskeletal settings including periodontal tissues.

  17. 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.

  18. An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor.

    Science.gov (United States)

    Tang, Shuang; Bertke, Andrea S; Patel, Amita; Wang, Kening; Cohen, Jeffrey I; Krause, Philip R

    2008-08-05

    Latency-associated transcript (LAT) sequences regulate herpes simplex virus (HSV) latency and reactivation from sensory neurons. We found a HSV-2 LAT-related microRNA (miRNA) designated miR-I in transfected and infected cells in vitro and in acutely and latently infected ganglia of guinea pigs in vivo. miR-I is also expressed in human sacral dorsal root ganglia latently infected with HSV-2. miR-I is expressed under the LAT promoter in vivo in infected sensory ganglia. We also predicted and identified a HSV-1 LAT exon-2 viral miRNA in a location similar to miR-I, implying a conserved mechanism in these closely related viruses. In transfected and infected cells, miR-I reduces expression of ICP34.5, a key viral neurovirulence factor. We hypothesize that miR-I may modulate the outcome of viral infection in the peripheral nervous system by functioning as a molecular switch for ICP34.5 expression.

  19. Effects of Brief Psychoeducational Program on Stigma in Malaysian Pre-clinical Medical Students: A Randomized Controlled Trial.

    Science.gov (United States)

    Fernandez, Aaron; Tan, Kit-Aun; Knaak, Stephanie; Chew, Boon How; Ghazali, Sazlina Shariff

    2016-12-01

    If presented with serious mental illness (SMI), individuals' low help-seeking behaviors and poor adherence to treatment are associated with negative stereotypes and attitudes of healthcare providers. In this study, we examined the effects of a brief psychoeducational program on reducing stigma in pre-clinical medical students. One hundred and two pre-clinical medical students (20-23 years old) were randomly assigned to face-to-face contact + educational lecture (n = 51) condition or video-based contact + educational lecture (n = 51) condition. Measures of pre-clinical medical students' mental illness-related stigma using the Opening Minds Stigma Scale for Health Care Providers (OMS-HC) were administered at pre-, post-treatment, and 1-month follow-up. A 2 (condition: face-to-face contact + educational lecture, video-based contact + educational lecture) by 3 (time: pre-treatment, post-treatment, and 1-month follow-up) mixed model MANOVA was conducted on the Attitudes, Disclosure and Help-Seeking, and Social Distance OMS-HC subscales. Participants' scores on all subscales changed significantly across time, regardless of conditions. To determine how participants' scores changed significantly over time on each subscale, Bonferroni follow-up comparisons were performed to access pairwise differences for the main effect of time. Specifically, pairwise comparisons produced a significant reduction in Social Distance subscale between pre-treatment and post-treatment and between pre-treatment and 1-month follow-up, and a significant increase between post-treatment and 1-month follow-up, regardless of conditions. With respect to the Attitudes and Disclosure and Help-Seeking subscales, pairwise comparisons produced a significant reduction in scores between pre-treatment and post-treatment and a significant increase between post-treatment and 1-month follow-up. Our findings provide additional evidence that educational lecture on mental illness, coupled

  20. A comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements.

    Science.gov (United States)

    Abdelgaied, A; Fisher, J; Jennings, L M

    2018-02-01

    A more robust pre-clinical wear simulation framework is required in order to simulate wider and higher ranges of activities, observed in different patient populations such as younger more active patients. Such a framework will help to understand and address the reported higher failure rates for younger and more active patients (National_Joint_Registry, 2016). The current study has developed and validated a comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements (TKR). The input mechanical (elastic modulus and Poisson's ratio) and wear parameters of the moderately cross-linked ultra-high molecular weight polyethylene (UHMWPE) bearing material were independently measured from experimental studies under realistic test conditions, similar to the loading conditions found in the total knee replacements. The wear predictions from the computational wear simulation were validated against the direct experimental wear measurements for size 3 Sigma curved total knee replacements (DePuy, UK) in an independent experimental wear simulation study under three different daily activities; walking, deep squat, and stairs ascending kinematic conditions. The measured compressive mechanical properties of the moderately cross-linked UHMWPE material were more than 20% lower than that reported in the literature under tensile test conditions. The pin-on-plate wear coefficient of moderately cross-linked UHMWPE was significantly dependant of the contact stress and the degree of cross-shear at the articulating surfaces. The computational wear predictions for the TKR from the current framework were consistent and in a good agreement with the independent full TKR experimental wear simulation measurements, with 0.94 coefficient of determination of the framework. In addition, the comprehensive combined experimental and computational framework was able to explain the complex experimental wear trends from the three different daily

  1. [Application of role-play simulation in pre-clinical practice of the fourth grade students in department of endodontics].

    Science.gov (United States)

    Zhu, Lin-lin; Qiu, Li-hong; Qu, Liu; Xue, Ming; Yan, Lu

    2014-10-01

    To apply role- play simulation in pre-clinical practice of the fourth grade students in department of endodontics. Thirty-two students were randomly divided into 2 groups, there were 16 students in each group. Students in one group were taught with role-play simulation while the other group with lecture-based learning method. The teaching effect was measured with examination and questionnaire survey. The data was analyzed by using SPSS 17.0 software package. There were no significant differences in basic knowledge, case analysis and oral examination between 2 groups (P>0.05), but there was significant difference in history taking and medical records writing, practical examination and total scores between 2 groups (Pendodontics.

  2. Radiotherapy-induced xerostomia, pre-clinical promise of LMS-611.

    Science.gov (United States)

    Paterson, Claire; Caldwell, B; Porteous, S; McLean, A; Messow, C M; Thomson, M

    2016-02-01

    Radiotherapy-induced xerostomia (RIX) is the most common permanent side effect of radiotherapy (RT) to the head and neck (H&N). There is no effective topical treatment. LMS-611 is a mimetic of a natural lamellar body which prevents thick secretions like saliva from congesting organs. The primary objective of this study was to assess saliva properties before and during RT to the H&N. The secondary objectives were to re-assess saliva properties with the addition of LMS-611, measure inter-patient variability, correlate patient-reported symptoms with laboratory measurements and design subsequent first-in-human clinical trial of LMS-611. Patients with H&N cancer receiving RT as primary treatment were recruited. Patients completed the Groningen RIX (GRIX) questionnaire and provided saliva samples at baseline and weeks 2, 4 and 6 of RT. Saliva adhesiveness and viscosity were tested by measuring time taken to travel 5 cm down an inclined plane. Thirty patients were enrolled. The inclined plane test (IPT) results (s) were as follows: baseline 31.3, week 2 49.7, week 4 51.1 and week 6 55.7. Wide inter-patient variability was seen at baseline. GRIX scores increased as RT progressed. Spearman rank correlation coefficient of inclined plane tests with GRIX scores was -0.06 at baseline, 0.25 at week 2, 0.12 at week 4 and 0.08 at week 6. LMS-611 concentrations of 10 and 20 mg/ml significantly reduced IPT times on saliva samples. Saliva becomes more visco-adhesive and RIX worsens as RT progresses. There is little correlation between objective and subjective measures of RIX. The addition of LMS-611 to thick, sticky saliva restores its fluidity ex vivo. This warrants in vivo analysis of the effect of LMS-611 upon RIX.

  3. Mechanical Validation of an MRI Compatible Stereotactic Neurosurgery Robot in Preparation for Pre-Clinical Trials

    Science.gov (United States)

    Nycz, Christopher J; Gondokaryono, Radian; Carvalho, Paulo; Patel, Nirav; Wartenberg, Marek; Pilitsis, Julie G; Fischer, Gregory S

    2018-01-01

    The use of magnetic resonance imaging (MRI) for guiding robotic surgical devices has shown great potential for performing precisely targeted and controlled interventions. To fully realize these benefits, devices must work safely within the tight confines of the MRI bore without negatively impacting image quality. Here we expand on previous work exploring MRI guided robots for neural interventions by presenting the mechanical design and assessment of a device for positioning, orienting, and inserting an interstitial ultrasound-based ablation probe. From our previous work we have added a 2 degree of freedom (DOF) needle driver for use with the aforementioned probe, revised the mechanical design to improve strength and function, and performed an evaluation of the mechanism’s accuracy and effect on MR image quality. The result of this work is a 7-DOF MRI robot capable of positioning a needle tip and orienting it’s axis with accuracy of 1.37 ± 0.06mm and 0.79° ± 0.41°, inserting it along it’s axis with an accuracy of 0.06 ± 0.07mm, and rotating it about it’s axis to an accuracy of 0.77° ± 1.31°. This was accomplished with no significant reduction in SNR caused by the robot’s presence in the MRI bore, ≤ 10.3% reduction in SNR from running the robot’s motors during a scan, and no visible paramagnetic artifacts. PMID:29696097

  4. Pre-clinical evaluation of OxyChip for long-term EPR oximetry.

    Science.gov (United States)

    Hou, Huagang; Khan, Nadeem; Gohain, Sangeeta; Kuppusamy, M Lakshmi; Kuppusamy, Periannan

    2018-03-16

    Tissue oxygenation is a critical parameter in various pathophysiological situations including cardiovascular disease and cancer. Hypoxia can significantly influence the prognosis of solid malignancies and the efficacy of their treatment by radiation or chemotherapy. Electron paramagnetic resonance (EPR) oximetry is a reliable method for repeatedly assessing and monitoring oxygen levels in tissues. Lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) has been developed as a probe for biological EPR oximetry, especially for clinical use. However, clinical applicability of LiNc-BuO crystals is hampered by potential limitations associated with biocompatibility, biodegradation, or migration of individual bare crystals in tissue. To overcome these limitations, we have embedded LiNc-BuO crystals in polydimethylsiloxane (PDMS), an oxygen-permeable biocompatible polymer and developed an implantable/retrievable form of chip, called OxyChip. The chip was optimized for maximum spin density (40% w/w of LiNc-BuO in PDMS) and fabricated in a form suitable for implantation using an 18-G syringe needle. In vitro evaluation of the OxyChip showed that it is robust and highly oxygen sensitive. The dependence of its EPR linewidth to oxygen was linear and highly reproducible. In vivo efficacy of the OxyChip was evaluated by implanting it in rat femoris muscle and following its response to tissue oxygenation for up to 12 months. The results revealed preservation of the integrity (size and shape) and calibration (oxygen sensitivity) of the OxyChip throughout the implantation period. Further, no inflammatory or adverse reaction around the implantation area was observed thereby establishing its biocompatibility and safety. Overall, the results demonstrated that the newly-fabricated high-sensitive OxyChip is capable of providing long-term measurements of oxygen concentration in a reliable and repeated manner under clinical conditions.

  5. Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

    International Nuclear Information System (INIS)

    Girelli, Roberto; Prejanò, Simona; Cataldo, Ivana; Corbo, Vincenzo; Martini, Lucia; Scarpa, Aldo; Claudio, Bassi

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium (MTS) assay. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma

  6. The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

    Energy Technology Data Exchange (ETDEWEB)

    Grant, Claire, E-mail: claire.grant@astrazeneca.com [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Ewart, Lorna [Drug Safety and Metabolism, AstraZeneca, Da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston SG8 6HB (United Kingdom); Muthas, Daniel [Respiratory, Inflammation and Autoimmunity iMED, AstraZeneca, Pepparedsleden 1, 431 83 Mölndal (Sweden); Deavall, Damian [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Smith, Simon A. [Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Royston SG8 6HB (United Kingdom); Clack, Glen [Translational Medicine Unit, Early Clinical Development, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Newham, Pete [Drug Safety and Metabolism, AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG (United Kingdom)

    2016-04-01

    Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used

  7. The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3' non-coding region of the genome

    International Nuclear Information System (INIS)

    Engel, Amber R.; Rumyantsev, Alexander A.; Maximova, Olga A.; Speicher, James M.; Heiss, Brian; Murphy, Brian R.; Pletnev, Alexander G.

    2010-01-01

    Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E 315 ) and NS5 (NS5 654,655 ) proteins, and into the 3' non-coding region (Δ30) of TBEV/DEN4. The variant that contained all three mutations (vΔ30/E 315 /NS5 654,655 ) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that vΔ30/E 315 /NS5 654,655 should be further evaluated as a TBEV vaccine.

  8. 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.

  9. Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies®

    Directory of Open Access Journals (Sweden)

    Sven Hoefman

    2015-07-01

    Full Text Available Nanobodies are antigen-binding, single variable domain proteins derived from naturally-occurring, heavy chain only antibodies. They are highly soluble, stable, and can be linked to build multi-specific formats. Several Nanobodies are currently in clinical development in different therapeutic areas, for both chronic and acute applications. For the former, prolonged exposure is achieved by half-life extending moieties that target endogenous albumin, while for the latter, non-half-life extended constructs are preferable. To demonstrate the general pharmacokinetic behavior of both formats, serum levels of seven intravenously administered Nanobodies were analyzed in cynomolgus monkeys, mice or rabbits. In monkeys, the total clearance of a monomeric irrelevant Nanobody was rapid (2.0 mL/(min*kg and approximated the species glomerular filtration rate, indirectly suggesting that the Nanobody was mainly eliminated via the kidneys. When linked to an anti-albumin Nanobody, a 376-fold decrease in clearance was observed, resulting in a terminal half-life of 4.9 days, corresponding to the expected species albumin half-life. Similar conclusions were drawn for (non- half-life extended mono-, bi- and trimeric Nanobodies in mice or rabbits, suggesting that these kinetic principles apply across species. Applying this knowledge to species translation and study design is crucial for successful pre-clinical development of novel therapeutic Nanobody candidates.

  10. TH-AB-206-02: Nuclear Medicine Theronostics: Wave of the Future; Pre-Clinical and Clinical Opportunities

    International Nuclear Information System (INIS)

    Delpassand, E.

    2016-01-01

    In the past few decades, the field of nuclear medicine has made long strides with the continued advancement of related sciences and engineering and the availability of diagnostic and therapeutic radionuclides. Leveraging these advancements while combining the advantages of therapeutic and diagnostic radionuclides into one radiopharmaceutical has also created a new subfield “theranostics” in nuclear medicine that has the potential to further propel the field into the future. This session is composed of two talks; one focused on the physics principles of theranostics from properties of beta and alpha emitting radionuclides to dosimetric models and quantification; while the second describes preclinical and clinical applications of theranostics and discusses the challenges and opportunities of bringing them to the clinic. At the end of the session the listener should be able to identify: The different properties of beta and alpha emitting radionuclides Which radionuclides are selected for which nuclear medicine therapies and why How PET can be used to accurately quantify the uptake of tumor targeting molecules How individualized dosimetry can be performed from the management of thyroid cancer to novel radiolabeled antibody therapies Promising pre-clinical radiopharmaceutical pairs in prostate cancer and melanoma. Promising clinical Theranostics in neuroendocrine cancers. Challenges of bringing Theranostics to the clinic. E. Delpassand, RITA Foundation -Houston; SBIR Grant; CEO and share holder of RadioMedix.

  11. 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.

  12. Implementing the Flipped Classroom in a Veterinary Pre-clinical Science Course: Student Engagement, Performance, and Satisfaction.

    Science.gov (United States)

    Dooley, Laura M; Frankland, Sarah; Boller, Elise; Tudor, Elizabeth

    2018-01-01

    There has been a recent move toward active learning pedagogies in veterinary education, with increasing use of a blended approach that incorporates both online resources and live classroom sessions. In this study, an established veterinary pre-clinical course in introductory animal health was transitioned from a traditional didactic lecture delivery mode to a flipped classroom approach with core content delivered online. This study compared the experiences of two cohorts of students who studied the same course in the different formats in consecutive years. Online learning resources included short video segments and a variety of short problems and activities. Online materials were complemented with weekly small-group case-based learning classes facilitated by academic staff. A mixed methods evaluation strategy was applied using student grades, surveys, and focus groups to compare student academic performance, satisfaction, and engagement between the two cohorts. The flipped classroom cohort achieved significantly higher grades in the written answer section of the final examination. Student satisfaction with learning resources was also higher in this cohort. However, satisfaction with other aspects of the course was largely the same for both cohorts. This study revealed some of the challenges associated with achieving adequate student preparation for class using online resources. The outcomes of this study have implications for veterinary educators considering the design and development of new online learning resources.

  13. TH-AB-206-02: Nuclear Medicine Theronostics: Wave of the Future; Pre-Clinical and Clinical Opportunities

    Energy Technology Data Exchange (ETDEWEB)

    Delpassand, E. [Excel Diagnostic & Nuclear Oncology Center, Houston, TX (United States)

    2016-06-15

    In the past few decades, the field of nuclear medicine has made long strides with the continued advancement of related sciences and engineering and the availability of diagnostic and therapeutic radionuclides. Leveraging these advancements while combining the advantages of therapeutic and diagnostic radionuclides into one radiopharmaceutical has also created a new subfield “theranostics” in nuclear medicine that has the potential to further propel the field into the future. This session is composed of two talks; one focused on the physics principles of theranostics from properties of beta and alpha emitting radionuclides to dosimetric models and quantification; while the second describes preclinical and clinical applications of theranostics and discusses the challenges and opportunities of bringing them to the clinic. At the end of the session the listener should be able to identify: The different properties of beta and alpha emitting radionuclides Which radionuclides are selected for which nuclear medicine therapies and why How PET can be used to accurately quantify the uptake of tumor targeting molecules How individualized dosimetry can be performed from the management of thyroid cancer to novel radiolabeled antibody therapies Promising pre-clinical radiopharmaceutical pairs in prostate cancer and melanoma. Promising clinical Theranostics in neuroendocrine cancers. Challenges of bringing Theranostics to the clinic. E. Delpassand, RITA Foundation -Houston; SBIR Grant; CEO and share holder of RadioMedix.

  14. Oral health knowledge among pre-clinical students of International Branch of Shiraz University of Medical Sciences

    Directory of Open Access Journals (Sweden)

    2015-01-01

    Full Text Available   Background and Aims: Oral health is an important issue in public health with a great impact on individuals’ general health status. A good access to oral healthcare services and a good knowledge of it play a key role in the oral disease prevention. A better health attitude and practice require a better knowledge. The aims of this study was to evaluate the oral health knowledge among the International students branch (Kish of Shiraz University of Medical Sciences in 2011-12.   Materials and Methods: 159 pre-clinical students in medicine (54 students, dentistry (69 students and pharmacy (36 students participated in this research. A standard questionnaire was used as the main tool of research to evaluate the attitude and knowledge of students about the oral health. Data were analyzed using Chi-square test.   Results: According to the results, dental students had the best level of knowledge and pharmacy students had a better knowledge level compared to the medical students. The results also showed a significant relationship between students’ oral health knowledge and their field and duration of study and the place of their secondary school (P0.05.   Conclusion: The results showed that the students at the International Branch of Shiraz University of Medical Sciences had a relatively good knowledge of oral health. Students’ knowledge level can be improved by providing students with educational materials, organized workshops and seminars.

  15. A Novel Approach to Simulation-Based Education for Veterinary Medical Communication Training Over Eight Consecutive Pre-Clinical Quarters.

    Science.gov (United States)

    Englar, Ryane E

    Experiential learning through the use of standardized patients (SPs) is the primary way by which human medical schools teach clinical communication. The profession of veterinary medicine has followed suit in response to new graduates' and their employers' concerns that veterinary interpersonal skills are weak and unsatisfactory. As a result, standardized clients (SCs) are increasingly relied upon as invaluable teaching tools within veterinary curricula to advance relationship-centered care in the context of a clinical scenario. However, there is little to no uniformity in the approach that various colleges of veterinary medicine take when designing simulation-based education (SBE). A further complication is that programs with pre-conceived curricula must now make room for training in clinical communication. Curricular time constraints challenge veterinary colleges to individually decide how best to utilize SCs in what time is available. Because it is a new program, Midwestern University College of Veterinary Medicine (MWU CVM) has had the flexibility and the freedom to prioritize an innovative approach to SBE. The author discusses the SBE that is currently underway at MWU CVM, which incorporates 27 standardized client encounters over eight consecutive pre-clinical quarters. Prior to entering clinical rotations, MWU CVM students are exposed to a variety of simulation formats, species, clients, settings, presenting complaints, and communication tasks. These represent key learning opportunities for students to practice clinical communication, develop self-awareness, and strategize their approach to future clinical experiences.

  16. Microbial landscape features in patients with generalized periodontitis at pre-clinical and radiological stage of its development

    Directory of Open Access Journals (Sweden)

    Vatamanyuk N.V.

    2014-11-01

    Full Text Available The paper presents the results of a comparative study of microbial landscape features in patients with generalized periodontitis at pre-clinical and radiological stage of its development in 42 patients. The purpose of the study is a comparative study of the composition of microbiocenosis of periodontal tissues in patients with chronic catarrhal gingivitis (CCG and chronic generalized periodontitis (CGP at an early stage of development and development studies of microbiological criteria for early emergence of the destructive process in periodontal structures. We found that the microflora isolated from dento-gingival grooves is of importance in diagnostics to identify the etiology of chronic generalized catarrhal gingivitis (CGCG and chronic generalized periodontitis in the early stages of its development. It was established that the presence of two or more types of fixed parodonto-pathogenic microorganisms in microbial association increases the likelihood of inflammatory and destructive events in periodontal tissues in patients with GCCG and is one of the reasons of is becoming CGP.

  17. A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

    Science.gov (United States)

    Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

    2011-01-01

    Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

  18. 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.

  19. Face validity of a pre-clinical model of operant binge drinking: just a question of speed.

    Science.gov (United States)

    Jeanblanc, Jérôme; Sauton, Pierre; Jeanblanc, Virginie; Legastelois, Rémi; Echeverry-Alzate, Victor; Lebourgeois, Sophie; Gonzalez-Marin, Maria Del Carmen; Naassila, Mickaël

    2018-06-04

    Binge drinking (BD) is often defined as a large amount of alcohol consumed in a 'short' period of time or 'per occasion'. In clinical research, few researchers have included the notion of 'speed of drinking' in the definition of BD. Here, we aimed to describe a novel pre-clinical model based on voluntary operant BD, which included both the quantity of alcohol and the rapidity of consumption. In adult Long-Evans male rats, we induced BD by regularly decreasing the duration of ethanol self-administration from 1-hour to 15-minute sessions. We compared the behavioral consequences of BD with the behaviors of rats subjected to moderate drinking or heavy drinking (HD). We found that, despite high ethanol consumption levels (1.2 g/kg/15 minutes), the total amounts consumed were insufficient to differentiate HD from BD. However, consumption speed could distinguish between these groups. The motivation to consume was higher in BD than in HD rats. After BD, we observed alterations in locomotor coordination in rats that consumed greater than 0.8 g/kg, which was rarely observed in HD rats. Finally, chronic BD led to worse performance in a decision-making task, and as expected, we observed a lower stimulated dopaminergic release within nucleus accumbens slices in poor decision makers. Our BD model exhibited good face validity and can now provide animals voluntarily consuming very rapidly enough alcohol to achieve intoxication levels and thus allowing the study of the complex interaction between individual and environmental factors underlying BD behavior. © 2018 Society for the Study of Addiction.

  20. PRE-CLINICAL EVALUATION OF EXTRACTS AND ESSENTIAL OILS FROM BETEL-LIKE SCENT PIPER SPECIES IDENTIFIED POTENTIAL CANCER TREATMENT.

    Science.gov (United States)

    Sanubol, Arisa; Chaveerach, Arunrat; Tanee, Tawatchai; Sudmoon, Runglawan

    2017-01-01

    Nine Piper species with betel-like scents are sources of industrial and medicinal aromatic chemicals, but there is lack of information on cytotoxicity and genotoxicity for human safety, including how these plants impact human cervical cancer cell line. Plant leaves were extracted with hexane and hydro-distilled for essential oils. The extracts and oils were pre-clinically studied based on cyto - and genotoxicity using microculture tetrazolium (MTT) and comet assays. The crude extracts showed an IC 50 in leukocytes and HeLa cells of 58.59-97.31 mg/ml and 34.91-101.79 mg/ml, the LD 50 is higher than 5000 mg/kg. With lower values than the crude extracts, the essential oils showed an IC 50 in leukocytes and HeLa cells of 0.023-0.059 μg/ml and 0.025-0.043 μg/ml the LD 50 is less than 50 mg/kg. IC 50 values showed that the essential oils were highly toxic than the crude extracts. At the level of human genetic materials, the crude extracts of two species, including P. betloides and P. crocatum , showed a significant toxicity ( p Piper species showed insignificant toxicity in leukocytes. For HeLa cells, the eight-studied species showed significant toxicity in HeLa cells, whereas only P. submultinerve showed insignificant toxicity. The crude extracts and essential oils should be tested as putative cervical cancer treatments due to less toxicity in human normal cells.

  1. Design and Effectiveness of a Required Pre-Clinical Simulation-based Curriculum for Fundamental Clinical Skills and Procedures

    Directory of Open Access Journals (Sweden)

    Daryl P. Lofaso

    2011-12-01

    Full Text Available For more than 20 years, medical literature has increasingly documented the need for students to learn, practice and demonstrate competence in basic clinical knowledge and skills. In 2001, the Louisiana State University Health Science Centers (LSUHSC School of Medicine – New Orleans replaced its traditional Introduction in to Clinical Medicine (ICM course with the Science and Practice of Medicine (SPM course. The main component within the SPM course is the Clinical Skills Lab (CSL. The CSL teaches 30 plus skills to all pre-clinical medical students (Years 1 and 2. Since 2002, an annual longitudinal evaluation questionnaire was distributed to all medical students targeting the skills taught in the CSL. Students were asked to rate their self- confidence (Dreyfus and Likert-type and estimate the number of times each clinical skill was performed (clinically/non-clinically. Of the 30 plus skills taught, 8 were selected for further evaluation. An analysis was performed on the eight skills selected to determine the effectiveness of the CSL. All students that participated in the CSL reported a significant improvement in self-confidence and in number performed in the clinically/non-clinically setting when compared to students that did not experience the CSL. For example, without CSL training, the percentage of students reported at the end of their second year self-perceived expertise as “novice” ranged from 21.4% (CPR to 84.7% (GU catheterization. Students who completed the two-years CSL, only 7.8% rated their self-perceived expertise at the end of the second year as “novice” and 18.8% for GU catheterization. The CSL design is not to replace real clinical patient experiences. It's to provide early exposure, medial knowledge, professionalism and opportunity to practice skills in a patient free environment.

  2. ATTITUDE AND PERCEPTION OF FACULTIES TOWARDS TEACHING EVIDENCE BASED MEDICINE TO PRE - CLINICAL & PARA - CLINICAL MEDICAL STUDENTS

    Directory of Open Access Journals (Sweden)

    Bhavita Patel

    2015-02-01

    Full Text Available NTRODUCTION: Evidence - based medicine (EBM is defined as the „conscientious, explicit, and judicious use of current best evidence‟. It i s an important tool for lifelong learning in medicine, and medical students can develop the skills necessary to understand and use EBM. The teaching of EBM in Sumandeep Vidyapeeth is as part of Evidence Based Education System (EBES. The university has imp lemented the 16 hours of teaching with project work on Evidence Based Medicine in 1st MBBS and 2nd MBBS curriculum in addition to MBBS syllabus. AIMS & OBJECTIVES: This study was planned to take feedback from all the faculties those who are involved in Evi dence based Medicine teaching to evaluate their attitude and perception towards this innovative teaching method and to recommend improvements. MATERIAL & METHODS: A Descriptive, self - structured , pilot pretested questionnaire based cross sectional study was conducted in the year 2013 - 2014 among 40 faculties from 7 Departments like Anatomy, Physiology, Biochemistry, Microbiology, Pharmacology, Pathology and Forensic Medicine teaching Evidence Base d Medicine to students at S.B.K.S MI & RC, Sumandeep Vidyapeeth. Data was expressed as percentage. RESULTS: The response rate for the study was 75%. Almost 87% of faculties agreed that teaching EBM is a welcoming development during pre and para clinical ye ars. About 80% faculties agreed that it will help them in future clinical learning. 87% faculties agreed that literature and research searching improves their day to day teaching. About 77% of faculties have attended workshop and training held in Universit y and 83% of faculties agreed that they are interested in more learning and improving skills necessary to incorporate Evidence based medicine into their discipline. Barriers included shortage of time and need for training in teaching EBM. CONCLUSION: Facul ties of this University teaching Pre - clinical and Para - clinical medical students recognized

  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. 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...

  5. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

    Science.gov (United States)

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-09-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

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

    Science.gov (United States)

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

    2015-07-14

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

  7. 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.

  8. 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

  9. Measurement of pO2 in a Pre-clinical Model of Rabbit Tumor Using OxyChip, a Paramagnetic Oxygen Sensor.

    Science.gov (United States)

    Hou, H; Khan, N; Kuppusamy, P

    2017-01-01

    The objective of this work was to establish a novel and robust technology, based on electron paramagnetic resonance (EPR) oximetry, as a practical tool for measurement of tumor oxygen. Previously, we have reported on the development of oxygen-sensing paramagnetic crystals (LiNc-BuO) encapsulated in a biocompatible polymer, called OxyChip. In this report we present our recent data on the use of OxyChip for pO 2 measurements in the tumor of a pre-clinical, large-animal rabbit model. The results establish that OxyChip is capable of noninvasive and repeated measurement of pO 2 in a large animal model.

  10. 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.

  11. Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever

    Science.gov (United States)

    Schäfer, Birgit; Holzer, Georg W.; Joachimsthaler, Alexandra; Coulibaly, Sogue; Schwendinger, Michael; Crowe, Brian A.; Kreil, Thomas R.; Barrett, P. Noel; Falkner, Falko G.

    2011-01-01

    Background Currently existing yellow fever (YF) vaccines are based on the live attenuated yellow fever virus 17D strain (YFV-17D). Although, a good safety profile was historically attributed to the 17D vaccine, serious adverse events have been reported, making the development of a safer, more modern vaccine desirable. Methodology/Principal Findings A gene encoding the precursor of the membrane and envelope (prME) protein of the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus. Candidate vaccines based on the recombinant vaccinia viruses were assessed for immunogenicity and protection in a mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced γ-interferon-secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 105 TCID50. Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negatively influence protection. Unlike the classical 17D vaccine, the vaccinia virus-based vaccines did not cause mortality following intracerebral administration in mice, demonstrating better safety profiles. Conclusions/Significance The non-replicating recombinant YF candidate live vaccines induced a broad immune response after single dose administration, were effective even in the presence of a pre-existing immunity against vaccinia virus and demonstrated an excellent safety profile in mice. PMID:21931732

  12. Pre-clinical efficacy and safety of experimental vaccines based on non-replicating vaccinia vectors against yellow fever.

    Directory of Open Access Journals (Sweden)

    Birgit Schäfer

    Full Text Available BACKGROUND: Currently existing yellow fever (YF vaccines are based on the live attenuated yellow fever virus 17D strain (YFV-17D. Although, a good safety profile was historically attributed to the 17D vaccine, serious adverse events have been reported, making the development of a safer, more modern vaccine desirable. METHODOLOGY/PRINCIPAL FINDINGS: A gene encoding the precursor of the membrane and envelope (prME protein of the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus. Candidate vaccines based on the recombinant vaccinia viruses were assessed for immunogenicity and protection in a mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced γ-interferon-secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 10(5 TCID(50. Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negatively influence protection. Unlike the classical 17D vaccine, the vaccinia virus-based vaccines did not cause mortality following intracerebral administration in mice, demonstrating better safety profiles. CONCLUSIONS/SIGNIFICANCE: The non-replicating recombinant YF candidate live vaccines induced a broad immune response after single dose administration, were effective even in the presence of a pre-existing immunity against vaccinia virus and demonstrated an excellent safety profile in mice.

  13. 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

  14. 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.

  15. Imaging performance of LabPET APD-based digital PET scanners for pre-clinical research

    International Nuclear Information System (INIS)

    Bergeron, Mélanie; Cadorette, Jules; Beaudoin, Jean-François; Lecomte, Roger; Tétrault, Marc-André; Leroux, Jean-Daniel; Fontaine, Réjean

    2014-01-01

    The LabPET is an avalanche photodiode (APD) based digital PET scanner with quasi-individual detector read-out and highly parallel electronic architecture for high-performance in vivo molecular imaging of small animals. The scanner is based on LYSO and LGSO scintillation crystals (2×2×12/14 mm 3 ), assembled side-by-side in phoswich pairs read out by an APD. High spatial resolution is achieved through the individual and independent read-out of an individual APD detector for recording impinging annihilation photons. The LabPET exists in three versions, LabPET4 (3.75 cm axial length), LabPET8 (7.5 cm axial length) and LabPET12 (11.4 cm axial length). This paper focuses on the systematic characterization of the three LabPET versions using two different energy window settings to implement a high-efficiency mode (250–650 keV) and a high-resolution mode (350–650 keV) in the most suitable operating conditions. Prior to measurements, a global timing alignment of the scanners and optimization of the APD operating bias have been carried out. Characteristics such as spatial resolution, absolute sensitivity, count rate performance and image quality have been thoroughly investigated following the NEMA NU 4-2008 protocol. Phantom and small animal images were acquired to assess the scanners' suitability for the most demanding imaging tasks in preclinical biomedical research. The three systems achieve the same radial FBP spatial resolution at 5 mm from the field-of-view center: 1.65/3.40 mm (FWHM/FWTM) for an energy threshold of 250 keV and 1.51/2.97 mm for an energy threshold of 350 keV. The absolute sensitivity for an energy window of 250–650 keV is 1.4%/2.6%/4.3% for LabPET4/8/12, respectively. The best count rate performance peaking at 362 kcps is achieved by the LabPET12 with an energy window of 250–650 keV and a mouse phantom (2.5 cm diameter) at an activity of 2.4 MBq ml −1 . With the same phantom, the scatter fraction for all scanners is about

  16. 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

  17. 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

  18. Plasminogen-based capture combined with amplification technology for the detection of PrP(TSE in the pre-clinical phase of infection.

    Directory of Open Access Journals (Sweden)

    Christiane Segarra

    Full Text Available BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD is a neurodegenerative infectious disorder, characterized by a prominent accumulation of pathological isoforms of the prion protein (PrP(TSE in the brain and lymphoid tissues. Since the publication in the United Kingdom of four apparent vCJD cases following transfusion of red blood cells and one apparent case following treatment with factor VIII, the presence of vCJD infectivity in the blood seems highly probable. For effective blood testing of vCJD individuals in the preclinical or clinical phase of infection, it is considered necessary that assays detect PrP(TSE concentrations in the femtomolar range. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a three-step assay that firstly captures PrP(TSE from infected blood using a plasminogen-coated magnetic-nanobead method prior to its serial amplification via protein misfolding cyclic amplification (PMCA and specific PrP(TSE detection by western blot. We achieved a PrP(TSE capture yield of 95% from scrapie-infected material. We demonstrated the possibility of detecting PrP(TSE in white blood cells, in buffy coat and in plasma isolated from the blood of scrapie-infected sheep collected at the pre-clinical stage of the disease. The test also allowed the detection of PrP(TSE in human plasma spiked with a 10(-8 dilution of vCJD-infected brain homogenate corresponding to the level of sensitivity (femtogram required for the detection of the PrP(TSE in asymptomatic carriers. The 100% specificity of the test was revealed using a blinded panel comprising 96 human plasma samples. CONCLUSION/SIGNIFICANCE: We have developed a sensitive and specific amplification assay allowing the detection of PrP(TSE in the plasma and buffy coat fractions of blood collected at the pre-clinical phase of the disease. This assay represents a good candidate as a confirmatory assay for the presence of PrP(TSE in blood of patients displaying positivity in large scale screening

  19. Volume CT with a flat-panel detector on a mobile, isocentric C-arm: Pre-clinical investigation in guidance of minimally invasive surgery

    International Nuclear Information System (INIS)

    Siewerdsen, J.H.; Moseley, D.J.; Burch, S.; Bisland, S.K.; Bogaards, A.; Wilson, B.C.; Jaffray, D.A.

    2005-01-01

    A mobile isocentric C-arm (Siemens PowerMobil) has been modified in our laboratory to include a large area flat-panel detector (in place of the x-ray image intensifier), providing multi-mode fluoroscopy and cone-beam computed tomography (CT) imaging capability. This platform represents a promising technology for minimally invasive, image-guided surgical procedures where precision in the placement of interventional tools with respect to bony and soft-tissue structures is critical. The image quality and performance in surgical guidance was investigated in pre-clinical evaluation in image-guided spinal surgery. The control, acquisition, and reconstruction system are described. The reproducibility of geometric calibration, essential to achieving high three-dimensional (3D) image quality, is tested over extended time scales (7 months) and across a broad range in C-arm angulation (up to 45 deg.), quantifying the effect of improper calibration on spatial resolution, soft-tissue visibility, and image artifacts. Phantom studies were performed to investigate the precision of 3D localization (viz., fiber optic probes within a vertebral body) and effect of lateral projection truncation (limited field of view) on soft-tissue detectability in image reconstructions. Pre-clinical investigation was undertaken in a specific spinal procedure (photodynamic therapy of spinal metastases) in five animal subjects (pigs). In each procedure, placement of fiber optic catheters in two vertebrae (L1 and L2) was guided by fluoroscopy and cone-beam CT. Experience across five procedures is reported, focusing on 3D image quality, the effects of respiratory motion, limited field of view, reconstruction filter, and imaging dose. Overall, the intraoperative cone-beam CT images were sufficient for guidance of needles and catheters with respect to bony anatomy and improved surgical performance and confidence through 3D visualization and verification of transpedicular trajectories and tool placement

  20. 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

  1. Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs

    Science.gov (United States)

    Kusner, Linda L.; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

    2015-01-01

    Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID:25743217

  2. The knowledge and attitude about HIV/AIDS among Jordanian dental students: (Clinical versus pre clinical students at the University of Jordan

    Directory of Open Access Journals (Sweden)

    Shayyab Mohammad H

    2011-06-01

    Full Text Available Abstract Background The present study aimed to address the suspected deficiency in the level of understanding of HIV/AIDS among clinical and pre clinical dental students at the University of Jordan. In this cross-sectional study, structured questionnaires were distributed to fifth year dental students (n = 121 and to third year dental students (n = 144 in the academic year 2008/2009. Findings Significantly higher percentage of fifth-year students compared to third-year students felt that the teaching they received on cross-infection precautions and barrier dentistry was adequate (P Significantly higher proportion of third-year students compared to fifth-year (39.2% vs. 26.3% thought that HIV patients should be referred to other centers or support groups for treatment (P = 0.04. Conclusions The level of knowledge of Jordanian dental students about HIV and AIDS was generally acceptable; there were inadequacies, however, in their understanding regarding some aspects of AIDS epidemic which demands that dental school curriculum needs some improvement.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre-clinical models.

    Science.gov (United States)

    Woods-Burnham, Leanne; Basu, Anamika; Cajigas-Du Ross, Christina K; Love, Arthur; Yates, Clayton; De Leon, Marino; Roy, Sourav; Casiano, Carlos A

    2017-12-01

    Understanding how biological factors contribute to prostate cancer (PCa) health disparities requires mechanistic functional analysis of specific genes or pathways in pre-clinical cellular and animal models of this malignancy. The 22Rv1 human prostatic carcinoma cell line was originally derived from the parental CWR22R cell line. Although 22Rv1 has been well characterized and used in numerous mechanistic studies, no racial identifier has ever been disclosed for this cell line. In accordance with the need for racial diversity in cancer biospecimens and recent guidelines by the NIH on authentication of key biological resources, we sought to determine the ancestry of 22RV1 and authenticate previously reported racial identifications for four other PCa cell lines. We used 29 established Ancestry Informative Marker (AIM) single nucleotide polymorphisms (SNPs) to conduct DNA ancestry analysis and assign ancestral proportions to a panel of five PCa cell lines that included 22Rv1, PC3, DU145, MDA-PCa-2b, and RC-77T/E. We found that 22Rv1 carries mixed genetic ancestry. The main ancestry proportions for this cell line were 0.41 West African (AFR) and 0.42 European (EUR). In addition, we verified the previously reported racial identifications for PC3 (0.73 EUR), DU145 (0.63 EUR), MDA-PCa-2b (0.73 AFR), and RC-77T/E (0.74 AFR) cell lines. Considering the mortality disparities associated with PCa, which disproportionately affect African American men, there remains a burden on the scientific community to diversify the availability of biospecimens, including cell lines, for mechanistic studies on potential biological mediators of these disparities. This study is beneficial by identifying another PCa cell line that carries substantial AFR ancestry. This finding may also open the door to new perspectives on previously published studies using this cell line. © 2017 Wiley Periodicals, Inc.

  8. 25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort.

    Directory of Open Access Journals (Sweden)

    Elina Hyppönen

    Full Text Available BACKGROUND: Vitamin D deficiency has been suggested as a cardiovascular risk factor, but little is known about underlying mechanisms or associations with inflammatory or hemostatic markers. Our aim was to investigate the association between 25-hydroxyvitamin D [25(OHD, a measure for vitamin D status] concentrations with pre-clinical variations in markers of inflammation and hemostasis. METHODOLOGY/PRINCIPAL FINDINGS: Serum concentrations of 25(OHD, C-reactive protein (CRP, fibrinogen, D-dimer, tissue plasminogen activator (tPA antigen, and von Willebrand factor (vWF were measured in a large population based study of British whites (aged 45 y. Participants for the current investigation were restricted to individuals free of drug treated cardiovascular disease (n = 6538. Adjusted for sex and month, 25(OHD was inversely associated with all outcomes (p or =75 nmol/l compared to < 25 nmol/l. D-dimer concentrations were lower for participants with 25(OHD 50-90 nmol/l compared to others (quadratic term p = 0.01. We also examined seasonal variation in hemostatic and inflammatory markers, and evaluated 25(OHD contribution to the observed patterns using mediation models. TPA concentrations varied by season (p = 0.02, and much of this pattern was related to fluctuations in 25(OHD concentrations (p < or =0.001. Some evidence of a seasonal variation was observed also for fibrinogen, D-dimer and vWF (p < 0.05 for all, with 25(OHD mediating some of the pattern for fibrinogen and D-dimer, but not vWF. CONCLUSIONS: Current vitamin D status was associated with tPA concentrations, and to a lesser degree with fibrinogen and D-dimer, suggesting that vitamin D status/intake may be important for maintaining antithrombotic homeostasis.

  9. H5N2 Highly Pathogenic Avian Influenza Viruses from the US 2014-2015 outbreak have an unusually long pre-clinical period in turkeys.

    Science.gov (United States)

    Spackman, Erica; Pantin-Jackwood, Mary J; Kapczynski, Darrell R; Swayne, David E; Suarez, David L

    2016-11-22

    From December 2014 through June 2015, the US experienced the most costly highly pathogenic avian influenza (HPAI) outbreak to date. Most cases in commercial poultry were caused by an H5N2 strain which was a reassortant with 5 Eurasian lineage genes, including a clade 2.3.4.4 goose/Guangdong/1996 lineage hemagglutinin, and 3 genes from North American wild waterfowl low pathogenicity avian influenza viruses. The outbreak primarily affected turkeys and table-egg layer type chickens. Three isolates were selected for characterization in turkeys: the US index isolate from December 2014 (A/northern pintail/WA/40964/2014), and two poultry isolates from April 2015 (A/chicken/IA/13388/2015 and A/turkey/MN/12528/2015). Four week old broad-breasted white turkeys were inoculated with one of three doses (10 2 , 10 4 or 10 6 50% egg infectious doses [EID 50 ] per bird) of each of the isolates to evaluate infectious dose and pathogenesis. The mean bird infectious dose of A/northern pintail/WA/40964/2014 and A/turkey/MN/12528/2015 was 10 5 EID 50 per bird, but was 10 3 EID 50 per bird for A/chicken/IA/13388/2015, suggesting the latter had greater adaptation to gallinaceous birds. All three isolates had unusually long mean death time of 5.3-5.9 days post challenge, and the primary clinical signs were severe lethargy and neurological signs which started no more than 24 h before death (the average pre-clinical period was 4 days). Infected turkeys also shed high levels of virus by both the oropharyngeal and cloacal routes. The unusually long mean death times, high levels of virus in feces, and increased adaptation of the later viruses may have contributed to the rapid spread of the virus during the peak of the outbreak.

  10. Country report: Italy (Chinol). Pre-clinical evaluation of a new biotin-DOTA conjugate labeled with 90Y for application in pretargeting clinical protocols

    International Nuclear Information System (INIS)

    Chinol, Marco

    2010-01-01

    In the attempt to improve the therapeutic efficacy of radiolabeled mAbs in cancer radioimmunotherapy, various studies have examined the concept of tumor pretargeting. The so called three-step pretargeting technique, employing the avidin–biotin system, was applied in phase I-II clinical trials showing low toxicity and therapeutic efficacy. The final step of the pretargeting protocols consists in the systemic injection of radiolabeled biotin. The worldwide recognized “successful association” is between 90 Y and the tetraazamacrocycle DOTA chelator chemically bound to biotin. Improvements in the structure of the biotin-DOTA conjugate have been reported by our group following a novel approach which simplified the synthetic pattern by reducing the amide group to a methylene group, thus transforming the amide into a secondary amine without affecting the length of the biotin side arm. Preliminary in-vitro experiments, previously published by our group, indicated the potential of the new conjugate. Based on our previous experience with avidin-based pre-targeting followed 90 Y-DOTA-biotin in the locoregional treatment of peritoneal carcinomatosis and malignant glioma suggested that similar radionuclide therapy might be worth investigating as a partial replacement of external beam radiotherapy in breast cancer. We have developed IART® the Intra-operative Avidination for Radionuclide Therapy that relies on the avidin-biotin binding system. In fact, the “avidination” of the anatomical area of the tumor with native avidin, directly injected by the surgeon into and around the tumor bed, provides a target for the radiolabeled biotin intravenously (iv) injected one day later. In order to optimize the overall strategy, further efforts were needed to optimize the use of the labeled new biotin conjugate and to elucidate its chemical and biological properties. In the first 18 months of this CRP, the pre-clinical evaluation of this new reduced biotinamidohexylamine

  11. Country report: Italy (Chinol). Pre-clinical evaluation of a new biotin-DOTA conjugate labeled with {sup 90}Y for application in pretargeting clinical protocols

    Energy Technology Data Exchange (ETDEWEB)

    Chinol, Marco

    2010-07-01

    In the attempt to improve the therapeutic efficacy of radiolabeled mAbs in cancer radioimmunotherapy, various studies have examined the concept of tumor pretargeting. The so called three-step pretargeting technique, employing the avidin–biotin system, was applied in phase I-II clinical trials showing low toxicity and therapeutic efficacy. The final step of the pretargeting protocols consists in the systemic injection of radiolabeled biotin. The worldwide recognized “successful association” is between {sup 90}Y and the tetraazamacrocycle DOTA chelator chemically bound to biotin. Improvements in the structure of the biotin-DOTA conjugate have been reported by our group following a novel approach which simplified the synthetic pattern by reducing the amide group to a methylene group, thus transforming the amide into a secondary amine without affecting the length of the biotin side arm. Preliminary in-vitro experiments, previously published by our group, indicated the potential of the new conjugate. Based on our previous experience with avidin-based pre-targeting followed {sup 90}Y-DOTA-biotin in the locoregional treatment of peritoneal carcinomatosis and malignant glioma suggested that similar radionuclide therapy might be worth investigating as a partial replacement of external beam radiotherapy in breast cancer. We have developed IART® the Intra-operative Avidination for Radionuclide Therapy that relies on the avidin-biotin binding system. In fact, the “avidination” of the anatomical area of the tumor with native avidin, directly injected by the surgeon into and around the tumor bed, provides a target for the radiolabeled biotin intravenously (iv) injected one day later. In order to optimize the overall strategy, further efforts were needed to optimize the use of the labeled new biotin conjugate and to elucidate its chemical and biological properties. In the first 18 months of this CRP, the pre-clinical evaluation of this new reduced biotinamidohexylamine

  12. 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.

  13. The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum.

    Science.gov (United States)

    Lucieer, Susanna M; van der Geest, Jos N; Elói-Santos, Silvana M; de Faria, Rosa M Delbone; Jonker, Laura; Visscher, Chris; Rikers, Remy M J P; Themmen, Axel P N

    2016-03-01

    Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

  14. Effort-reward imbalance at work and pre-clinical biological indices of ill-health: the case for salivary immunoglobulin A.

    Science.gov (United States)

    Bathman, Lauren Marjorie; Almond, Jacinta; Hazi, Agnes; Wright, Bradley James

    2013-10-01

    Physiological indices of stress and ill-health (cortisol and salivary immunoglobulin A) were assessed to determine if they were predicted by Siegrist's effort-reward imbalance model (ERI) with an aim of identifying employees at risk of illness. Male Australian dairy farmers (N=66) completed the Perceived Stress Scale, Work related Questions II & III, Eysenck Personality Questionnaire Revised--Short and demographic questions and provided morning saliva samples (at awakening and 30 min post awakening) on a working day, which were subsequently analysed for cortisol and salivary immunoglobulin A (sIgA) concentration levels. A high percentage (45.5%) of the sample reported an imbalance between efforts and rewards in the workplace that may place them 'at risk' for ill-health. After controlling for disposition, sIgA scores were more successfully predicted by the ERI than the cortisol assessments. Although both efforts and rewards were significantly associated with sIgA, efforts were most strongly associated. The dispositional trait overcommitment, did not moderate the experience of stress on the physiologic indices. The current investigation supports the continued use of sIgA in studies that use biomarkers to assess occupational stress. ERI ratio scores >1 aligned with previous findings that suggest elevated risk of illness for these employees. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Correlation of X-Ray Computed Tomography with Quantitative Nuclear Magnetic Resonance Methods for Pre-Clinical Measurement of Adipose and Lean Tissues in Living Mice

    Directory of Open Access Journals (Sweden)

    Matthew N. Metzinger

    2014-10-01

    Full Text Available Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT or quantitative nuclear magnetic resonance (QMR. Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR. First, an in vitro analysis of oil/water mixtures was used to calibrate and assess the overall accuracy of microCT vs. QMR data. Next, experiments were conducted with two cohorts of living mice (either homogenous or heterogeneous by sex, age and genetic backgrounds to assess the microCT imaging technique for adipose tissue segmentation and quantification relative to QMR. Adipose mass values were obtained from microCT data with three different resolutions, after which the data were analyzed with different filter and segmentation settings. Strong linearity was noted between the adipose mass values obtained with microCT and QMR, with optimal parameters and scan conditions reported herein. Lean tissue (muscle, internal organs was also segmented and quantified using the microCT method relative to the analogous QMR values. Overall, the rigorous calibration and validation of the microCT method for murine body composition, relative to QMR, ensures its validity for segmentation, quantification and visualization of both adipose and lean tissues.

  16. Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

    Science.gov (United States)

    Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

    2014-10-01

    We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  17. 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.

  18. Pre-clinical evaluation of soybean-based wound dressings and dermal substitute formulations in pig healing and non-healing in vivo models

    Directory of Open Access Journals (Sweden)

    Rostislav V Shevchenko

    2014-10-01

    Full Text Available In the last decade, a new class of natural biomaterials derived from de-fatted soybean flour processed by either thermoset or extraction procedures has been developed. These biomaterials uniquely combine adaptability to various clinical applications to proven tissue regeneration properties. In the present work, the biomaterials were formulated either as hydrogel or as paste formulation and their potential as wound dressing material or as dermal substitute was assessed by two in vivo models in pig skin: The healing full-thickness punch biopsy model and the non-healing full-thickness polytetrafluoroethylene (PTFE chamber model. The results clearly show that collagen deposition is induced by the presence of these biomaterials. A unique pattern of early inflammatory response, eliciting neutrophils and controlling macrophage infiltration, is followed by tissue cell colonization of the wound bed with a significant deposition of collagen fibers. The study also highlighted the importance in the use of optimal formulations and appropriate handling upon implantation. In large size, non-healing wounds, wound dermis was best obtained with the paste formulation as hydrogels appeared to be too loose to ensure lasting scaffolding properties. On the contrary, packing of the granules during the application of paste reduced biomaterial degradation rate and prevent the penetration of newly vascularized tissue, thus impeding grafting of split-thickness autologous skin grafts on the dermal substitute base.

  19. Chronic low back pain: a mini-review on pharmacological management and pathophysiological insights from clinical and pre-clinical data.

    Science.gov (United States)

    Park, Thomas S W; Kuo, Andy; Smith, Maree T

    2018-05-12

    Globally, low back pain (LBP) is one of the most common health problems affecting humans. The lifetime prevalence of non-specific LBP is approximately 84%, with the chronic prevalence at about 23%. Chronic LBP in humans is defined as LBP that persists for more than 12 weeks without a significant pain improvement. Although there are numerous evidence-based guidelines on the management of acute LBP, this is not the case for chronic LBP, which is regarded as particularly difficult to treat. Research aimed at discovering new drug treatments for alleviation of chronic mechanical LBP is lacking due to the paucity of knowledge on the pathobiology of this condition, despite its high morbidity in the affected adult population. For a debilitating condition such as chronic LBP, it is necessary to assess the sustained effects of pharmacotherapy of various agents spanning months to years. Although many rodent models of mechanical LBP have been developed to mimic the human condition, some of the major shortcomings of many of these models are (1) the presence of a concurrent neuropathic component that develops secondary to posterior intervertebral disc puncture, (2) severe model phenotype, and/or (3) use of behavioural endpoints that have yet to be validated for pain. Hence, there is a great, unmet need for research aimed at discovering new biological targets in rodent models of chronic mechanical LBP for use in drug discovery programs as a means to potentially produce new highly effective and well-tolerated analgesic agents to improve relief of chronic LBP. On a cautionary note, it must be borne in mind that because humans and rats display orthograde and pronograde postures, respectively, the different mechanical forces on their spines add to the difficulty in translation of promising rodent data to humans.

  20. In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Kentaro Minagawa

    Full Text Available Approximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.We developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85-90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non

  1. A meta-analysis of the antiviral activity of the HBV-specific immunotherapeutic TG1050 confirms its value over a wide range of HBsAg levels in a persistent HBV pre-clinical model.

    Science.gov (United States)

    Kratzer, Roland; Sansas, Benoît; Lélu, Karine; Evlachev, Alexei; Schmitt, Doris; Silvestre, Nathalie; Inchauspé, Geneviève; Martin, Perrine

    2018-02-01

    Pre-clinical models mimicking persistent hepatitis B virus (HBV) expression are seldom, do not capture all features of a human chronic infection and due to their complexity, are subject to variability. We report a meta-analysis of seven experiments performed with TG1050, an HBV-targeted immunotherapeutic, 1 in an HBV-persistent mouse model based on the transduction of mice by an adeno-associated virus coding for an infectious HBV genome (AAV-HBV). To mimic the clinical diversity seen in HBV chronically infected patients, AAV-HBV transduced mice displaying variable HBsAg levels were treated with TG1050. Overall mean percentages of responder mice, displaying decrease in important clinical parameters i.e. HBV-DNA (viremia) and HBsAg levels, were 52% and 51% in TG1050 treated mice, compared with 8% and 22%, respectively, in untreated mice. No significant impact of HBsAg level at baseline on response to TG1050 treatment was found. TG1050-treated mice displayed a significant shorter Time to Response (decline in viral parameters) with an Hazard Ratio (HR) of 8.3 for viremia and 2.6 for serum HBsAg. The mean predicted decrease for TG1050-treated mice was 0.5 log for viremia and 0.8 log for HBsAg, at the end of mice follow-up, compared to no decrease for viremia and 0.3 log HBsAg decrease for untreated mice. For mice receiving TG1050, a higher decline of circulating viremia and serum HBsAg level over time was detected by interaction term meta-analysis with a significant treatment effect (p = 0.002 and pHBV-persistent model mimicking clinical situations.

  2. [Effectiveness and difficulty of education on nosocomial infection control for pre-clinical practice in the clinic, so-called inclusive clinical practice phase I, for students in the Faculty of Dentistry, Tokyo Medical and Dental University].

    Science.gov (United States)

    Sunakawa, Mitsuhiro; Matsumoto, Hiroyuki

    2009-03-01

    It has been planned to give pre-clinical practice in the clinic, so-called inclusive clinical practice phase I, for fifth-grade students in the School of Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, to give them the clinical training needed to perform dental practice and clinical practicum for comprehensive patient care, namely inclusive clinical practice phase II. This study analyzed the educative efficiency of the class on nosocomial infection control (NIC) by comparing achievements pre- and post-test, and discussed appropriate education planning on the NIC for dental students. Sixty-two fifth-grade students in the 2007 academic year sat the pre- and post-tests; the mean score and standard deviation of these tests were 5.30 +/- 1.26 (n = 56) and 8.59 +/- 1.18 (n = 59), respectively. There was a statistically significant difference between them (paired t-test, p < 0.01). Another finding was that students with high scores in the post-test did not necessarily achieve high ratings in the pre-test. It is suggested that the introduction of pre- and post-tests and the clarification of main points in the class as a theme of NIC could be a useful tool for increasing the comprehension of students on the theme. Since students at lower grades will attend clinical practice in the university hospital, it is thought that students should be given NIC training early in the clinical course, and the current curriculum should be improved to increase the opportunity for students to study this important issue.

  3. 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

  4. Animal models of enterovirus 71 infection: applications and limitations

    Science.gov (United States)

    2014-01-01

    Human enterovirus 71 (EV71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the Asia-Pacific region over the past 15 years. Appropriate animal models are needed to understand EV71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. Non-human primate models have been used to characterize and evaluate the neurovirulence of EV71 after the early outbreaks in late 1990s. However, these models were not suitable for assessing the neurovirulence level of the virus and were associated with ethical and economic difficulties in terms of broad application. Several strategies have been applied to develop mouse models of EV71 infection, including strategies that employ virus adaption and immunodeficient hosts. Although these mouse models do not closely mimic human disease, they have been applied to determine the pathogenesis of and treatment and prevention of the disease. EV71 receptor-transgenic mouse models have recently been developed and have significantly advanced our understanding of the biological features of the virus and the host-parasite interactions. Overall, each of these models has advantages and disadvantages, and these models are differentially suited for studies of EV71 pathogenesis and/or the pre-clinical testing of antiviral drugs and vaccines. In this paper, we review the characteristics, applications and limitation of these EV71 animal models, including non-human primate and mouse models. PMID:24742252

  5. Botulinum toxin type-A effect as a preemptive treatment in a model of acute trigeminal pain: a pre-clinical double-blind and placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Elcio Juliato Piovesan

    2011-02-01

    Full Text Available The purpose of this study was to investigate if botulinum neurotoxin type-A (BoNT/A had a preemptive antinociceptive effect in a formalin-induced orofacial pain model (FT. To test this hypothesis, male Rattus norvegicus were injected with isotonic saline solution 0.9% or BoNT/A administered as a 40 μl bolus, lateral to their nose, at 24 hours, 8, 15, 22, 29 or 36 days pre-FT. The procedures were repeated 42 days later. Influence on motor activity was assessed through the open-field test. Pain scores corresponded to the time spent rubbing and flicking the injected area. Animals pre-treated with BoNT/A at the first protocol (8 days subgroup showed reduced inflammatory scores (p=0.011. For the other groups no significant results were observed at any phase. Motor activity was similar in both groups. BoNT/A showed to be effective preventing inflammatory pain up to eight days after the first treatment, an effect not reproduced on the second dose administration.

  6. 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

    Science.gov (United States)

    Koumarianou, E; Loktionova, N S; Fellner, M; Roesch, F; Thews, O; Pawlak, D; Archimandritis, S C; Mikolajczak, R

    2012-12-01

    In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga. The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. The affinity to GRP receptors in the PC-3 cell line was higher for (nat)Ga-DOTA-BN[2-14]NH(2) (IC(50)(nM)=0.85 ± 0.06) than that of (nat)Sc-DOTA-BN[2-14]NH(2) (IC(50) (nM)=6.49 ± 0.13). The internalization rate of (68)Ga labeled DOTA-BN[2-14]NH(2) was slower than that of (44)Sc, but their final internalization percents were comparable. (68)Ga-DOTA-BN[2-14]NH(2) was externalized faster than (44)Sc-DOTA-BN[2-14]NH(2). The biodistribution of (44)Sc-DOTA-BN[2-14]NH(2) and (68)Ga-DOTA-BN[2-14]NH(2) in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. Despite the differences in the receptor affinity both the (68)Ga- and the (44)Sc-labeled DOTA-BN[2-14]NH(2) tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either (44)Sc or (68)Ga for detecting tumors with GRP receptors is equivalent. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

    International Nuclear Information System (INIS)

    Koumarianou, E.; Loktionova, N.S.; Fellner, M.; Roesch, F.; Thews, O.; Pawlak, D.; Archimandritis, S.C.; Mikolajczak, R.

    2012-01-01

    Aim: In the present study we demonstrate the in vitro and in vivo comparison of the 44 Sc and 68 Ga labeled DOTA-BN[2-14]NH 2 . 44 Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of 68 Ga. Methods: The binding affinity of nat Sc-DOTA-BN[2-14]NH 2 and nat Ga-DOTA-BN[2-14]NH 2 to GRP receptors was studied in competition to [ 125 I-Tyr 4 ]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. Results: The affinity to GRP receptors in the PC-3 cell line was higher for nat Ga-DOTA-BN[2-14]NH 2 (IC 50 (nM)=0.85±0.06) than that of nat Sc-DOTA-BN[2-14]NH 2 (IC 50 (nM)=6.49±0.13). The internalization rate of 68 Ga labeled DOTA-BN[2-14]NH 2 was slower than that of 44 Sc, but their final internalization percents were comparable. 68 Ga-DOTA-BN[2-14]NH 2 was externalized faster than 44 Sc-DOTA-BN[2-14]NH 2 . The biodistribution of 44 Sc-DOTA-BN[2-14]NH 2 and 68 Ga-DOTA-BN[2-14]NH 2 in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. Conclusions: Despite the differences in the receptor affinity both the 68 Ga- and the 44 Sc-labeled DOTA-BN[2-14]NH 2 tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either 44 Sc or 68 Ga for detecting tumors with GRP receptors is equivalent. - Highlights: ► In vitro and in vivo evaluation of 44 Sc- and 68 Ga-DOTA-BN[2-14]NH 2 in reference to published

  8. Assessing Assessment.

    Science.gov (United States)

    Steen, Lynn Arthur

    Assessment not only places value, it also identifies which elements to value. In this era of accountability, the constituents of educational assessment are not just students, faculty, and administrators, but also parents, legislators, journalists, and the public. For these broader audiences, simple numerical indicators of student performance take…

  9. Preparation and pre-clinical characterization of sustained- release ...

    African Journals Online (AJOL)

    This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and .... with the help of screw gauge (n = 3). Hardness .... performed by ANOVA using GraphPad Prism©. 4.0. Values of p ...

  10. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma

    Directory of Open Access Journals (Sweden)

    Oren J Becher

    2015-07-01

    Full Text Available Diffuse Intrinsic Pontine Glioma (DIPG is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of six and eight. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab, as well as to potentially treat them in the clinic. This review will detail the initial strides towards modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Lastly, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.

  11. Medical beam monitor—Pre-clinical evaluation and future applications

    Science.gov (United States)

    Frais-Kölbl, Helmut; Griesmayer, Erich; Schreiner, Thomas; Georg, Dietmar; Pernegger, Heinz

    2007-10-01

    Future medical ion beam applications for cancer therapy which are based on scanning technology will require advanced beam diagnostics equipment. For a precise analysis of beam parameters we want to resolve time structures in the range of microseconds to nanoseconds. A prototype of an advanced beam monitor was developed by the University of Applied Sciences Wiener Neustadt and its research subsidiary Fotec in co-operation with CERN RD42, Ohio State University and the Jožef Stefan Institute in Ljubljana. The detector is based on polycrystalline Chemical Vapor Deposition (pCVD) diamond substrates and is equipped with readout electronics up to 2 GHz analog bandwidth. In this paper we present the design of the pCVD-detector system and results of tests performed in various particle accelerator based facilities. Measurements performed in clinical high energy photon beams agreed within 1.2% with results obtained by standard ionization chambers.

  12. Medical beam monitor—Pre-clinical evaluation and future applications

    CERN Document Server

    Frais-Kölbl, H; Schreiner, T; Georg, D; Pernegger, H

    2007-01-01

    Future medical ion beam applications for cancer therapy which are based on scanning technology will require advanced beam diagnostics equipment. For a precise analysis of beam parameters we want to resolve time structures in the range of microseconds to nanoseconds. A prototype of an advanced beam monitor was developed by the University of Applied Sciences Wiener Neustadt and its research subsidiary Fotec in co-operation with CERN RD42, Ohio State University and the Jožef Stefan Institute in Ljubljana. The detector is based on polycrystalline Chemical Vapor Deposition (pCVD) diamond substrates and is equipped with readout electronics up to 2 GHz analog bandwidth. In this paper we present the design of the pCVD-detector system and results of tests performed in various particle accelerator based facilities. Measurements performed in clinical high energy photon beams agreed within 1.2% with results obtained by standard ionization chambers.

  13. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

    Science.gov (United States)

    Lammers, Twan; Kiessling, Fabian; Hennink, Wim E; Storm, Gert

    2012-07-20

    Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Kiessling, F.; Hennink, W.E.; Storm, Gerrit

    2012-01-01

    Abstract Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells,

  15. Pre-clinical toxicity of Morinda citrifolia Linn. leaf extract

    African Journals Online (AJOL)

    Jane

    2011-10-24

    Oct 24, 2011 ... pharmacological, biological and toxicological effects of leaves of M. citrifolia. ... and color of the internal organs (lungs, heart, stomach, liver, brain and kidneys) .... significant differences in the relative weights of the livers, as shown. .... groups were unremarkable and comparable to each sex. Microscopical ...

  16. Multi-modality molecular imaging: pre-clinical laboratory configuration

    Science.gov (United States)

    Wu, Yanjun; Wellen, Jeremy W.; Sarkar, Susanta K.

    2006-02-01

    In recent years, the prevalence of in vivo molecular imaging applications has rapidly increased. Here we report on the construction of a multi-modality imaging facility in a pharmaceutical setting that is expected to further advance existing capabilities for in vivo imaging of drug distribution and the interaction with their target. The imaging instrumentation in our facility includes a microPET scanner, a four wavelength time-domain optical imaging scanner, a 9.4T/30cm MRI scanner and a SPECT/X-ray CT scanner. An electronics shop and a computer room dedicated to image analysis are additional features of the facility. The layout of the facility was designed with a central animal preparation room surrounded by separate laboratory rooms for each of the major imaging modalities to accommodate the work-flow of simultaneous in vivo imaging experiments. This report will focus on the design of and anticipated applications for our microPET and optical imaging laboratory spaces. Additionally, we will discuss efforts to maximize the daily throughput of animal scans through development of efficient experimental work-flows and the use of multiple animals in a single scanning session.

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

    Directory of Open Access Journals (Sweden)

    Gustavo H. Dayan

    2013-12-01

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

  18. TU-F-12A-01: Quantitative Non-Linear Compartment Modeling of 89Zr- and 124I- Labeled J591 Monoclonal Antibody Kinetics Using Serial Non-Invasive Positron Emission Tomography Imaging in a Pre-Clinical Human Prostate Cancer Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Fung, EK; Cheal, SM; Chalasani, S; Fareedy, SB; Punzalan, B; Humm, JL; Osborne, JR; Larson, SM; Zanzonico, PB [Memorial Sloan Kettering Cancer Center, New York, NY (United States); Otto, B; Bander, NH [Weill Cornell Medical College, New York, NY (United States)

    2014-06-15

    Purpose: To examine the binding kinetics of human IgG monoclonal antibody J591 which targets prostate-specific membrane antigen (PSMA) in a pre-clinical mouse cancer model using quantitative PET compartmental analysis of two radiolabeled variants. Methods: PSMA is expressed in normal human prostate, and becomes highly upregulated in prostate cancer, making it a promising therapeutic target. Two forms of J591, radiolabeled with either {sup 89}Zr or {sup 124}I, were prepared. {sup 89}Zr is a radiometal that becomes trapped in the cell upon internalization by the antigen-antibody complex, while radioiodine leaves the cell. Mice with prostate cancer xenografts underwent non-invasive serial imaging on a Focus 120 microPET up to 144 hours post-injection of J591. A non-linear compartmental model describing the binding and internalization of antibody in tumor xenograft was developed and applied to the PET-derived time-activity curves. The antibody-antigen association rate constant (ka), total amount of antigen per gram tumor (Ag-total), internalization rate of antibody-antigen complex, and efflux rate of radioisotope from tumor were fitted using the model. The surface-bound and the internalized activity were also estimated. Results: Values for ka, Ag-total, and internalization rate were found to be similar regardless of radiolabel payload used. The efflux rate, however, was ∼ 9-fold higher for {sup 124}I-J591 than for {sup 89}Zr-J591. Time-dependent surface-bound and internalized radiotracer activity were similar for both radiolabels at early times post-injection, but clearly differed beyond 24 hours. Conclusion: Binding and internalization of J591 to PSMA-expressing tumor xenografts were similar when radiolabeled with either {sup 89}Zr or {sup 124}I payload. The difference in efflux of radioactivity from tumor may be attributable to differential biological fate intracellularly of the radioisotopes. This has great significance for radioimmunotherapy and antibody

  19. EEG INTERFACE MODULE FOR COGNITIVE ASSESSMENT THROUGH NEUROPHYSIOLOGIC TESTS

    Directory of Open Access Journals (Sweden)

    Kundan Lal Verma

    2014-12-01

    Full Text Available The cognitive signal processing is one of the important interdisciplinary field came from areas of life sciences, psychology, psychiatry, engi-neering, mathematics, physics, statistics and many other fields of research. Neurophysiologic tests are utilized to assess and treat brain injury, dementia, neurological conditions, and useful to investigate psychological and psychiatric disorders. This paper presents an ongoing research work on development of EEG interface device based on the principles of cognitive assessments and instrumentation. The method proposed engineering and science of cogni-tive signal processing in case of brain computer in-terface based neurophysiologic tests. The future scope of this study is to build a low cost EEG device for various clinical and pre-clinical applications with specific emphasis to measure the effect of cognitive action on human brain.

  20. A replication-deficient rabies virus vaccine expressing Ebola virus glycoprotein is highly attenuated for neurovirulence

    International Nuclear Information System (INIS)

    Papaneri, Amy B.; Wirblich, Christoph; Cann, Jennifer A.; Cooper, Kurt; Jahrling, Peter B.; Schnell, Matthias J.; Blaney, Joseph E.

    2012-01-01

    We are developing inactivated and live-attenuated rabies virus (RABV) vaccines expressing Ebola virus (EBOV) glycoprotein for use in humans and endangered wildlife, respectively. Here, we further characterize the pathogenesis of the live-attenuated RABV/EBOV vaccine candidates in mice in an effort to define their growth properties and potential for safety. RABV vaccines expressing GP (RV-GP) or a replication-deficient derivative with a deletion of the RABV G gene (RVΔG-GP) are both avirulent after intracerebral inoculation of adult mice. Furthermore, RVΔG-GP is completely avirulent upon intracerebral inoculation of suckling mice unlike parental RABV vaccine or RV-GP. Analysis of RVΔG-GP in the brain by quantitative PCR, determination of virus titer, and immunohistochemistry indicated greatly restricted virus replication. In summary, our findings indicate that RV-GP retains the attenuation phenotype of the live-attenuated RABV vaccine, and RVΔG-GP would appear to be an even safer alternative for use in wildlife or consideration for human use.

  1. Dual miRNA targeting restricts host range and attenuates neurovirulence of flaviviruses.

    Directory of Open Access Journals (Sweden)

    Konstantin A Tsetsarkin

    2015-04-01

    Full Text Available Mosquito-borne flaviviruses are among the most significant arboviral pathogens worldwide. Vaccinations and mosquito population control programs remain the most reliable means for flavivirus disease prevention, and live attenuated viruses remain one of the most attractive flavivirus vaccine platforms. Some live attenuated viruses are capable of infecting principle mosquito vectors, as demonstrated in the laboratory, which in combination with their intrinsic genetic instability could potentially lead to a vaccine virus reversion back to wild-type in nature, followed by introduction and dissemination of potentially dangerous viral strains into new geographic locations. To mitigate this risk we developed a microRNA-targeting approach that selectively restricts replication of flavivirus in the mosquito host. Introduction of sequences complementary to a mosquito-specific mir-184 and mir-275 miRNAs individually or in combination into the 3'NCR and/or ORF region resulted in selective restriction of dengue type 4 virus (DEN4 replication in mosquito cell lines and adult Aedes mosquitos. Moreover a combined targeting of DEN4 genome with mosquito-specific and vertebrate CNS-specific mir-124 miRNA can silence viral replication in two evolutionally distant biological systems: mosquitoes and mouse brains. Thus, this approach can reinforce the safety of newly developed or existing vaccines for use in humans and could provide an additional level of biosafety for laboratories using viruses with altered pathogenic or transmissibility characteristics.

  2. A replication-deficient rabies virus vaccine expressing Ebola virus glycoprotein is highly attenuated for neurovirulence

    Energy Technology Data Exchange (ETDEWEB)

    Papaneri, Amy B. [Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, MD 21702 (United States); Wirblich, Christoph [Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Cann, Jennifer A.; Cooper, Kurt [Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick MD, 21702 (United States); Jahrling, Peter B. [Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, MD 21702 (United States); Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick MD, 21702 (United States); Schnell, Matthias J., E-mail: matthias.schnell@jefferson.edu [Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Jefferson Vaccine Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Blaney, Joseph E., E-mail: jblaney@niaid.nih.gov [Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, MD 21702 (United States)

    2012-12-05

    We are developing inactivated and live-attenuated rabies virus (RABV) vaccines expressing Ebola virus (EBOV) glycoprotein for use in humans and endangered wildlife, respectively. Here, we further characterize the pathogenesis of the live-attenuated RABV/EBOV vaccine candidates in mice in an effort to define their growth properties and potential for safety. RABV vaccines expressing GP (RV-GP) or a replication-deficient derivative with a deletion of the RABV G gene (RV{Delta}G-GP) are both avirulent after intracerebral inoculation of adult mice. Furthermore, RV{Delta}G-GP is completely avirulent upon intracerebral inoculation of suckling mice unlike parental RABV vaccine or RV-GP. Analysis of RV{Delta}G-GP in the brain by quantitative PCR, determination of virus titer, and immunohistochemistry indicated greatly restricted virus replication. In summary, our findings indicate that RV-GP retains the attenuation phenotype of the live-attenuated RABV vaccine, and RV{Delta}G-GP would appear to be an even safer alternative for use in wildlife or consideration for human use.

  3. Zebrafish as a correlative and predictive model for assessing biomaterial nanotoxicity.

    Science.gov (United States)

    Fako, Valerie E; Furgeson, Darin Y

    2009-06-21

    The lack of correlative and predictive models to assess acute and chronic toxicities limits the rapid pre-clinical development of new therapeutics. This barrier is due in part to the exponential growth of nanotechnology and nanotherapeutics, coupled with the lack of rigorous and robust screening assays and putative standards. It is a fairly simple and cost-effective process to initially screen the toxicity of a nanomaterial by using invitro cell cultures; unfortunately it is nearly impossible to imitate a complimentary invivo system. Small mammalian models are the most common method used to assess possible toxicities and biodistribution of nanomaterials in humans. Alternatively, Daniorerio, commonly known as zebrafish, are proving to be a quick, cheap, and facile model to conservatively assess toxicity of nanomaterials.

  4. [Reliability and validity of assessment of educational outcomes obtained by students of Medical Rescue at Medical University of Warsaw].

    Science.gov (United States)

    Panczyk, Mariusz; Stachacz, Grzegorz; Gałązkowski, Robert; Gotlib, Joanna

    2016-01-01

    In the interest of preservation of high degree of objectivity of information about students' educational outcomes, a system of assessment needs to meet criteria of appropriate reliability and validity. Analysis of reliability and validity of the system of assessment of students' educational outcomes for courses followed by an examination and covered by a curriculum in Medical Rescue at Medical University of Warsaw (MU W). A retrospective study enrolling a group of 421 students of eight subsequent full education cycles. Detailed data concerning grades for fourteen courses followed by an examination in the entire course of studies were collected. Reliability (Cronbach's alpha coefficient) and criteria validity (Spearman's rank correlation) were assessed. Internal consistency was estimated using a multiple regression model. The levels of assessment reliability for the general university, pre-clinical, and clinical scopes amounted to alpha: 0.42, 0.53, and 0.70, respectively. The strongest positive correlations between the results of pre-clinical and clinical trainings were found for the Anatomy course (r ≈ 0.30). Only in the case of the Pharmacology course it was found that students' achievements in this field were significantly correlated with all other courses of clinical training. The influence of educational outcomes in particular areas of clinical training on the final grade for the entire course of studies was diverse (β regression between 0.04 and 0.11). While the Pharmacology course had the strongest impact on final results, the Surgery course had the least influence on students' final grades (β = 0.04). 1. Sufficient reliability of the system of assessment of educational outcomes in Medical Rescue showed good precision and repeatability of assessment. 2. A low level of validity was caused by a failure to keep the appropriateness of the assessment of educational outcomes in several clinical courses. 3. Prognostic and diagnostic validity of methods used for

  5. Assessment of skin barrier function and biochemical changes of ex vivo human skin in response to physical and chemical barrier disruption.

    Science.gov (United States)

    Döge, Nadine; Avetisyan, Araks; Hadam, Sabrina; Pfannes, Eva Katharina Barbosa; Rancan, Fiorenza; Blume-Peytavi, Ulrike; Vogt, Annika

    2017-07-01

    Topical dermatotherapy is intended to be used on diseased skin. Novel drug delivery systems even address differences between intact and diseased skin underlining the need for pre-clinical assessment of different states of barrier disruption. Herein, we studied how short-term incubation in culture media compared to incubation in humidified chambers affects human skin barrier function and viability. On both models we assessed different types and intensities of physical and chemical barrier disruption methods with regard to structural integrity, biophysical parameters and cytokine levels. Tissue degeneration and proliferative activity limited the use of tissue cultures to 48h. Viability is better preserved in cultured tissue. Tape-stripping (50×TS) and 4h sodium lauryl sulfate (SLS) pre-treatment were identified as highly reproducible and effective procedures for barrier disruption. Transepidermal water loss (TEWL) values reproducibly increased with the intensity of disruption while sebum content and skin surface pH were of limited value. Interleukin (IL)-6/8 and various chemokines and proteases were increased in tape-stripped skin which was more pronounced in SLS-treated skin tissue extracts. Thus, albeit limited to 48h, cultured full-thickness skin maintained several barrier characteristics and responded to different intensities of barrier disruption. Potentially, these models can be used to assess pre-clinically the efficacy and penetration of anti-inflammatory compounds. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency.

    Science.gov (United States)

    Sehic, Amer; Utheim, Øygunn Aass; Ommundsen, Kristoffer; Utheim, Tor Paaske

    2015-08-28

    The cornea is essential for normal vision by maintaining transparency for light transmission. Limbal stem cells, which reside in the corneal periphery, contribute to the homeostasis of the corneal epithelium. Any damage or disease affecting the function of these cells may result in limbal stem cell deficiency (LSCD). The condition may result in both severe pain and blindness. Transplantation of ex vivo cultured cells onto the cornea is most often an effective therapeutic strategy for LSCD. The use of ex vivo cultured limbal epithelial cells (LEC), oral mucosal epithelial cells, and conjunctival epithelial cells to treat LSCD has been explored in humans. The present review focuses on the current state of knowledge of the many other cell-based therapies of LSCD that have so far exclusively been explored in animal models as there is currently no consensus on the best cell type for treating LSCD. Major findings of all these studies with special emphasis on substrates for culture and transplantation are systematically presented and discussed. Among the many potential cell types that still have not been used clinically, we conclude that two easily accessible autologous sources, epidermal stem cells and hair follicle-derived stem cells, are particularly strong candidates for future clinical trials.

  7. 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.

  8. Attitudes towards smoking and tobacco control among pre-clinical medical students in Malaysia.

    Science.gov (United States)

    Tee, G H; Hairi, N N; Hairi, F

    2012-08-01

    Physicians should play a leading role in combatting smoking; information on attitudes of future physicians towards tobacco control measures in a middle-income developing country is limited. Of 310 future physicians surveyed in a medical school in Malaysia, 50% disagreed that it was a doctor's duty to advise smokers to stop smoking; 76.8% agreed that physicians should not smoke before advising others not to smoke; and 75% agreed to the ideas of restricting the sale of cigarettes to minors, making all public places smoke-free and banning advertising of tobacco-related merchandise. Future physicians had positive attitudes towards tobacco regulations but had not grasped their responsibilities in tobacco control measures.

  9. Pre-clinical and Clinical Evaluation of High Resolution, Mobile Gamma Camera and Positron Imaging Devices

    Science.gov (United States)

    2010-10-01

    Downloaded on February 20,2010 at 10:55:59 EST from IEEE Xplore . Restrictions apply. STUDENSKI et al.: ACQUISITION AND PROCESSING METHODS FOR A BEDSIDE...February 20,2010 at 10:55:59 EST from IEEE Xplore . Restrictions apply. 208 IEEE TRANSACTIONS ON NUCLEAR SCIENCE, VOL. 57, NO. 1, FEBRUARY 2010 from the...59 EST from IEEE Xplore . Restrictions apply. STUDENSKI et al.: ACQUISITION AND PROCESSING METHODS FOR A BEDSIDE CARDIAC SPECT IMAGING SYSTEM 209

  10. [{sup 177}Lu]DOTA-anti-CD20: Labeling and pre-clinical studies

    Energy Technology Data Exchange (ETDEWEB)

    Audicio, Paola F., E-mail: paudicio@cin.edu.u [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Castellano, Gustavo, E-mail: gcas@famaf.unc.edu.a [FaMAF, Universidad Nacional de Cordoba, Ciudad Universitaria, 5016 Cordoba (Argentina); Tassano, Marcos R.; Rezzano, Maria E.; Fernandez, Marcelo [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Riva, Eloisa [Clinica Hematologica ' Prof. Dra. L. Diaz' , Hospital de Clinicas. Av. Italia. sn, Montevideo (Uruguay); Robles, Ana; Cabral, Pablo; Balter, Henia; Oliver, Patricia [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay)

    2011-07-15

    Anti-CD20 (Rituximab), a specific chimeric monoclonal antibody used in CD20-positive Non-Hodgkin's Lymphoma, was conjugated to a bifunctional quelate (DOTA) and radiolabeled with {sup 177}Lu through a simple method. [{sup 177}Lu]-DOTA-anti-CD20 was obtained with a radiochemical purity higher than 97%, and showed good chemical and biological stability, maintaining its biospecificity to CD20 antigens. Monte Carlo simulation showed high doses deposited on a spheroid tumor mass model. This method seems to be an appropriate alternative for the production of [{sup 177}Lu]-DOTA-anti-CD20 as therapeutic radiopharmaceutical.

  11. Pre-Clinical Studies of Dendritic Cell-Tumor Cell Fusion Vaccines to Treat Breast Cancer

    National Research Council Canada - National Science Library

    Akporiaye, Emmanuel

    2002-01-01

    ...+ T-helper cells, CD8+ cytotoxic T lymphocytes (CTLs), NK and NKT cells (1,2). Because DC have the capacity to take up various types of molecules, the cells can be loaded with tumor-associated antigens (TAAs...

  12. Pre-Clinical and Clinical Investigation of the Impact of Obesity on Ovarian Cancer Pathogenesis

    Science.gov (United States)

    2015-12-01

    clinical cancer drug discovery , including 10 years as a Research Assistant Professor in the Department of Surgery at Duke University Medical Center...cancer therapy. Nature chemical biology . 2015;11(1):9-15. Epub 2014/12/18. doi: 10.1038/nchembio.1712. PubMed PMID: 25517383; PubMed Central PMCID...Assistant Professor of Nutrition, a member of the Nutrition Obesity Research Center, Center for Gastrointestinal Biology and Disease, McCallister Heart

  13. 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

  14. Conditioned Stimuli’s Role in Relapse: Pre-Clinical Research on Pavlovian Instrumental Transfer

    Science.gov (United States)

    Lamb, R.J.; Schindler, W.; Pinkston, Jonathan W.

    2016-01-01

    Rationale and Objective Pavlovian learning is central to many theories of addiction. In these theories, stimuli paired with drug ingestion become Conditioned Stimuli (CS) and subsequently elicit drug-seeking and -taking. However in most relevant studies, Pavlovian and instrumental learning are confounded. This confound may be avoided in Pavlovian-Instrumental-Transfer (PIT) procedures. In PIT, Pavlovian and instrumental learning are established separately, and then combined. In order to better understand the role of CSs in addiction, we review the relevant studies using PIT. Findings We identified seven articles examining PIT effects of ethanol- or cocaine-paired CSs. Under at least one condition six of these articles reported CS-elicited increases in responding previously maintained by drug. However, the only study using the optimal control condition failed to find a CS-elicited increase. Two studies examining CS specificity found the CS also increased responding maintained by a different reinforcer. Two studies examined if CSs elicit increases in actual drug-taking. Both failed to find CS-elicited increases, i.e., no study shows CS-elicited increases in actual drug-taking. Further, CS-elicited increases in extinguished responding are short-lived. Conclusions These findings are not entirely consistent with Pavlovian learning playing a central role in addiction. However, design issues can explain most of these inconsistencies. Studies without these design issues are needed. Additionally, existing theories hypothesize drug-paired CSs increase drug-taking by increasing motivation, by eliciting conditioned responses that make drug-seeking more probable, or by a combination of these. Work distinguishing between these mechanisms would also be useful. PMID:26800688

  15. The use of DNA markers in the pre-clinical diagnosis of familial ...

    African Journals Online (AJOL)

    informative or partially informative in all the families studied. Five haplotypes were found to segregate with the disease locus. The predominant association of two of these haplotypes with FAP in the South African families suggests that two mutations may cause the disease in about 70% of families in this population. Meiotic.

  16. Pre-clinical functional magnetic resonance imaging. Pt. II. The heart

    Energy Technology Data Exchange (ETDEWEB)

    Messner, Nadja M.; Zoellner, Frank G.; Kalayciyan, Raffi; Schad, Lothar R. [Heidelberg Univ., Mannheim (Germany). Computer Assisted Clinical Medicine

    2014-07-01

    One third of all deaths worldwide in 2008 were caused by cardiovascular diseases (CVD), and the incidence of CVD related deaths rises ever more. Thus, improved imaging techniques and modalities are needed for the evaluation of cardiac morphology and function. Cardiac magnetic resonance imaging (CMRI) is a minimally invasive technique that is increasingly important due to its high spatial and temporal resolution, its high soft tissue contrast and its ability of functional and quantitative imaging. It is widely accepted as the gold standard of cardiac functional analysis. In the short period of small animal MRI, remarkable progress has been achieved concerning new, fast imaging schemes as well as purpose-built equipment. Dedicated small animal scanners allow for tapping the full potential of recently developed animal models of cardiac disease. In this paper, we review state-of-the-art cardiac magnetic resonance imaging techniques and applications in small animals at ultra-high fields (UHF).

  17. Displacement of the abomasum in dairy cows: risk factors and pre-clinical alterations

    NARCIS (Netherlands)

    Winden, Stefanus Cornelis Leonardus van

    2002-01-01

    Displacement of the abomasum (DA) in dairy cows is a disorder described since the fifties of the previous century. Since then, a considerable amount of research concerning DA is conducted. The normal, healthy abomasum is positioned in the ventral part of the abdominal cavity. As a result of

  18. Feasibility and safety of electrochemotherapy (ECT in the pancreas: a pre-clinical investigation

    Directory of Open Access Journals (Sweden)

    Girelli Roberto

    2015-06-01

    Full Text Available Background. Pancreatic ductal adenocarcinoma (PDAC is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT, thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents.

  19. Ethnic and social disparities in different types of examinations in undergraduate pre-clinical training

    NARCIS (Netherlands)

    K.M. Stegers-Jager (Karen); F.N. Brommet; A.P.N. Themmen (Axel)

    2016-01-01

    textabstractMedical schools are increasingly faced with a more diverse student population. Generally, ethnic minority students are reported to underperform compared with those from the ethnic majority. However, there are inconsistencies in findings in different types of examinations. Additionally,

  20. Microarray analysis in clinical oncology: pre-clinical optimization using needle core biopsies from xenograft tumors

    International Nuclear Information System (INIS)

    Goley, Elizabeth M; Anderson, Soni J; Ménard, Cynthia; Chuang, Eric; Lü, Xing; Tofilon, Philip J; Camphausen, Kevin

    2004-01-01

    DNA microarray profiling performed on clinical tissue specimens can potentially provide significant information regarding human cancer biology. Biopsy cores, the typical source of human tumor tissue, however, generally provide very small amounts of RNA (0.3–15 μg). RNA amplification is a common method used to increase the amount of material available for hybridization experiments. Using human xenograft tissue, we sought to address the following three questions: 1) is amplified RNA representative of the original RNA profile? 2) what is the minimum amount of total RNA required to perform a representative amplification? 3) are the direct and indirect methods of labeling the hybridization probe equivalent? Total RNA was extracted from human xenograft tissue and amplified using a linear amplification process. RNA was labeled and hybridized, and the resulting images yielded data that was extracted into two categories using the mAdb system: 'all genes' and 'outliers'. Scatter plots were generated for each slide and Pearson Coefficients of correlation were obtained. Results show that the amplification of 5 μg of total RNA yields a Pearson Correlation Coefficient of 0.752 (N = 6,987 genes) between the amplified and total RNA samples. We subsequently determined that amplification of 0.5 μg of total RNA generated a similar Pearson Correlation Coefficient as compared to the corresponding original RNA sample. Similarly, sixty-nine percent of total RNA outliers were detected with 5 μg of amplified starting RNA, and 55% of outliers were detected with 0.5 μg of starting RNA. However, amplification of 0.05 μg of starting RNA resulted in a loss of fidelity (Pearson Coefficient 0.669 between amplified and original samples, 44% outlier concordance). In these studies the direct or indirect methods of probe labeling yielded similar results. Finally, we examined whether RNA obtained from needle core biopsies of human tumor xenografts, amplified and indirectly labeled, would generate representative array profiles compared to larger excisional biopsy material. In this analysis correlation coefficients were obtained ranging from 0.750–0.834 between U251 biopsy cores and excised tumors, and 0.812–0.846 between DU145 biopsy cores and excised tumors. These data suggest that needle core biopsies can be used as reliable tissue samples for tumor microarray analysis after linear amplification and either indirect or direct labeling of the starting RNA

  1. Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model

    Directory of Open Access Journals (Sweden)

    Barua Neil U

    2012-01-01

    Full Text Available Abstract Background Convection-enhanced delivery (CED, a direct method for drug delivery to the brain through intraparenchymal microcatheters, is a promising strategy for intracerebral pharmacological therapy. By establishing a pressure gradient at the tip of the catheter, drugs can be delivered in uniform concentration throughout a large volume of interstitial fluid. However, the variables affecting perivascular distribution of drugs delivered by CED are not fully understood. The aim of this study was to determine whether the perivascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, by co-infusion of vasodilator, alteration of infusion rates or use of a ramping regime. We also wanted to make a preliminary comparison of the distribution of solutes with that of nanoparticles. Methods We analysed the perivascular distribution of 4, 10, 20, 70, 150 kDa fluorescein-labelled dextran and fluorescent nanoparticles at 10 min and 3 h following CED into rat striatum. We investigated the effect of local vasodilatation, slow infusion rates and ramping on the perivascular distribution of solutes. Co-localisation with perivascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by perivascular macrophages was quantified using stereological methods. Results Widespread perivascular distribution and macrophage uptake of fluorescein-labelled dextran was visible 10 min after cessation of CED irrespective of molecular weight. However, a significantly higher proportion of perivascular macrophages had taken up 4, 10 and 20 kDa fluorescein-labelled dextran than 150 kDa dextran (p Conclusions This study suggests that widespread perivascular distribution and interaction with perivascular macrophages is likely to be an inevitable consequence of CED of solutes. The potential consequences of perivascular distribution of therapeutic agents, and in particular cytotoxic chemotherapies, delivered by CED must be carefully considered to ensure safe and effective translation to clinical trials.

  2. 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

    Full text: The classic radioimmunotherapy is based on transporting to the tumor, the necessary activity of a therapeutic isotope using a monoclonal antibody (MAb) against tumor associated antigen, which constitutes an ideal vehicle given its inherent specificity. In this sense, the immunoglobulin (Ig) has some severe practical limitations due to its unhappy pharmacokinetics, relatively high molecular weight (150 kDa) and slower clearance. Likewise the Ig molecule presents a poor diffusion through the tumor mass and a relative high immunogenicity. The solution to these problems has been offered by genetic engineering, methods where the multivalent recombinant fragments have become the paradigm of design of constructed molecules. They are able to retain the specificity of the parental antibody and affinity, with reduced immunogenicity and improved pharmacokinetics. The monoclonal antibody ior-CEA1 has been employed for the diagnosis of primary tumors, recurrences and metastatic disease, and has also been used extensively in the daily clinical practice as well. Inserted in this rebirth of the antibodies, this report explores the use of a new smaller molecular weight multivalent analogue of the parent ior-CEA1 antibody to be used for the diagnosis and therapy of CEA-expressing malignant tumors such as colorectal, lung, ovary among others. The dimeric scFv-ior- CEA1 construct was produced in the Centre for Genetic Engineering and Biotechnology and displayed to bind CEA epitope with a similar binding affinity to that of the murine IgG. Method: Labelling was achieved using Chloramine T, with a molar ration of Chloramine T:Tyrosine of 2.5. For the comparison of the immunoreactivity of labeled and unlabelled diabodies, was plotted the specific union vs the antibody concentration for both molecules and adjusted to a straight line. The immunoreactivity was also assayed using size-exclusion FPLC to evaluate their antigen-binding capacities after radiolabelling. Seventy-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 critical organ. Being this, an advantage for its possible use as radioimmunotherapeu tic agent, since the exposition levels in healthy tissues will be low. It could be also observed a high uptake in tumor. The excellent tumor:blood ratios reflect the specific retention in the target tumour and avidity of the biomolecule for the CEA antigen. Conclusions: The divalent scFv of MAb ior-CEA1 was constructed to improve the tumor targeting. This construct has showed to have better functional affinity than the previous variant. Biodistribution studies in xenografted mice demonstrated that the construct showed high tumour accretion with low uptake by the normal organs and no cross-reactions. These properties aim to use the ior- CEA 1dimer sc Fv construct as potential radioimmunotherapeutic agents. (author)

  3. Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

    Science.gov (United States)

    Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

    2016-12-01

    Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Academic performance in Iranian medical students during the pre-clinical stage

    OpenAIRE

    Davoudi, Farnoush; Esmaeeli, Shooka; AhmadzadAsl, Masoud; Nojomi, Marzieh

    2017-01-01

    Background: Better understanding of factors associated with medical school performance is necessary to improve admission processes and to help students succeed in their career. This study follows a group of Iranian med students during their first 2.5 years of medical education, to evaluate their academic success in accordance with their demographic, cognitive and non-cognitive characteristics. Methods: 143 of 200 matriculants of Iran University of Medical Sciences medical school in 2010, were...

  5. Nasal Carriage of Staphylococcus aureus in Australian (pre-clinical and clinical) Medical Students

    NARCIS (Netherlands)

    E. Stubbs; M. Pegler; A. Vickery; C. Harbour

    1994-01-01

    textabstractThe nasal carriage of Staphylococcus aureus in 808 Australian medical students was studied. Five groups of students experienced varying degrees of clinical exposure in a hospital environment ranging from 0 to 42 months. The overall percentage of carriers among the five groups did not

  6. Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application.

    Science.gov (United States)

    Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro; Wang, Baomei; Yancopoulou, Despina; Ricklin, Daniel; Lambris, John D

    2016-06-01

    Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Advances in quantitative UV-visible spectroscopy for clinical and pre-clinical application in cancer.

    Science.gov (United States)

    Brown, J Quincy; Vishwanath, Karthik; Palmer, Gregory M; Ramanujam, Nirmala

    2009-02-01

    Methods of optical spectroscopy that provide quantitative, physically or physiologically meaningful measures of tissue properties are an attractive tool for the study, diagnosis, prognosis, and treatment of various cancers. Recent development of methodologies to convert measured reflectance and fluorescence spectra from tissue to cancer-relevant parameters such as vascular volume, oxygenation, extracellular matrix extent, metabolic redox states, and cellular proliferation have significantly advanced the field of tissue optical spectroscopy. The number of publications reporting quantitative tissue spectroscopy results in the UV-visible wavelength range has increased sharply in the past three years, and includes new and emerging studies that correlate optically measured parameters with independent measures such as immunohistochemistry, which should aid in increased clinical acceptance of these technologies.

  8. 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.

  9. Analysis of Investigational Drugs in Biological Fluids - Method Development and Analysis of Pre-Clinical Samples

    National Research Council Canada - National Science Library

    Lin, Emil

    2001-01-01

    ... (and metabolites and artesunate). Work on routine analyses of biological specimens during this period was performed for studies that required determination of concentrations of artelinic acid, choroquine...

  10. Pre-clinical evaluation of a diode-based In vivo dosimetry system

    International Nuclear Information System (INIS)

    Trujillo, G.

    1998-01-01

    Diode detector systems are routinely used in a number of departments for the quality assurance of the delivered dose in radiation oncology (1,2,3,4,5). The main advantage of diode detectors for in vivo dosimetry (over TLDs, film dosimetry, ionization chambers) is that results are immediately available in real time, do not need external bias voltage and are more sensitive for the same detection volume than ionization chambers thereby allowing a direct and immediate check of the treatment accuracy. Also, is important to mention that is possible to obtain different accuracy levels. For example, in the case of the measurements designed for evaluating the dosimetric accuracy of a new treatment technique for dose escalation studies the action level should be tighter (the order of 2 % to 4 %, 2 standard deviations) than for routine measurements aiming to discover and correct for errors in the treatment of individual patients (± 5 % - 10 % or to avoid mis administrations (10 % - 15 %). This work describes the calibration method adopted and the evaluation of the accuracy and precision of in vivo dosimetry at Co 60 and 23 MV photon energies. Extensive phantoms measurements were made to determine the influence of physical conditions on the diode response. Parameters investigated included diode linearity, leakage, and measurement reproducibility, as well as the field size, SSD, and angular dependence. the practical consequences of these measurements are reported. There is still some controversy as to whether in vivo (diode) dosemeters are required for routine quality assurance purposes. Our work has shown that while care must be taken in choosing and handling diode detector systems they are able to provide an efficient and effective method of ensuring the dose delivered to the patient during treatment is within acceptable limits. (Author)

  11. Introduction to Pre-clinical Imaging Techniques; Introduccion a las tecnicas de imagen preclinica

    Energy Technology Data Exchange (ETDEWEB)

    Mulero, F.

    2008-07-01

    Biomedical research poses increasingly complex problems regarding the biochemical processes that take place in living organisms. Just as in clinical research, medical imaging techniques are an excellent tool to study these processes. One of the most outstanding techniques is what is called molecular imaging, the best tool for which is positron emission tomography (PET). PET is capable of monitoring those processes in vivo at a molecular level and it can be used in multiple applications, including the development of new drugs, the study of human disease models in animals, and the characterization of gene expression and phenotype changes caused by genetic manipulation (transgenic and knockout animals). (Author) 5 refs.

  12. [Overview of the Ebola vaccines in pre-clinical and clinical development].

    Science.gov (United States)

    Buchy, P

    2016-10-01

    The Ebola epidemic that occurred in West Africa between 2013-2016 significantly accelerated the research and development of Ebola vaccines. Few dozens of clinical trials have been recently conducted leading to opportunities to test several new vaccine candidates. Other vaccines are still in early development phases (table 1). This paper provides an overview of the new developments in that area.

  13. Is Autism a Disease of the Cerebellum?: An integration of clinical and pre-clinical results

    Directory of Open Access Journals (Sweden)

    Tiffany D. Rogers

    2013-05-01

    Full Text Available Autism spectrum disorders are a group of neurodevelopmental disorders characterized by deficits in social skills and communication, unusual and repetitive behavior, and a range of deficits in cognitive function. While the etiology of autism is unknown, current research indicates that abnormalities of the cerebellum, now believed to be involved in cognitive function and the prefrontal cortex (PFC, are associated with autism. The current paper proposes that impaired cerebello-cortical circuitry could, at least in part, underlie autistic symptoms. The use of animal models that allow for manipulation of genetic and environmental influences are an effective means of elucidating both distal and proximal etiological factors in autism and their potential impact on cerebello-cortical circuitry. Some existing rodent models of autism, as well as some models not previously applied to the study of the disorder, display cerebellar and behavioral abnormalities that parallel those commonly seen in autistic patients. The novel findings produced from research utilizing rodent models could provide a better understanding of the neurochemical and behavioral impact of changes in cerebello-cortical circuitry in autism.

  14. Pre-Clinical Traumatic Brain Injury Common Data Elements: Toward a Common Language Across Laboratories.

    Science.gov (United States)

    Smith, Douglas H; Hicks, Ramona R; Johnson, Victoria E; Bergstrom, Debra A; Cummings, Diana M; Noble, Linda J; Hovda, David; Whalen, Michael; Ahlers, Stephen T; LaPlaca, Michelle; Tortella, Frank C; Duhaime, Ann-Christine; Dixon, C Edward

    2015-11-15

    Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of "big data" approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms, and a data dictionary of "common data elements" (CDEs), as well as "unique data elements" has been created for clinical TBI research. There is no data dictionary, however, for preclinical TBI research despite similar opportunities to accelerate knowledge. To address this gap, a committee of experts was tasked with creating a defined set of data elements to further collaboration across laboratories and enable the merging of data for meta-analysis. The CDEs were subdivided into a Core module for data elements relevant to most, if not all, studies, and Injury-Model-Specific modules for non-generalizable data elements. The purpose of this article is to provide both an overview of TBI models and the CDEs pertinent to these models to facilitate a common language for preclinical TBI research.

  15. Comparative pre clinic pharmacokinetics of Mebrofenin - Tc 99 m produced in Colombia

    International Nuclear Information System (INIS)

    Aristizabal, G.; Ponce, F.; Mendoza, M.

    1993-01-01

    By using a test battery from experimental pharmacology, the preclinical pharmacokinetic profile of mebrofenin is described since 1988, this compound is being produce and used in Colombia for the hepatobiary diagnosis. These results are compared with those obtained from French and Argentine. The biokinetic behaviour of the compound is monitorized in the central compartment and the two main excretion routes; biodistribution and plasma protein binding are also measured. Finally on efficiency valorisation in relation to the standard parameters of maximum extraction by the hepatic system, and mass excretion through the biliary system is accounted. The mebrofenin produced in Colombia offers a competitive quality because of this its chemical synthesis and final elaboration is encouraged for it represents an advantage over it represents an advantage over the importation of the finished product or raw materials for its final production

  16. Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

    DEFF Research Database (Denmark)

    Chang, Joan; Lucas, Morghan C; Leonte, Lidia Elena

    2017-01-01

    inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis. Dual inhibition of LOXL2 and LOX showed...... a greater effect and also led to a lower overall metastatic burden in the lung and liver. Our data provides the first evidence to support a role for LOXL2 specific small molecule inhibitors as a potential therapy in breast cancer....

  17. Measuring serotonin synthesis : From conventional methods to PET tracers and their (pre)clinical implications

    NARCIS (Netherlands)

    Visser, Anniek K. D.; van Waarde, Aren; Willemsen, Antoon T. M.; Bosker, Fokko J.; Luiten, Paul G. M.; den Boer, Johan A.; Kema, Ido P.; Dierckx, Rudi A. J. O.

    The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning

  18. 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.

  19. 3D Mapping of Language Networks in Clinical and Pre-Clinical Alzheimer's Disease

    Science.gov (United States)

    Apostolova, Liana G.; Lu, Po; Rogers, Steve; Dutton, Rebecca A.; Hayashi, Kiralee M.; Toga, Arthur W.; Cummings, Jeffrey L.; Thompson, Paul M.

    2008-01-01

    We investigated the associations between Boston naming and the animal fluency tests and cortical atrophy in 19 probable AD and 5 multiple domain amnestic mild cognitive impairment patients who later converted to AD. We applied a surface-based computational anatomy technique to MRI scans of the brain and then used linear regression models to detect…

  20. Normal Skin Microbiota is Altered in Pre-clinical Hidradenitis Suppurativa

    DEFF Research Database (Denmark)

    Ring, Hans Christian; Bay, Lene; Kallenbach, Klaus

    2017-01-01

    therefore hypothesized that clinically unaffected HS skin would also have an increased presence of biofilm compared with that of healthy controls. We conducted a case-control study, investigating the morphology of the axillary skin microbiota. Peptide nucleic acid – fluorescence in situ hybridization probes...... were used in combination with confocal laser scanning microscopy. Significant differences were found in both distribution and quantity of the cutaneous microbiota in clinically non-affected axillary skin of patients with HS compared with healthy controls. Surprisingly, we detected fewer bacteria...... and less biofilm in patients with HS. The reduced microbiota in patients with HS may play an important role in the early course of the disease....

  1. Pre-Clinical Tests of an Integrated CMOS Biomolecular Sensor for Cardiac Diseases Diagnosis.

    Science.gov (United States)

    Lee, Jen-Kuang; Wang, I-Shun; Huang, Chi-Hsien; Chen, Yih-Fan; Huang, Nien-Tsu; Lin, Chih-Ting

    2017-11-26

    Coronary artery disease and its related complications pose great threats to human health. In this work, we aim to clinically evaluate a CMOS field-effect biomolecular sensor for cardiac biomarkers, cardiac-specific troponin-I (cTnI), N -terminal prohormone brain natriuretic peptide (NT-proBNP), and interleukin-6 (IL-6). The CMOS biosensor is implemented via a standard commercialized 0.35 μm CMOS process. To validate the sensing characteristics, in buffer conditions, the developed CMOS biosensor has identified the detection limits of IL-6, cTnI, and NT-proBNP as being 45 pM, 32 pM, and 32 pM, respectively. In clinical serum conditions, furthermore, the developed CMOS biosensor performs a good correlation with an enzyme-linked immuno-sorbent assay (ELISA) obtained from a hospital central laboratory. Based on this work, the CMOS field-effect biosensor poses good potential for accomplishing the needs of a point-of-care testing (POCT) system for heart disease diagnosis.

  2. Micro-polarimetry for pre-clinical diagnostics of pathological changes in human tissues

    Science.gov (United States)

    Golnik, Andrzej; Golnik, Natalia; Pałko, Tadeusz; Sołtysiński, Tomasz

    2008-05-01

    The paper presents a practical study of several methods of image analysis applied to polarimetric images of regular and malignant human tissues. The images of physiological and pathologically changed tissues from body and cervix of uterus, intestine, kidneys and breast were recorded in transmitted light of different polarization state. The set up of the conventional optical microscope with CCD camera and rotating polarizer's were used for analysis of the polarization state of the light transmitted through the tissue slice for each pixel of the camera image. The set of images corresponding to the different coefficients of the Stockes vectors, a 3×3 subset of the Mueller matrix as well as the maps of the magnitude and in-plane direction of the birefringent components in the sample were calculated. Then, the statistical analysis and the Fourier transform as well as the autocorrelation methods were used to analyze spatial distribution of birefringent elements in the tissue samples. For better recognition of tissue state we proposed a novel method that takes advantage of multiscale image data decomposition The results were used for selection of the optical characteristics with significantly different values for regular and malignant tissues.

  3. Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Visser, Anniek K.D.; Waarde, Aren van; Willemsen, Antoon T.M. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Bosker, Fokko J. [University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Luiten, Paul G.M. [University of Groningen, Center for Behavior and Neurosciences, Department of Molecular Neurobiology, Haren (Netherlands); Boer, Johan A. den [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Kema, Ido P. [University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Dierckx, Rudi A.J.O. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University Hospital Ghent, Department of Nuclear Medicine, Ghent (Belgium)

    2011-03-15

    The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are {alpha}-[{sup 11}C]methyltryptophan ([{sup 11}C]AMT) and 5-hydroxy-L-[{beta}-{sup 11}C]tryptophan ([{sup 11}C]5-HTP). Both tracers have advantages and disadvantages. [{sup 11}C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [{sup 11}C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain. (orig.)

  4. Comparison of single and dual layer detector blocks for pre-clinical MRI–PET

    International Nuclear Information System (INIS)

    Thompson, Christopher; Stortz, Greg; Goertzen, Andrew; Berg, Eric; Retière, Fabrice; Kozlowski, Piotr; Ryner, Lawrence; Sossi, Vesna; Zhang, Xuezhu

    2013-01-01

    Dual or multi-layer crystal blocks have been proposed to minimise the radial blurring effect in PET scanners with small ring diameters. We measured two potential PET detector blocks' performance in a configuration which would allow 16 blocks in a ring which could be inserted in a small animal 7T MRI scanner. Two crystal sizes, 1.60×1.60 mm 2 and 1.20×1.20 mm 2 , were investigated. Single layer blocks had 10 or 12 mm deep crystals, the dual layer blocks had 4 mm deep crystals on the top layer and 6 mm deep crystals on the bottom layer. The crystals in the dual layer blocks are offset by ½ of the crystal pitch to allow for purely geometric crystal identification. Both were read out with SensL 4×4 SiPM arrays. The software identifies 64 crystals in the single layer and either 85 or 113 crystals in the dual layer array, (either 49 or 64 in the lower layers and 36 or 49 in the upper layers). All the crystals were clearly visible in the crystal identification images and their resolvability indexes (average FWHM/crystal separation) were shown to range from 0.29 for the best single layer block to 0.33 for the densest dual layer block. The best coincidence response FWHM was 0.95 mm for the densest block at the centre of the field. This degraded to 1.83 mm at a simulated radial offset of 16 mm from the centre, while the single layer crystals blurred this result to 3.4 mm. The energy resolution was 16.4±2.2% averaged over the 113 crystals of the densest block

  5. Pre-clinical evaluation of extracts and essential oils from betel-like ...

    African Journals Online (AJOL)

    The extracts and oils were preclinically studied based on cyto - and genotoxicity using microculture tetrazolium (MTT) and comet assays. Results: The crude extracts showed an IC50 in leukocytes and HeLa cells of 58.59 -97.31 mg/ml and 34.91-101.79 mg/ml, the LD50 is higher than 5000 mg/kg. With lower values than the ...

  6. 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

  7. Tailored treatment of metastatic colorectal cancer: clinical and pre-clinical developments

    NARCIS (Netherlands)

    Kuijpers, A.M.J.

    2015-01-01

    Colorectal cancer is the third leading cause of cancer-related death in males and females in developed countries. Metastases in distant organs, which develop in 50% of colorectal cancer patients, are responsible for the majority of colorectal cancer deaths. Treatment of metastatic disease should

  8. Importance of dosimetry of irradiators for pre-clinical radiobiological experiments

    International Nuclear Information System (INIS)

    Vikram, Bhadrasain

    2014-01-01

    Importance of radiation dose in radiation biology has been increasingly recognized due to translational use of beyond 2Gy dose is in current practice. Hence, accurate dosimetry of biological irradiators is warranted. To address these problems and propose recommendations, the National Cancer Institute (NCI) along with the National Institute of Allergy and Infectious Diseases (NIAID) as well as the National Institute of Standards and Technology (NIST) highlighted a number of recommendations that will be presented in this talk that includes creating dosimetry standard operating procedures (SOPs) for both in-vitro as well as in-vivo experiments. Other recommendations include for journals (as well as to funding agencies) mandating the reporting of dosimetry of biological irradiators. (author)

  9. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.

    Directory of Open Access Journals (Sweden)

    Tianyu Zhang

    Full Text Available Buruli ulcer (BU caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound

  10. Risk Assessment

    Science.gov (United States)

    How the EPA conducts risk assessment to protect human health and the environment. Several assessments are included with the guidelines, models, databases, state-based RSL Tables, local contacts and framework documents used to perform these assessments.

  11. Does a Rater's Professional Background Influence Communication Skills Assessment?

    Science.gov (United States)

    Artemiou, Elpida; Hecker, Kent G; Adams, Cindy L; Coe, Jason B

    2015-01-01

    There is increasing pressure in veterinary education to teach and assess communication skills, with the Objective Structured Clinical Examination (OSCE) being the most common assessment method. Previous research reveals that raters are a large source of variance in OSCEs. This study focused on examining the effect of raters' professional background as a source of variance when assessing students' communication skills. Twenty-three raters were categorized according to their professional background: clinical sciences (n=11), basic sciences (n=4), clinical communication (n=5), or hospital administrator/clinical skills technicians (n=3). Raters from each professional background were assigned to the same station and assessed the same students during two four-station OSCEs. Students were in year 2 of their pre-clinical program. Repeated-measures ANOVA results showed that OSCE scores awarded by the rater groups differed significantly: (F(matched_station_1) [2,91]=6.97, p=.002), (F(matched_station_2) [3,90]=13.95, p=.001), (F(matched_station_3) [3,90]=8.76, p=.001), and ((Fmatched_station_4) [2,91]=30.60, p=.001). A significant time effect between the two OSCEs was calculated for matched stations 1, 2, and 4, indicating improved student performances. Raters with a clinical communication skills background assigned scores that were significantly lower compared to the other rater groups. Analysis of written feedback provided by the clinical sciences raters showed that they were influenced by the students' clinical knowledge of the case and that they did not rely solely on the communication checklist items. This study shows that it is important to consider rater background both in recruitment and training programs for communication skills' assessment.

  12. Comparative values of medical school assessments in the prediction of internship performance.

    Science.gov (United States)

    Lee, Ming; Vermillion, Michelle

    2018-02-01

    Multiple undergraduate achievements have been used for graduate admission consideration. Their relative values in the prediction of residency performance are not clear. This study compared the contributions of major undergraduate assessments to the prediction of internship performance. Internship performance ratings of the graduates of a medical school were collected from 2012 to 2015. Hierarchical multiple regression analyses were used to examine the predictive values of undergraduate measures assessing basic and clinical sciences knowledge and clinical performances, after controlling for differences in the Medical College Admission Test (MCAT). Four hundred eighty (75%) graduates' archived data were used in the study. Analyses revealed that clinical competencies, assessed by the USMLE Step 2 CK, NBME medicine exam, and an eight-station objective structured clinical examination (OSCE), were strong predictors of internship performance. Neither the USMLE Step 1 nor the inpatient internal medicine clerkship evaluation predicted internship performance. The undergraduate assessments as a whole showed a significant collective relationship with internship performance (ΔR 2  = 0.12, p < 0.001). The study supports the use of clinical competency assessments, instead of pre-clinical measures, in graduate admission consideration. It also provides validity evidence for OSCE scores in the prediction of workplace performance.

  13. Assessment and evaluation of individual prerequisites for dental education.

    Science.gov (United States)

    Heintze, U; Radeborg, K; Bengtsson, H; Stenlåås, A

    2004-11-01

    Since 2001 the School of Dentistry of Malmo University in Sweden has used an alternative admissions procedure based on results of an investigation supported by the Swedish Council for the Renewal of Undergraduate Education. The investigation concerned possibilities of predicting dental school performance on the basis of an interview, as well as tests of general intelligence, spatial ability, manual dexterity, empathy and social competence. Two groups of incoming students were followed from start to completion of their training. Significant relationships were found between (i) number of course examinations failed and poor results on interviews, as well as low scores on intelligence, spatial ability, and a test of spatial-manual ability, (ii) good results in a pre-clinical course in cavity preparation and high scores on spatial ability, (iii) assessments of high social competence during training and good results on interviews, as well as high scores on empathy and non-verbal intelligence. Dropout from the study programme could not be predicted, possibly due to the varying reasons for it. Copyright 2004 Blackwell Munksgaard

  14. Evaluating Student Self-Assessment through Video-Recorded Patient Simulations.

    Science.gov (United States)

    Sanderson, Tammy R; Kearney, Rachel C; Kissell, Denise; Salisbury, Jessica

    2016-08-01

    The purpose of this pilot study was to determine if the use of a video-recorded clinical session affects the accuracy of dental hygiene student self-assessment and dental hygiene instructor feedback. A repeated measures experiment was conducted. The use of the ODU 11/12 explorer was taught to students and participating faculty through video and demonstration. Students then demonstrated activation of the explorer on a student partner using the same technique. While faculty completed the student assessment in real time, the sessions were video recorded. After completing the activation of the explorer, students and faculty completed an assessment of the student's performance using a rubric. A week later, both students and faculty viewed the video of the clinical skill performance and reassessed the student's performance using the same rubric. The student videos were randomly assigned a number, so faculty reassessed the performance without access to the student's identity or the score that was initially given. Twenty-eight students and 4 pre-clinical faculty completed the study. Students' average score was 4.68±1.16 on the first assessment and slightly higher 4.89±1.45 when reviewed by video. Faculty average scores were 5.07±2.13 at the first assessment and 4.79±2.54 on the second assessment with the video. No significant differences were found between the differences in overall scores, there was a significant difference in the scores of the grading criteria compared to the expert assessment scores (p=0.0001). This pilot study shows that calibration and assessment without bias in education is a challenge. Analyzing and incorporating new techniques can result in more exact assessment of student performance and self-assessment. Copyright © 2016 The American Dental Hygienists’ Association.

  15. Undergraduate Information Literacy Instruction Is Not Enough to Prepare Junior Doctors for Evidence Based Practice. A Review of: Cullen, R., Clark, M., & Esson, R. (2011. Evidence-based information-seeking skills of junior doctors entering the workforce: An evaluation of the impact of information literacy training during pre-clinical years. Health Information & Libraries Journal, 28(2, 119-129. doi:10.1111/j.1471-1842.2011.00933.x

    Directory of Open Access Journals (Sweden)

    Carol D. Howe

    2012-06-01

    systematic reviews as well as using “explode” and “focus”, which tied for the lowest rating. The observed searches on average were rated lower than the self-assessments on all but one parameter. None of the average scores for either the self-rating or the observer-rating approached “highly skilled”. Conclusion – The authors concluded that the information literacy instruction the participants received as undergraduates did not prepare them adequately for evidence-based practice. Even though most participants said they remembered their undergraduate information literacy instruction, neither the average scores for the self-rating nor the observer-rating approached “highly skilled”. From that they could surmise that the attainment of information literacy should be a career-long learning process, beginning with undergraduate instruction and extending throughout one’s clinical practice.The authors also found that the level of instruction cohorts received as undergraduates did not seem to correspond to their current ability. Cohort 1, who received no information literacy instruction as undergraduates, scored higher on average than cohorts 3 and 4 on the self-assessment and higher than cohorts 3, 4, and 5 on the observer assessment. Cohort 1 also used more evidence based sources than did cohort 4, who received the most training on evidence-based medicine. Cohorts 1 and 2 reported the most postgraduate information literacy instruction, leading the authors to postulate that the further along one is in his medical career, the more important evidence based practice, and thus information literacy instruction, becomes. Even with additional instruction, however, the participants did not seem prepared for evidence-based practice. The authors concluded that information literacy instruction during postgraduate training and clinical practice—possibly giving the doctor’s specialty consideration when designing instruction—might be more important than undergraduate

  16. Assessing Believability

    DEFF Research Database (Denmark)

    Togelius, Julian; Yannakakis, Georgios N.; Karakovskiy, Sergey

    2012-01-01

    (or at least complementary) assessment might be made by an external observer that does not participate in the game, through comparing and ranking the performance of human and non-human agents playing a game. This assessment philosophy was embodied in the Turing Test Track of the recent Mario AI......We discuss what it means for a non-player character (NPC) to be believable or human-like, and how we can accurately assess believability. We argue that participatory observation, where the human assessing believability takes part in the game, is prone to distortion effects. For many games, a fairer...... Championship, where non-expert bystanders evaluated the human-likeness of several agents and humans playing a version of Super Mario Bros. We analyze the results of this competition. Finally, we discuss the possibilities for forming models of believability and of maximizing believability through adjusting game...

  17. Performance assessment

    International Nuclear Information System (INIS)

    Doe, T.

    1985-01-01

    The purpose of performance assessment is to show that the repository is expected to serve its stated function - disposing of radioactive waste safely both during operation and for the postclosure period. Performance assessment is a straightforward concept, but its application may be very complicated. The concept of performance assessment has been clarified by the Nuclear Regulatory Commission (NRC) in their Draft Generic Technical Position on Licensing Assessment Methodology for High-Level Waste Geologic Repositories (NRC, 1984). This document has gone a long way toward defining the criteria that the NRC will use to determine whether or not information from site characterization is adequate to meet the regulations of the Nuclear Regulatory Commission and the Environmental Protection Agency (EPA). A favorable determination is required for issuance of a construction authorization, which is the first major regulatory requirement for developing a working repository. It is, therefore, essential that a research program be developed that not only resolves the outstanding technical issues, but also does it in such a way that the results are clearly applicable to the formal performance assessment and licensing procedures. The definitions of performance assessment are reviewed and the current NRC thinking is summarized

  18. Combining Cytotoxicity Assessment and Xenopus laevis Phenotypic Abnormality Assay as a Predictor of Nanomaterial Safety.

    Science.gov (United States)

    Al-Yousuf, Karamallah; Webster, Carl A; Wheeler, Grant N; Bombelli, Francesca Baldelli; Sherwood, Victoria

    2017-08-04

    The African clawed frog, Xenopus laevis, has been used as an efficient pre-clinical screening tool to predict drug safety during the early stages of the drug discovery process. X. laevis is a relatively inexpensive model that can be used in whole organism high-throughput assays whilst maintaining a high degree of homology to the higher vertebrate models often used in scientific research. Despite an ever-increasing volume of biomedical nanoparticles (NPs) in development, their unique physico-chemical properties challenge the use of standard toxicology assays. Here, we present a protocol that directly compares the sensitivity of X. laevis development as a tool to assess potential NP toxicity by observation of embryo phenotypic abnormalities/lethality after NP exposure, to in vitro cytotoxicity obtained using mammalian cell lines. In combination with conventional cytotoxicity assays, the X. laevis phenotypic assay provides accurate data to efficiently assess the safety of novel biomedical NPs. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 by John Wiley & Sons, Inc.

  19. Texture analysis for the assessment of structural changes in parotid glands induced by radiotherapy

    International Nuclear Information System (INIS)

    Scalco, Elisa; Fiorino, Claudio; Cattaneo, Giovanni Mauro; Sanguineti, Giuseppe; Rizzo, Giovanna

    2013-01-01

    Background and purpose: During radiotherapy (RT) for head-and-neck cancer, parotid glands undergo significant anatomic, functional and structural changes which could characterize pre-clinical signs of an increased risk of xerostomia. Texture analysis is proposed to assess structural changes of parotids induced by RT, and to investigate whether early variations of textural parameters (such as mean intensity and fractal dimension) can predict parotid shrinkage at the end of treatment. Material and methods: Textural parameters and volumes of 42 parotids from 21 patients treated with intensity-modulated RT for nasopharyngeal cancer were extracted from CT images. To individuate which parameters changed during RT, a Wilcoxon signed-rank test between textural indices (first and second RT week; first and last RT week) was performed. Discriminant analysis was applied to variations of these parameters in the first two weeks of RT to assess their power in predicting parotid shrinkage at the end of RT. Results: A significant decrease in mean intensity (1.7 HU and 3.8 HU after the second and last weeks, respectively) and fractal dimension (0.016 and 0.021) was found. Discriminant analysis, based on volume and fractal dimension, was able to predict the final parotid shrinkage (accuracy of 71.4%). Conclusion: Textural features could be used in combination with volume to characterize structural modifications on parotid glands and to predict parotid shrinkage at the end of RT

  20. Sectoral assessments

    Energy Technology Data Exchange (ETDEWEB)

    Callaway, J M; Fenhann, J; Gorham, R; Makundi, W; Sathaye, J

    1999-09-01

    This publication contains five papers that were written as a part of the GEF project, The Economics of Greenhouse Gas Limitations. The main goal of the project was to assess the greenhouse gas reductions and incremental costs of mitigation option sin Ecuador, Argentina, Senegal, Mauritius, Vietnam, Indonesia, Estonia and Hungary. In addition, regional studies were conducted for the Andean Pact nations and Southern Africa to assess various aspects of regional co-operation in reducing greenhouse gas emissions. The GEF study also involved the development of a methodological framework for climate change assessment, with a special emphasis on developing countries. These guidelines have been published in a separate document, Economics of Greenhouse Gas Limitations: Methodological Guidelines. The papers in this publication focus on various methodological and policy aspects of greenhouse gas mitigation at the sectoral level, and are outgrowth of work performed on other parts of the GEF project. (au)

  1. Energy assessments

    International Nuclear Information System (INIS)

    Unruh, T.D.

    1998-01-01

    Energy industry initiatives during the 1970s and during the 1990s are compared. During the 1970s, the objective was to reduce energy consumption and to reduce dependency on foreign fuel. Today, the emphasis is on reducing energy costs and to improve net operating income. The challenges posed by the drive to reduce energy costs are discussed. As a tool in the drive to reduce energy cost, the energy assessment process was described. The process entails a detailed analysis of energy consumption, an investigation of energy rates and an assessment of site conditions and equipment, with a view towards an optimum combination that will lead to energy cost reductions

  2. Innovation Assessment

    DEFF Research Database (Denmark)

    Hasselbalch, Jacob

    2017-01-01

    Current regulatory approaches are ill-equipped to address the challenges of governing through periods of disruptive technological change. This article hones in on the use of assessment regimes at the level of the European Union, particularly in the work of the Commission, to argue for a missing...... I label innovation assessment, to steer polities through periods of disruptive technological change, during which innovations have taken concrete forms and are beginning to diffuse, but still exhibit much scope for rapid, unexpected change and alternative trajectories of development. By juxtaposing...

  3. Ambulatory Assessment.

    Science.gov (United States)

    Carpenter, Ryan W; Wycoff, Andrea M; Trull, Timothy J

    2016-08-01

    In recent years, significant technological advances have changed our understanding of dynamic processes in clinical psychology. A particularly important agent of change has been ambulatory assessment (AA). AA is the assessment of individuals in their daily lives, combining the twin benefits of increased ecological validity and minimized retrospective biases. These benefits make AA particularly well-suited to the assessment of dynamic processes, and recent advancements in technology are providing exciting new opportunities to understand these processes in new ways. In the current article, we briefly detail the capabilities currently offered by smartphones and mobile physiological devices, as well as some of the practical and ethical challenges of incorporating these new technologies into AA research. We then provide several examples of recent innovative applications of AA methodology in clinical research, assessment, and intervention and provide a case example of AA data generated from a study utilizing multiple mobile devices. In this way, we aim to provide a sense of direction for researchers planning AA studies of their own.

  4. Risk assessment

    International Nuclear Information System (INIS)

    Kinchin, G.H.

    1983-01-01

    After defining risk and introducing the concept of individual and societal risk, the author considers each of these, restricting considerations to risk of death. Some probabilities of death arising from various causes are quoted, and attention drawn to the care necessary in making comparisons between sets of data and to the distinction between voluntary and involuntary categories and between early and delayed deaths. The presentation of information on societal risk is discussed and examples given. The history of quantified risk assessment is outlined, particularly related to the nuclear industry, the process of assessing risk discussed: identification of hazard causes, the development of accident chains and the use of event trees, the evaluation of probability through the collection of data and their use with fault trees, and the assessment of consequences of hazards in terms of fatalities. Reference is made to the human element and common-made failures, and to studies supporting the development of reliability assessment techniques. Acceptance criteria are discussed for individual and societal risk in the nuclear field, and it is shown that proposed criteria lead to risks conservative by comparison with risks from day-to-day accidents and other potentially hazardous industries. (U.K.)

  5. Reference Assessment

    Science.gov (United States)

    Bivens-Tatum, Wayne

    2006-01-01

    This article presents interesting articles that explore several different areas of reference assessment, including practical case studies and theoretical articles that address a range of issues such as librarian behavior, patron satisfaction, virtual reference, or evaluation design. They include: (1) "Evaluating the Quality of a Chat Service"…

  6. Environmental Assessment

    OpenAIRE

    The Inspection Panel

    2017-01-01

    The Inspection Panel, the World Bank’s independent accountability mechanism, has released the third report in its Emerging Lessons Series. The latest report identifies lessons from Panel cases related to environmental assessment (EA) issues. The Panel is an impartial fact-finding body, independent from the World Bank management and staff, reporting directly to the Board. In response to com...

  7. Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

    Science.gov (United States)

    Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

    2016-11-01

    Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

  8. Risk Assessment

    OpenAIRE

    Hrdová, Edita

    2012-01-01

    This diploma thesis is focused on companies risk evaluation before endorsement of Loan deriving from business relationships. The aim of this thesis is not only to describe individual steps of risk assessment, but also perfom analysis of particular companies based on available data, i.e. Balance sheet, Profit and Loss statement and external rating and after that propose solution for each company. My analysis will be based on theoretical knowledge, further on experience related to my job role a...

  9. Risk assessment

    DEFF Research Database (Denmark)

    Pedersen, Liselotte; Rasmussen, Kirsten; Elsass, Peter

    2010-01-01

    International research suggests that using formalized risk assessment methods may improve the predictive validity of professionals' predictions of risk of future violence. This study presents data on forensic psychiatric patients discharged from a forensic unit in Denmark in year 2001-2002 (n=107...... and the individual dynamic items strengthen the use of this scheme in clinical practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved) (journal abstract)...

  10. EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer

    NARCIS (Netherlands)

    Van Driel, Pieter B A A; Boonstra, Martin C.; Slooter, Maxime D.; Heukers, Raimond; Stammes, Marieke A.; Snoeks, Thomas J A; De Bruijn, Henriette S.; Van Diest, Paul J.; Vahrmeijer, Alexander L.; Van Bergen En Henegouwen, Paul M P; Van De Velde, Cornelis J H; Löwik, Clemens W G M; Robinson, Dominic J.; Oliveira, Sabrina

    2016-01-01

    Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has

  11. Glucose Metabolism as a Pre-clinical Biomarker for the Golden Retriever Model of Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Schneider, Sarah Morar; Sridhar, Vidya; Bettis, Amanda K; Heath-Barnett, Heather; Balog-Alvarez, Cynthia J; Guo, Lee-Jae; Johnson, Rachel; Jaques, Scott; Vitha, Stanislav; Glowcwski, Alan C; Kornegay, Joe N; Nghiem, Peter P

    2018-03-05

    Metabolic dysfunction in Duchenne muscular dystrophy (DMD) is characterized by reduced glycolytic and oxidative enzymes, decreased and abnormal mitochondria, decreased ATP, and increased oxidative stress. We analyzed glucose metabolism as a potential disease biomarker in the genetically homologous golden retriever muscular dystrophy (GRMD) dog with molecular, biochemical, and in vivo imaging. Pelvic limb skeletal muscle and left ventricle tissue from the heart were analyzed by mRNA profiling, qPCR, western blotting, and immunofluorescence microscopy for the primary glucose transporter (GLUT4). Physiologic glucose handling was measured by fasting glucose tolerance test (GTT), insulin levels, and skeletal and cardiac positron emission tomography/X-ray computed tomography (PET/CT) using the glucose analog 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG). MRNA profiles showed decreased GLUT4 in the cranial sartorius (CS), vastus lateralis (VL), and long digital extensor (LDE) of GRMD vs. normal dogs. QPCR confirmed GLUT4 downregulation but increased hexokinase-1. GLUT4 protein levels were not different in the CS, VL, or left ventricle but increased in the LDE of GRMD vs. normal. Microscopy revealed diffuse membrane expression of GLUT4 in GRMD skeletal but not cardiac muscle. GTT showed higher basal glucose and insulin in GRMD but rapid tissue glucose uptake at 5 min post-dextrose injection in GRMD vs. normal/carrier dogs. PET/ CT with [ 18 F]FDG and simultaneous insulin stimulation showed a significant increase (p = 0.03) in mean standard uptake values (SUV) in GRMD skeletal muscle but not pelvic fat at 5 min post-[ 18 F]FDG /insulin injection. Conversely, mean cardiac SUV was lower in GRMD than carrier/normal (p < 0.01). Altered glucose metabolism in skeletal and cardiac muscle of GRMD dogs can be monitored with molecular, biochemical, and in vivo imaging studies and potentially utilized as a biomarker for disease progression and therapeutic response.

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

    Science.gov (United States)

    2015-04-01

    results in less robust conditioned fear and post- extinction fear cue responses in adult rats. Pharmacol Biochem Behav. 120:17-24.  The Pre-pubertal...LT, Berthelsen H. (2000) The effect of environmental enrichment on the behaviour of caged rabbits (Oryctolagus cuniculus). Appl Anim Behav Sci. 68(2...the Beta 2 adrenergic receptor, Beta Arrestin-1 and p53 with Mdm2 in the ventral hippocampus one month after underwater trauma. Behavioural Brain

  13. 78 FR 21131 - Prospective Grant of An Exclusive Evaluation Option License: Pre-clinical Evaluation of Anti...

    Science.gov (United States)

    2013-04-09

    ... technology family, to SPEED BioSystems, LLC. The patent rights in these inventions have been assigned to the... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Prospective Grant of An... Immunotoxins for the Treatment of Human Cancers AGENCY: National Institutes of Health, HHS. ACTION: Notice...

  14. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

    DEFF Research Database (Denmark)

    Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

    2016-01-01

    Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

  15. Characterization of a high resolution and high sensitivity pre-clinical PET scanner with 3D event reconstruction

    CERN Document Server

    Rissi, M; Bolle, E; Dorholt, O; Hines, K E; Rohne, O; Skretting, A; Stapnes, S; Volgyes, D

    2012-01-01

    COMPET is a preclinical PET scanner aiming towards a high sensitivity, a high resolution and MRI compatibility by implementing a novel detector geometry. In this approach, long scintillating LYSO crystals are used to absorb the gamma-rays. To determine the point of interaction (P01) between gamma-ray and crystal, the light exiting the crystals on one of the long sides is collected with wavelength shifters (WLS) perpendicularly arranged to the crystals. This concept has two main advantages: (1) The parallax error is reduced to a minimum and is equal for the whole field of view (FOV). (2) The P01 and its energy deposit is known in all three dimension with a high resolution, allowing for the reconstruction of Compton scattered gamma-rays. Point (1) leads to a uniform point source resolution (PSR) distribution over the whole FOV, and also allows to place the detector close to the object being imaged. Both points (1) and (2) lead to an increased sensitivity and allow for both high resolution and sensitivity at the...

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

    Science.gov (United States)

    2014-04-01

    month later rats were re-exposed to the context of the WAZM while their behavior was video recorded. Furthermore, c-Fos expression in the amygdala...Alexa Fluor 555 donkey α rabbit 1:1000 + Alexa Fluor 488 donkey α mouse 1:1000; both Invitrogen, Carlsbad, CA, USA) in 3% BSA + 0.3% TritonX + PBS for

  17. SU-G-TeP3-08: Pre-Clinical Radionuclide Therapy Dosimetry in Several Pediatric Cancer Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, I; Otto, M; Weichert, J; Baiu, D; Bednarz, B [University of Wisconsin, Madison, WI (United States)

    2016-06-15

    Purpose: The focus of this work is to perform Monte Carlo-based dosimetry for several pediatric cancer xenografts in mice treated with a novel radiopharmaceutical {sup 131}I-CLR1404. Methods: Four mice for each tumor cell line were injected with 8–13 µCi/g of the {sup 124}124I-CLR1404. PET/CT images of each individual mouse were acquired at 5–6 time points over the span of 96–170 hours post-injection. Following acquisition, the images were co-registered, resampled, rescaled, corrected for partial volume effects (PVE), and masked. For this work the pre-treatment PET images of {sup 124}I-CLR1404 were used to predict therapeutic doses from {sup 131}I-CLR1404 at each time point by assuming the same injection activity and accounting for the difference in physical decay rates. Tumors and normal tissues were manually contoured using anatomical and functional images. The CT and the PET images were used in the Geant4 (v9.6) Monte Carlo simulation to define the geometry and source distribution, respectively. The total cumulated absorbed dose was calculated by numerically integrating the dose-rate at each time point over all time on a voxel-by-voxel basis. Results: Spatial distributions of the absorbed dose rates and dose volume histograms as well as mean, minimum, maximum, and total dose values for each ROI were generated for each time point. Conclusion: This work demonstrates how mouse-specific MC-based dosimetry could potentially provide more accurate characterization of efficacy of novel radiopharmaceuticals in radionuclide therapy. This work is partially funded by NIH grant CA198392.

  18. Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Pinniger, Gavin J; Terrill, Jessica R; Assan, Evanna B; Grounds, Miranda D; Arthur, Peter G

    2017-12-01

    Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a therapeutic intervention for DMD boys, but potential adverse effects of NAC have not been widely investigated. We used young (6 weeks old) growing mdx mice to investigate the capacity of NAC supplementation (2% in drinking water for 6 weeks) to improve dystrophic muscle function and to explore broader systemic effects of NAC treatment. NAC treatment improved normalised measures of muscle function, and decreased inflammation and oxidative stress, but significantly reduced body weight gain, muscle weight and liver weight. Unexpected significant adverse effects of NAC on body and muscle weights indicate that interpretation of muscle function based on normalised force measures should be made with caution and careful consideration is needed when proposing the use of NAC as a therapeutic treatment for young DMD boys. Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease characterised by severe muscle weakness, necrosis, inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a potential therapeutic intervention for DMD boys. We investigated the capacity of NAC to improve dystrophic muscle function in the mdx mouse model of DMD. Young (6 weeks old) mdx and non-dystrophic C57 mice receiving 2% NAC in drinking water for 6 weeks were compared with untreated mice. Grip strength and body weight were measured weekly, before the 12 week old mice were anaesthetised and extensor digitorum longus (EDL) muscles were excised for functional analysis and tissues were sampled for biochemical analyses. Compared to untreated mice, the mean (SD) normalised grip strength was significantly greater in NAC-treated mdx [3.13 (0.58) vs 4.87 (0.78) g body weight (bw) -1 ; P muscles [9.80 (2.27) vs 13.07 (3.37) N cm -2 ; P = 0.038]. Increased force in mdx mice was associated with reduced thiol oxidation and inflammation in fast muscles, and increased citrate synthase activity in slow muscle. Importantly, NAC significantly impaired body weight gain in both strains of young growing mice, and reduced liver weight in C57 mice and muscle weight in mdx mice. These potentially adverse effects of NAC emphasise the need for caution when interpreting improvements in muscle function based on normalised force measures, and that careful consideration be given to these effects when proposing NAC as a potential treatment for young DMD boys. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  19. SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Hendrikx, Geert [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Voeoe, Stefan [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Bauwens, Matthias [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht (Netherlands); Post, Mark J. [Maastricht University, Department of Physiology, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); University Hospital, RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

    2016-12-15

    The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging. (orig.)

  20. Pre-clinical evaluation of AAV5-miHTT gene therapy of Huntington´s disease

    Czech Academy of Sciences Publication Activity Database

    Konstantinová, P.; Miniarikova, J.; Blits, B.; Zimmer, V.; Spoerl, A.; Southwell, A.; Hayden, M.; van Deventer, S.; Deglon, N.; Motlík, Jan; Juhás, Štefan; Juhásová, Jana; Richard, Ch.; Petry, H.

    2015-01-01

    Roč. 78, Supl 2 (2015), s. 8-8 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : Huntington ´s disease * gene therapy * AAV5-miHTT Subject RIV: EB - Genetics ; Molecular Biology

  1. Atorvastatin improves cardiac function and remodeling in chronic non-ischemic heart failure: A clinical and pre-clinical study

    Directory of Open Access Journals (Sweden)

    Ibrahim Elmadbouh

    2015-12-01

    Conclusions: Atorvastatin with standard CHF therapy improved cardiac function and remodeling. Cardio-protective “pleiotropic” actions of atorvastatin are anti-inflammatory, anti-fibrotic and anti-oxidative. Thus, atorvastatin has a potential therapeutic value in the management of CHF patients.

  2. Dietary and Lifestyle Factors Associated with Dyspepsia among Pre-clinical Medical Students in Ajman, United Arab Emirates

    Directory of Open Access Journals (Sweden)

    Noorallah Jaber

    2016-08-01

    Conclusion: Dyspepsia was reported by 43.8% of the repondents. These findings emphasize the importance of improving lifestyle and dietary factors associated with dyspepsia and raising awareness of reducing risk factors associated with dyspepsia. Further studies are needed on dyspepsia in a larger cohort of students in order to fully understand the complexity of this problem and be able to generalize the findings to other cohorts.

  3. Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin.

    Science.gov (United States)

    Alexander, Jeff; Ward, Simone; Mendy, Jason; Manayani, Darly J; Farness, Peggy; Avanzini, Jenny B; Guenther, Ben; Garduno, Fermin; Jow, Lily; Snarsky, Victoria; Ishioka, Glenn; Dong, Xin; Vang, Lo; Newman, Mark J; Mayall, Tim

    2012-01-01

    Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.

  4. Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin.

    Directory of Open Access Journals (Sweden)

    Jeff Alexander

    Full Text Available Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4 vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn. Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis.The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus.Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.

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

    Science.gov (United States)

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

    2014-01-01

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

  6. Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.

    Science.gov (United States)

    Abbattista, Maria R; Jamieson, Stephen M F; Gu, Yongchuan; Nickel, Jennifer E; Pullen, Susan M; Patterson, Adam V; Wilson, William R; Guise, Christopher P

    2015-01-01

    PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.

  7. A microfluidic chip platform with electrochemical carbon nanotube electrodes for pre-clinical evaluation of antibiotics nanocapsules.

    Science.gov (United States)

    Hong, Chien-Chong; Wang, Chih-Ying; Peng, Kuo-Ti; Chu, I-Ming

    2011-04-15

    This paper presents a microfluidic chip platform with electrochemical carbon nanotube electrodes for preclinical evaluation of antibiotics nanocapsules. Currently, there has been an increasing interest in the development of nanocapsules for drug delivery applications for localized treatments of diseases. So far, the methods to detect antibiotics are liquid chromatography (LC), high performance liquid chromatography (HPLC), mass spectroscopy (MS). These conventional instruments are bulky, expensive, not ease of access, and talented operator required. In order to help the development of nanocapsules and understand drug release profile before planning the clinical experiments, it is important to set up a biosensing platform which could monitor and evaluate the real-time drug release profile of nanocapsules with high sensitivity and long-term measurement ability. In this work, a microfluidic chip platform with electrochemical carbon nanotube electrodes has been developed and characterized for rapid detection of antibiotics teicoplanin nanocapsules. Multi-walled carbon nanotubes are used to modify the gold electrode surfaces to enhance the performance of the electrochemical biosensors. Experimental results show that the limit of detection of the developed platform using carbon nanotubes electrodes is 0.1 μg/ml with a linear range from 1 μg/ml to 10 μg/ml. The sensitivity of the developed system is 0.023 mA ml/μg at 37°C. The drug release profile of teicoplanin nanocapsules in PBS shows that the antibiotics nanocapsules significantly increased the release of drug on the 4th day, measuring 0.4858 μg/(ml hr). The release of drug from the antibiotics nanocapsules reached 34.98 μg/ml on the 7th day. The results showed a similar trend compared with the measurement result using the HPLC instrument. Compared with the traditional HPLC measurements, the electrochemical sensing platform we developed measures results with increased flexibility in controlling experimental factors for long-term preclinical measurement of nanocapsules in real time and at low cost. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state

    Directory of Open Access Journals (Sweden)

    Staii Anca

    2010-12-01

    Full Text Available Abstract Background Our Thyroid-Multidisciplinary Clinic is a large referral site for thyroid diseases. Thyroid biopsies are mainly performed for thyroid cancer screening. Yet, Hashimoto thyroiditis (HT is being too frequently diagnosed. The prevalence of HT is reported as 0.3-1.2% or twice the prevalence of type 1 diabetes. However, the prevalence of HT confirmed by cytology is still uncertain. To evaluate different aspects of thyroid physiopathology including prevalence of Hashimoto's, a database of clinical features, ultrasound images and cytology results of patients referred for FNA of thyroid nodules was prospectively developed. Methods We retrospectively studied 811 consecutive patients for whom ultrasound guided thyroid FNA biopsies were performed at our clinic over 2.5 year period (Mar/2006-Sep/2008. Results The analysis of our database revealed that from 761 patients, 102 (13.4% had HT, from whom 56 (7.4% were euthyroid or had sub-clinical (non-hypothyroid disease, and 46 (6% were clinically hypothyroid. Conclusions This is the first study to show such a high prevalence of HT diagnosed by ultrasound-guided FNA. More strikingly, the prevalence of euthyroid HT, appears to be >5% similar to that of type 2 diabetes. Based on our results, there might be a need to follow up on cytological Hashimoto's to monitor for thyroid failure, especially in high risk states, like pregnancy. The potential risk for thyroid cancer in patients with biopsy-proven inflammation of thyroid epithelium remains to be established prospectively. However, it may explain the increased risk for thyroid cancer observed in patients with elevated but within normal TSH.

  9. Pre-clinical and Clinical Development of Low Dose Methamphetamine for the Treatment of Traumatic Brain Injury

    Science.gov (United States)

    2014-12-01

    Aim 3: Secure FDA approval of a phase I/II clinical trial plan and obtain an amended IND in preparation for initiating human clinical testing in TBI...Neurology 6:193–201. Raineri M, Gonzalez B, Goitia B, Garcia-Rill E, Krasnova IN, Cadet JL, Urbano FJ, Bisagno V. 2012. Modafinil abrogates

  10. TNF-related apoptosis-inducing ligand (TRAIL) for bone sarcoma treatment: Pre-clinical and clinical data.

    Science.gov (United States)

    Gamie, Zakareya; Kapriniotis, Konstantinos; Papanikolaou, Dimitra; Haagensen, Emma; Da Conceicao Ribeiro, Ricardo; Dalgarno, Kenneth; Krippner-Heidenreich, Anja; Gerrand, Craig; Tsiridis, Eleftherios; Rankin, Kenneth Samora

    2017-11-28

    Bone sarcomas are rare, highly malignant mesenchymal tumours that affect teenagers and young adults, as well as older patients. Despite intensive, multimodal therapy, patients with bone sarcomas have poor 5-year survival, close to 50%, with lack of improvement over recent decades. TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumour necrosis factor (TNF) ligand superfamily (TNFLSF), has been found to induce apoptosis in cancer cells while sparing nontransformed cells, and may therefore offer a promising new approach to treatment. We cover the existing preclinical and clinical evidence about the use of TRAIL and other death receptor agonists in bone sarcoma treatment. In vitro studies indicate that TRAIL and other death receptor agonists are generally potent against bone sarcoma cell lines. Ewing's sarcoma cell lines present the highest sensitivity, whereas osteosarcoma and chondrosarcoma cell lines are considered less sensitive. In vivo studies also demonstrate satisfactory results, especially in Ewing's sarcoma xenograft models. However, the few clinical trials in the literature show only low or moderate efficacy of TRAIL in treating bone sarcoma. Potential strategies to overcome the in vivo resistance reported include co-administration with other drugs and the potential to deliver TRAIL on the surface of primed mesenchymal or immune cells and the use of targeted single chain antibodies such as scFv-scTRAIL. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Determination of esculentoside A in dog plasma by LC-MS/MS method: application to pre-clinical pharmacokinetics.

    Science.gov (United States)

    Guan, Xiaoduo; Chang, Huichao; Sun, Fanlu; Chen, Xiaohui; Zhang, Wen; Fan, Guorong

    2013-01-01

    A simple and rapid high performance liquid chromatography electrospray ionization ion-trap tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantitative determination of esculentoside A (EsA) in dog plasma using ginsenoside Rg1 as the internal standard (IS). After liquid-liquid extraction (LLE) with n-butanol, the analyte and IS were separated on a Diamonsil C(18) (2.1 mm × 50 mm, 3 μm) column with the mobile phase of methanol-water containing 0.1% acetic acid (70:30, v/v) at a flow rate of 0.2 ml/min. An ion trap mass spectrometer equipped with an electrospray ionization source performed in selected reaction monitoring (SRM) mode was used as the detector. The precursor-product ion transitions were m/z 849.3 [M+Na](+)→m/z 805.3 for EsA and m/z 823.3 [M+Na](+)→m/z 643.3 for IS. The total chromatographic run time was 5 min. The method was sensitive enough with a lower limit of quantitation (LLOQ) of 5 ng/ml and had a good linearity (r(2)>0.997) over the linear range of 5-500 ng/ml. The mean extraction recovery of EsA from spiked plasma samples was over 75%. The intra- and inter-precisions were no more than 8.8% and accuracies were within the range of -4.6 to 8.7%. All the validated data were within the accepted criteria as stated in the FDA bioanalytical method validation guideline. The developed method was suitable for the quantification of EsA and successfully applied to the pharmacokinetic study of EsA after an oral administration to beagle dogs. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. A novel pre-clinical murine model to study the life cycle and progression of cervical and anal papillomavirus infections.

    Directory of Open Access Journals (Sweden)

    Nancy M Cladel

    Full Text Available Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice.The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and "Doctor's BrushPicks" and MmuPV1 was delivered into the vaginal tract or the anal canal.Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals.Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system.

  13. Pre-clinical evaluation of the mechanical properties of a low-stiffness cement-injectable hip stem.

    Science.gov (United States)

    Eldesouky, Ibrahim; Harrysson, Ola; Marcellin-Little, Denis J; West, Harvey; El-Hofy, Hassan

    2017-11-01

    In total hip arthroplasty (THA), the femoral stem can be fixed with or without bone cement. Cementless stem fixation is recommended for young and active patients as it eliminates the risk of loss of fixation at the bone-cement and cement-implant interfaces. Cementless fixation, however, suffers from a relatively high early revision rate. In the current research, a novel low-stiffness hip stem was designed, fabricated and tested. The stem design provided the option to inject biodegradable bone cement that could enhance initial stem stability. The stem was made of Ti6Al4V alloy. The proximal portion of the stem was porous, with cubic cells. The stem was fabricated using electron beam melting (EBM) technology and tested in compression and bending. Finite-element analysis was used to evaluate stem performance under a dynamic load representing a stair descending cycle and compare it to the performance of a solid stem with similar geometry. The von Mises stresses and maximum principal strains generated within the bone increased after porous stem insertion compared to solid stem insertion. The low-modulus stem tested in this study has acceptable mechanical properties and generates strain patterns in bone that appear compatible with clinical use.

  14. Pre-clinical evaluation of a nanoparticle-based blood-pool contrast agent for MR imaging of the placenta.

    Science.gov (United States)

    Ghaghada, Ketan B; Starosolski, Zbigniew A; Bhayana, Saakshi; Stupin, Igor; Patel, Chandreshkumar V; Bhavane, Rohan C; Gao, Haijun; Bednov, Andrey; Yallampalli, Chandrasekhar; Belfort, Michael; George, Verghese; Annapragada, Ananth V

    2017-09-01

    Non-invasive 3D imaging that enables clear visualization of placental margins is of interest in the accurate diagnosis of placental pathologies. This study investigated if contrast-enhanced MRI performed using a liposomal gadolinium blood-pool contrast agent (liposomal-Gd) enables clear visualization of the placental margins and the placental-myometrial interface (retroplacental space). Non-contrast MRI and contrast-enhanced MRI using a clinically approved conventional contrast agent were used as comparators. Studies were performed in pregnant rats under an approved protocol. MRI was performed at 1T using a permanent magnet small animal scanner. Pre-contrast and post-liposomal-Gd contrast images were acquired using T1-weighted and T2-weighted sequences. Dynamic Contrast enhanced MRI (DCE-MRI) was performed using gadoterate meglumine (Gd-DOTA, Dotarem ® ). Visualization of the retroplacental clear space, a marker of normal placentation, was judged by a trained radiologist. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated for both single and averaged acquisitions. Images were reviewed by a radiologist and scored for the visualization of placental features. Contrast-enhanced CT (CE-CT) imaging using a liposomal CT agent was performed for confirmation of the MR findings. Transplacental transport of liposomal-Gd was evaluated by post-mortem elemental analysis of tissues. Ex-vivo studies in perfused human placentae from normal, GDM, and IUGR pregnancies evaluated the transport of liposomal agent across the human placental barrier. Post-contrast T1w images acquired with liposomal-Gd demonstrated significantly higher SNR (p = 0.0002) in the placenta compared to pre-contrast images (28.0 ± 4.7 vs. 6.9 ± 1.8). No significant differences (p = 0.39) were noted between SNR in pre-contrast and post-contrast liposomal-Gd images of the amniotic fluid, indicating absence of transplacental passage of the agent. The placental margins were significantly (p contrast liposomal-Gd images. DCE-MRI with the conventional Gd agent demonstrated retrograde opacification of the placenta from fetal edge to the myometrium, consistent with the anatomy of the rat placenta. However, no consistent and reproducible visualization of the retroplacental space was demonstrated on the conventional Gd-enhanced images. The retroplacental space was only visualized on post-contrast T1w images acquired using the liposomal agent (SNR = 15.5 ± 3.4) as a sharply defined, hypo-enhanced interface. The retroplacental space was also visible as a similar hypo-enhancing interface on CE-CT images acquired using a liposomal CT contrast agent. Tissue analysis demonstrated undetectably low transplacental permeation of liposomal-Gd, and was confirmed by lack of permeation through a perfused human placental model. Contrast-enhanced T1w-MRI performed using liposomal-Gd enabled clear visualization of placental margins and delineation of the retroplacental space from the rest of the placenta; the space is undetectable on non-contrast imaging and on post-contrast T1w images acquired using a conventional, clinically approved Gd chelate contrast agent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. High Resolution Spatio Temporal Moments Analysis of Solute Migration Captured using Pre-clinical Medical Imaging Techniques

    Science.gov (United States)

    Dogan, M.; Moysey, S. M.; Powell, B. A.; DeVol, T. A.

    2016-12-01

    Advances in medical imaging technologies are continuously expanding the range of applications enabled within the earth sciences. While computed x-ray tomography (CT) scans have traditionally been used for investigating the structure of geologic materials, it is now possible to perform 3D time-lapse imaging of dynamic processes, such as monitoring the infiltration of water into a soil, with sub-millimeter resolution. Likewise, single photon emission computed tomography (SPECT) can provide information on the evolution of solute transport with spatial resolution on the order of a millimeter by tracking the migration of gamma-ray emitting isotopes like 99mTc and 111In. While these imaging techniques are revolutionizing our ability to look within porous media, techniques for the analysis of such rich and large data sets are limited. The spatial and temporal moments of a plume have long been used to provide quantitative measures to describe plume movement in a wide range of settings from the lab to field. Moment analysis can also be used to estimate the hydrologic properties of the porous media. In this research, we investigate the use of moments for analyzing a high resolution 4D SPECT data set collected during a 99mTc transport experiment performed in a heterogeneous column. The 4D nature of the data set makes it amenable to the use of data mining and pattern recognition methods, such as cluster analysis, to identify regions or zones within the data that exhibit abnormal or unexpected behaviors. We then compare anomalous features within the SPECT data to similar features identified within the CT image to relate the flow behavior to pore-scale structures, such as porosity differences and macropores. Such comparisons help to identify whether these features are good predictors of preferential transport. Likewise, we evaluate whether local analysis of moments can be used to infer apparent parameters governing non-conservative transport in a heterogeneous porous media, such as hydraulic conductivity, mass transfer coefficients, and geochemical reaction rates. Our work suggests that the combination of CT and SPECT imaging can provide useful insights into flow and transport processes that may contradict traditional assumptions regarding one-dimensional flow within a laboratory column.

  16. Prolonged mechanical ventilation alters the expression pattern of angio-neogenetic factors in a pre-clinical rat model.

    Directory of Open Access Journals (Sweden)

    Christian S Bruells

    Full Text Available OBJECTIVE: Mechanical ventilation (MV is a life saving intervention for patients with respiratory failure. Even after 6 hours of MV, diaphragm atrophy and dysfunction (collectively referred to as ventilator-induced diaphragmatic dysfunction, VIDD occurs in concert with a blunted blood flow and oxygen delivery. The regulation of hypoxia sensitive factors (i.e. hypoxia inducible factor 1α, 2α (HIF-1α,-2α, vascular endothelial growth factor (VEGF and angio-neogenetic factors (angiopoietin 1-3, Ang might contribute to reactive and compensatory alterations in diaphragm muscle. METHODS: Male Wistar rats (n = 8 were ventilated for 24 hours or directly sacrificed (n = 8, diaphragm and mixed gastrocnemius muscle tissue was removed. Quantitative real time PCR and western blot analyses were performed to detect changes in angio-neogenetic factors and inflammatory markers. Tissues were stained using Isolectin (IB 4 to determine capillarity and calculate the capillary/fiber ratio. RESULTS: MV resulted in up-regulation of Ang 2 and HIF-1α mRNA in both diaphragm and gastrocnemius, while VEGF mRNA was down-regulated in both tissues. HIF-2α mRNA was reduced in both tissues, while GLUT 4 mRNA was increased in gastrocnemius and reduced in diaphragm samples. Protein levels of VEGF, HIF-1α, -2α and 4 did not change significantly. Additionally, inflammatory cytokine mRNA (Interleukin (IL-6, IL-1β and TNF α were elevated in diaphragm tissue. CONCLUSION: The results demonstrate that 24 hrs of MV and the associated limb disuse induce an up-regulation of angio-neogenetic factors that are connected to HIF-1α. Changes in HIF-1α expression may be due to several interactions occurring during MV.

  17. Evaluation of several pre-clinical tools for identifying characteristics associated with limb bone fracture in thoroughbred racehorses

    OpenAIRE

    Corsten, Anthony Nicholas

    2016-01-01

    Catastrophic skeletal fractures in racehorses are devastating not only to the animals, owners and trainers, but also to the perception of the sport in the public eye. The majority of these fatal accidents are unlikely to be due to chance, but are rather an end result failure from stress fractures. Stress fractures are overuse injuries resulting from an accumulation of bone tissue damage over time. Because stress fractures are pathological, it is possible that overt fractures can be predicted ...

  18. Development and Pre-Clinical Evaluation of a Novel Prostate-Restricted Replication Competent Adenovirus-AD-IU-1

    National Research Council Canada - National Science Library

    Gardner, Thomas A

    2006-01-01

    ... independent prostate cancers. The goal of this research is to develop a novel therapeutic agent, Ad-IU-1, using PSES to control the replication of adenovirus and the expression of a therapeutic gene, herpes simplex thymidine kinase (TK...

  19. Development and Pre-Clinical Evaluation of a Novel Prostate-Restricted Replication Competent Adenovirus-AD-IU-1

    National Research Council Canada - National Science Library

    Gardner, Thomas

    2004-01-01

    ... independent prostate cancers. The goal of this research is to develop a novel therapeutic agent, Ad-lu-1, using PSES to control the replication of adenovirus and the expression of a therapeutic gene, herpes simplex thymidine kinase...

  20. Development and Pre-Clinical Evaluation of a Novel Prostate-Restricted Replication Competent Adenovirus-Ad-IU-1

    National Research Council Canada - National Science Library

    Gardner, Thomas A

    2005-01-01

    .... The goal of this research is to develop a novel therapeutic agent, Ad-IU-1, using PSES to control the replication of adenovirus and the expression of a therapeutic gene, herpes simplex thymidine kinase (TK...

  1. Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.

    Directory of Open Access Journals (Sweden)

    Douglas W McMillin

    Full Text Available Polo-like kinases (PLKs play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM. We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM and rapid (commitment to cell death <24 hrs in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.

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

    NARCIS (Netherlands)

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

    2012-01-01

    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

  3. Attitudes towards anorexia nervosa: volitional stigma differences in a sample of pre-clinical medicine and psychology students.

    Science.gov (United States)

    Bannatyne, Amy Jean; Stapleton, Peta Berenice

    2017-10-01

    Anorexia nervosa (AN) is a highly stigmatised condition, with treatment often involving multidisciplinary care. As such, understanding and comparing the attitudes of emerging mental health and medical professionals towards AN, within the content of sex-based differences, is pertinent to facilitate the development of targeted stigma interventions. Examine the volitional stigmatisation of AN in emerging medical and mental health professionals. Participants (N = 126) were medical (n = 41) and psychology students (n = 85) who completed a range of attitudinal outcome measures (e.g. Causal Attributions Scale, Eating Disorder Stigma Scale, Opinions Scale, Characteristics Scale and Affective Reaction Scale). Across both disciplines, men were found to exhibit significantly higher eating disorder (ED) stigma, considered AN to be a more trivial and weak illness, and attributed greater levels of blame and responsibility to AN sufferers. Men also had significantly lower biogenetic causal attributions. Compared with psychology students, medicine students exhibited slightly greater anticipation of negative reactions in response to AN, obtained higher selfish/vain scores and considered sociocultural factors to contribute "a lot" in the development and maintenance of AN. Overall, results indicate interventions aimed at improving ED mental health literacy are needed, specifically targeting males and potentially medical students.

  4. Hashimoto thyroiditis is more frequent than expected when diagnosed by cytology which uncovers a pre-clinical state

    Science.gov (United States)

    2010-01-01

    Background Our Thyroid-Multidisciplinary Clinic is a large referral site for thyroid diseases. Thyroid biopsies are mainly performed for thyroid cancer screening. Yet, Hashimoto thyroiditis (HT) is being too frequently diagnosed. The prevalence of HT is reported as 0.3-1.2% or twice the prevalence of type 1 diabetes. However, the prevalence of HT confirmed by cytology is still uncertain. To evaluate different aspects of thyroid physiopathology including prevalence of Hashimoto's, a database of clinical features, ultrasound images and cytology results of patients referred for FNA of thyroid nodules was prospectively developed. Methods We retrospectively studied 811 consecutive patients for whom ultrasound guided thyroid FNA biopsies were performed at our clinic over 2.5 year period (Mar/2006-Sep/2008). Results The analysis of our database revealed that from 761 patients, 102 (13.4%) had HT, from whom 56 (7.4%) were euthyroid or had sub-clinical (non-hypothyroid) disease, and 46 (6%) were clinically hypothyroid. Conclusions This is the first study to show such a high prevalence of HT diagnosed by ultrasound-guided FNA. More strikingly, the prevalence of euthyroid HT, appears to be >5% similar to that of type 2 diabetes. Based on our results, there might be a need to follow up on cytological Hashimoto's to monitor for thyroid failure, especially in high risk states, like pregnancy. The potential risk for thyroid cancer in patients with biopsy-proven inflammation of thyroid epithelium remains to be established prospectively. However, it may explain the increased risk for thyroid cancer observed in patients with elevated but within normal TSH. PMID:21172028

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

    Directory of Open Access Journals (Sweden)

    Mihajlo Jakovljević

    2012-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-06-15

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

  7. Assessment of variability in cerebral vasculature for neuro-anatomical surgery planning in rodent brain

    Science.gov (United States)

    Rangarajan, J. R.; Van Kuyck, K.; Himmelreich, U.; Nuttin, B.; Maes, F.; Suetens, P.

    2011-03-01

    Clinical and pre-clinical studies show that deep brain stimulation (DBS) of targeted brain regions by neurosurgical techniques ameliorate psychiatric disorder such as anorexia nervosa. Neurosurgical interventions in preclinical rodent brain are mostly accomplished manually with a 2D atlas. Considering both the large number of animals subjected to stereotactic surgical experiments and the associated imaging cost, feasibility of sophisticated pre-operative imaging based surgical path planning and/or robotic guidance is limited. Here, we spatially normalize vasculature information and assess the intra-strain variability in cerebral vasculature for a neurosurgery planning. By co-registering and subsequently building a probabilistic vasculature template in a standard space, we evaluate the risk of a user defined electrode trajectory damaging a blood vessel on its path. The use of such a method may not only be confined to DBS therapy in small animals, but also could be readily applicable to a wide range of stereotactic small animal surgeries like targeted injection of contrast agents and cell labeling applications.

  8. Technology assessments

    International Nuclear Information System (INIS)

    Rohwer, P.S.; Anderson, D.L.; Christian, D.J.

    1978-01-01

    Theoretical studies in assessment methodology have concentrated in the past year on computerization of state-of-the-art models for internal radiation dosimetry and development and evaluation of environmental transport models. Methodology applications continued to cover a broad spectrum of radiation exposure scenarios. Potential exposure situations requiring assessment arise from assorted deployments of all parts of nuclear fuel cycles, including comparisons of alternative uranium and thorium based cycles, and preliminary evaluations of advanced reactor fuel concepts. Measurements and samples were collected characterizing and documenting the current radiological status of formerly used Manhattan Engineer District/Atomic Energy Commission (MED/AEC) sites. This survey program encompasses research activities in the areas of survey design, instrumentation development, sample analysis, and data reduction and analysis. Other laboratory activities within TAS center around the unique capabilities of the Health Physics Research Reactor (HPRR) as an irradiation source. Typically the HPRR was involved in testing and intercomparison of dosimetry and criticality alarm systems and in exposure of physical and biological experiments

  9. Accounting assessment

    Directory of Open Access Journals (Sweden)

    Kafka S.М.

    2017-03-01

    Full Text Available The proper evaluation of accounting objects influences essentially upon the reliability of assessing the financial situation of a company. Thus, the problem in accounting estimate is quite relevant. The works of home and foreign scholars on the issues of assessment of accounting objects, regulatory and legal acts of Ukraine controlling the accounting and compiling financial reporting are a methodological basis for the research. The author uses the theoretical methods of cognition (abstraction and generalization, analysis and synthesis, induction and deduction and other methods producing conceptual knowledge for the synthesis of theoretical and methodological principles in the evaluation of assets accounting, liabilities and equity. The tabular presentation and information comparison methods are used for analytical researches. The article considers the modern approaches to the issue of evaluation of accounting objects and financial statements items. The expedience to keep records under historical value is proved and the articles of financial statements are to be presented according to the evaluation on the reporting date. In connection with the evaluation the depreciation of fixed assets is considered as a process of systematic return into circulation of the before advanced funds on the purchase (production, improvement of fixed assets and intangible assets by means of including the amount of wear in production costs. Therefore it is proposed to amortize only the actual costs incurred, i.e. not to depreciate the fixed assets received free of charge and surplus valuation of different kinds.

  10. Accident Assessment

    International Nuclear Information System (INIS)

    Tripputi, Ivo; Lund, Ingemar

    2002-01-01

    There is a general feeling that decommissioning is an activity involving limited risks, compared to NPP operation, and in particular risks involving the general public. This is technically confirmed by licensing analysis and evaluations, where, once the spent fuel has been removed from the plant, the radioactivity inventory available to be released to the environment is very limited. Decommissioning activities performed so far in the world have also confirmed the first assumptions and no specific issue has been identified, in this field, to justify a completely new approach. Commercial interests in international harmonization, which could drive an in-depth discussion about the bases of this approach, are weak at the moment. However, there are several reasons why a discussion in an international framework about the Safety Case for decommissioning (and, in particular, about Accident Assessment) may be considered necessary and important, and why it may show some specific and peculiar aspects. An effort for a comprehensive and systematic D and D accident safety assessment of the decommissioning process is justified. It is necessary also to explore in a holistic way the aspects of industrial safety, and develop tools for the decision-making process optimization. The expected results are the implementation of appropriate and optimized protective measures in any event and of adequate on/off-site emergency plans for optimal public and workers protection. The experience from other decommissioning projects and large-scale industrial activities is essential to balance provisions and an Operating Experience review process (specific for decommissioning) should help to focus on real issues

  11. Assessing Assessment Texts: Where Is Planning?

    Science.gov (United States)

    Fives, Helenrose; Barnes, Nicole; Dacey, Charity; Gillis, Anna

    2016-01-01

    We conducted a content analysis of 27 assessment textbooks to determine how assessment planning was framed in texts for preservice teachers. We identified eight assessment planning themes: alignment, assessment purpose and types, reliability and validity, writing goals and objectives, planning specific assessments, unpacking, overall assessment…

  12. Better Assessments Require Better Assessment Literacy

    Science.gov (United States)

    Stiggins, Rick

    2018-01-01

    Stiggins says that, to build better assessment systems, educators and education leaders need more opportunities to learn the basic principles of sound assessment practice. He lays out what he views as the fundamental elements of assessment literacy.

  13. Unicompartmental knee prostheses: in vitro wear assessment of the menisci tibial insert after two different fixation methods

    International Nuclear Information System (INIS)

    Affatato, S; Spinelli, M; Zavalloni, M; Viceconti, M; Carmignato, S; Lopomo, N; Marcacci, M

    2008-01-01

    Knee osteoarthritis is a complex clinical scenario where many biological and mechanical factors influence the severity of articular degenerative changes. Minimally invasive knee prosthetic surgery, with only a compartment replacement (unicompartmental knee replacement), might be a good compromise between osteotomy and total knee prosthesis. The focus of this study was to develop and validate a protocol to assess the fixation method of the femoral components in mechanical simulation, for pre-clinical validation; the wear behaviour of two different fixation frames was quantified and compared. In particular, two different wear tests were conducted using the same knee simulator, the same load profiles and the same kinematics; two different fixation methods were applied to the femoral sleds (synthetic femur and metal block). Surface characterization on both articulating bearings was performed by a roughness measuring machine and coordinate measuring machine. The wear produced by the tibial inserts using the synthetic femur was considerably higher than the wear registered by the metal-block holder. Roughness measurements on femoral sleds showed a limited number of scratches with high R t values for the metal-block set-up; the damaged surface broadened in the case of femoral condyles and tibial inserts mounted on composite bone, but lower R t and linear penetration values were measured. The two holding frames showed different wear activities as a consequence of dissimilar dynamic performance. Further observations should be made in vivo to prove the actual importance of synthetic bone simulations and specific material behaviour

  14. Self-assessed learning style correlates to use of supplemental learning materials in an online course management system.

    Science.gov (United States)

    Halbert, Caitlin; Kriebel, Richard; Cuzzolino, Robert; Coughlin, Patrick; Fresa-Dillon, Kerin

    2011-01-01

    The benefit of online learning materials in medical education is not well defined. The study correlated certain self-identified learning styles with the use of self-selected online learning materials. First-year osteopathic medical students were given access to review and/or summary materials via an online course management system (CMS) while enrolled in a pre-clinical course. At the end of the course, students completed a self-assessment of learning style based on the Index of Learning Styles and a brief survey regarding their usage and perceived advantage of the online learning materials. Students who accessed the online materials earned equivalent grades to those who did not. However, the study found that students who described their learning styles as active, intuitive, global, and/or visual were more likely to use online educational resources than those who identified their learning style as reflective, sensing, sequential, and/or verbal. Identification of a student's learning style can help medical educators direct students to learning resources that best suit their individual needs.

  15. In vivo micro-CT assessment of airway remodeling in a flexible OVA-sensitized murine model of asthma.

    Directory of Open Access Journals (Sweden)

    Mathieu Lederlin

    Full Text Available Airway remodeling is a major pathological feature of asthma. Up to now, its quantification still requires invasive methods. In this study, we aimed at determining whether in vivo micro-computed tomography (micro-CT is able to demonstrate allergen-induced airway remodeling in a flexible mouse model of asthma. Sixty Balb/c mice were challenged intranasally with ovalbumin or saline at 3 different endpoints (Days 35, 75, and 110. All mice underwent plethysmography at baseline and just prior to respiratory-gated micro-CT. Mice were then sacrificed to assess bronchoalveolar lavage and lung histology. From micro-CT images (voxel size = 46×46×46 µm, the numerical values of total lung attenuation, peribronchial attenuation (PBA, and PBA normalized by total lung attenuation were extracted. Each parameter was compared between OVA and control mice and correlation coefficients were calculated between micro-CT and histological data. As compared to control animals, ovalbumin-sensitized mice exhibited inflammation alone (Day 35, remodeling alone (Day 110 or both inflammation and remodeling (Day 75. Normalized PBA was significantly greater in mice exhibiting bronchial remodeling either alone or in combination with inflammation. Normalized PBA correlated with various remodeling markers such as bronchial smooth muscle size or peribronchial fibrosis. These findings suggest that micro-CT may help monitor remodeling non-invasively in asthmatic mice when testing new drugs targeting airway remodeling in pre-clinical studies.

  16. Unicompartmental knee prostheses: in vitro wear assessment of the menisci tibial insert after two different fixation methods

    Energy Technology Data Exchange (ETDEWEB)

    Affatato, S; Spinelli, M; Zavalloni, M; Viceconti, M [Laboratorio di Tecnologia Medica, Istituti Ortopedici Rizzoli, Via di Barbiano, 1/10, 40136 Bologna (Italy); Carmignato, S [Laboratorio di Metrologia Geometrica e Industriale, Universita degli Studi di Padova, Padova (Italy); Lopomo, N; Marcacci, M [Laboratorio di Biomeccanica, Istituti Ortopedici Rizzoli, Bologna (Italy)], E-mail: affatato@tecno.ior.it

    2008-10-07

    Knee osteoarthritis is a complex clinical scenario where many biological and mechanical factors influence the severity of articular degenerative changes. Minimally invasive knee prosthetic surgery, with only a compartment replacement (unicompartmental knee replacement), might be a good compromise between osteotomy and total knee prosthesis. The focus of this study was to develop and validate a protocol to assess the fixation method of the femoral components in mechanical simulation, for pre-clinical validation; the wear behaviour of two different fixation frames was quantified and compared. In particular, two different wear tests were conducted using the same knee simulator, the same load profiles and the same kinematics; two different fixation methods were applied to the femoral sleds (synthetic femur and metal block). Surface characterization on both articulating bearings was performed by a roughness measuring machine and coordinate measuring machine. The wear produced by the tibial inserts using the synthetic femur was considerably higher than the wear registered by the metal-block holder. Roughness measurements on femoral sleds showed a limited number of scratches with high R{sub t} values for the metal-block set-up; the damaged surface broadened in the case of femoral condyles and tibial inserts mounted on composite bone, but lower R{sub t} and linear penetration values were measured. The two holding frames showed different wear activities as a consequence of dissimilar dynamic performance. Further observations should be made in vivo to prove the actual importance of synthetic bone simulations and specific material behaviour.

  17. Magnetic Particle Imaging for High Temporal Resolution Assessment of Aneurysm Hemodynamics.

    Directory of Open Access Journals (Sweden)

    Jan Sedlacik

    Full Text Available The purpose of this work was to demonstrate the capability of magnetic particle imaging (MPI to assess the hemodynamics in a realistic 3D aneurysm model obtained by additive manufacturing. MPI was compared with magnetic resonance imaging (MRI and dynamic digital subtraction angiography (DSA.The aneurysm model was of saccular morphology (7 mm dome height, 5 mm cross-section, 3-4 mm neck, 3.5 mm parent artery diameter and connected to a peristaltic pump delivering a physiological flow (250 mL/min and pulsation rate (70/min. High-resolution (4 h long 4D phase contrast flow quantification (4D pc-fq MRI was used to directly assess the hemodynamics of the model. Dynamic MPI, MRI, and DSA were performed with contrast agent injections (3 mL volume in 3 s through a proximally placed catheter.4D pc-fq measurements showed distinct pulsatile flow velocities (20-80 cm/s as well as lower flow velocities and a vortex inside the aneurysm. All three dynamic methods (MPI, MRI, and DSA also showed a clear pulsation pattern as well as delayed contrast agent dynamics within the aneurysm, which is most likely caused by the vortex within the aneurysm. Due to the high temporal resolution of MPI and DSA, it was possible to track the contrast agent bolus through the model and to estimate the average flow velocity (about 60 cm/s, which is in accordance with the 4D pc-fq measurements.The ionizing radiation free, 4D high resolution MPI method is a very promising tool for imaging and characterization of hemodynamics in human. It carries the possibility of overcoming certain disadvantages of other modalities like considerably lower temporal resolution of dynamic MRI and limited 2D characteristics of DSA. Furthermore, additive manufacturing is the key for translating powerful pre-clinical techniques into the clinic.

  18. Introduction to risk assessment

    International Nuclear Information System (INIS)

    Raina, V.M.

    2002-01-01

    This paper gives an introduction to risk assessment. It discusses the basic concepts of risk assessment, nuclear risk assessment process and products, the role of risk assessment products in nuclear safety assurance, the relationship between risk assessment and other safety analysis and risk assessment and safe operating envelope

  19. The conditioned place preference test for assessing welfare consequences and potential refinements in a mouse bladder cancer model.

    Directory of Open Access Journals (Sweden)

    John V Roughan

    Full Text Available Most pre-clinical analgesic efficacy assays still involve nociceptive testing in rodents. This is despite concerns as to the relevance of these tests for evaluating the pain-preventative properties of drugs. More appropriate methods would target pain rather than nociception, but these are currently not available, so it remains unknown whether animal pain equates to the negatively affective and subjective/emotional state it causes in humans. Mouse cancer models are common despite the likelihood of substantial pain. We used Conditioned Place Preference (CPP testing, assessments of thermal hyperalgesia and behaviour to determine the likelihood that MBT-2 bladder cancer impacts negatively on mouse welfare, such as by causing pain. There was no CPP to saline, but morphine preference in tumour bearing mice exceeded that seen in tumour-free controls. This occurred up to 10 days before the study end-point alongside reduced body weight, development of hyperalgesia and behaviour changes. These effects indicated mice experienced a negative welfare state caused by malaise (if not pain before euthanasia. Due to the complexity of the assessments needed to demonstrate this, it is unlikely that this approach could be used for routine welfare assessment on a study-by-study basis. However, our results show mice in sufficiently similar studies are likely to benefit from more intensive severity assessment and re-evaluation of end-points with a view to implementing appropriate refinements. In this particular case, a refinement would have been to have euthanased mice at least 7 days earlier or possibly by provision of end-stage pain relief. CPP testing was found to be a helpful method to investigate the responses of mice to analgesics, possibly on a subjective level. These findings and those of other recent studies show it could be a valuable method of screening candidate analgesics for efficacy against cancer pain and possibly other pain or disease models.

  20. A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 2): In vitro biological assessment and comparison with different tobacco-heating products.

    Science.gov (United States)

    Breheny, Damien; Adamson, Jason; Azzopardi, David; Baxter, Andrew; Bishop, Emma; Carr, Tony; Crooks, Ian; Hewitt, Katherine; Jaunky, Tomasz; Larard, Sophie; Lowe, Frazer; Oke, Oluwatobiloba; Taylor, Mark; Santopietro, Simone; Thorne, David; Zainuddin, Benjamin; Gaça, Marianna; Liu, Chuan; Murphy, James; Proctor, Christopher

    2017-08-01

    This study assessed the toxicological and biological responses of aerosols from a novel hybrid tobacco product. Toxicological responses from the hybrid tobacco product were compared to those from a commercially available Tobacco Heating Product (c-THP), a prototype THP (p-THP) and a 3R4F reference cigarette, using in vitro test methods which were outlined as part of a framework to substantiate the risk reduction potential of novel tobacco and nicotine products. Exposure matrices used included total particulate matter (TPM), whole aerosol (WA), and aqueous aerosol extracts (AqE) obtained after machine-puffing the test products under the Health Canada Intense smoking regime. Levels of carbonyls and nicotine in these matrices were measured to understand the aerosol dosimetry of the products. The hybrid tobacco product tested negative across the in vitro assays including mutagenicity, genotoxicity, cytotoxicity, tumour promotion, oxidative stress and endothelial dysfunction. All the THPs tested demonstrated significantly reduced responses in these in vitro assays when compared to 3R4F. The findings suggest these products have the potential for reduced health risks. Further pre-clinical and clinical assessments are required to substantiate the risk reduction of these novel products at individual and population levels. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

    Energy Technology Data Exchange (ETDEWEB)

    Kirby, R. Jason [Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 6400 Sanger Rd, Orlando, FL 32827 (United States); Qi, Feng [Sanford Burnham Prebys Medical Discovery Institute, Applied Bioinformatics Facility, 6400 Sanger Rd, Orlando, FL 32827 (United States); Phatak, Sharangdhar; Smith, Layton H. [Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 6400 Sanger Rd, Orlando, FL 32827 (United States); Malany, Siobhan, E-mail: smalany@sbpdiscovery.org [Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 6400 Sanger Rd, Orlando, FL 32827 (United States)

    2016-08-15

    Cardiac safety assays incorporating label-free detection of human stem-cell derived cardiomyocyte contractility provide human relevance and medium throughput screening to assess compound-induced cardiotoxicity. In an effort to provide quantitative analysis of the large kinetic datasets resulting from these real-time studies, we applied bioinformatic approaches based on nonlinear dynamical system analysis, including limit cycle analysis and autocorrelation function, to systematically assess beat irregularity. The algorithms were integrated into a software program to seamlessly generate results for 96-well impedance-based data. Our approach was validated by analyzing dose- and time-dependent changes in beat patterns induced by known proarrhythmic compounds and screening a cardiotoxicity library to rank order compounds based on their proarrhythmic potential. We demonstrate a strong correlation for dose-dependent beat irregularity monitored by electrical impedance and quantified by autocorrelation analysis to traditional manual patch clamp potency values for hERG blockers. In addition, our platform identifies non-hERG blockers known to cause clinical arrhythmia. Our method provides a novel suite of medium-throughput quantitative tools for assessing compound effects on cardiac contractility and predicting compounds with potential proarrhythmia and may be applied to in vitro paradigms for pre-clinical cardiac safety evaluation. - Highlights: • Impedance-based monitoring of human iPSC-derived cardiomyocyte contractility • Limit cycle analysis of impedance data identifies aberrant oscillation patterns. • Nonlinear autocorrelation function quantifies beat irregularity. • Identification of hERG and non-hERG inhibitors with known risk of arrhythmia • Automated software processes limit cycle and autocorrelation analyses of 96w data.

  2. Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

    International Nuclear Information System (INIS)

    Kirby, R. Jason; Qi, Feng; Phatak, Sharangdhar; Smith, Layton H.; Malany, Siobhan

    2016-01-01

    Cardiac safety assays incorporating label-free detection of human stem-cell derived cardiomyocyte contractility provide human relevance and medium throughput screening to assess compound-induced cardiotoxicity. In an effort to provide quantitative analysis of the large kinetic datasets resulting from these real-time studies, we applied bioinformatic approaches based on nonlinear dynamical system analysis, including limit cycle analysis and autocorrelation function, to systematically assess beat irregularity. The algorithms were integrated into a software program to seamlessly generate results for 96-well impedance-based data. Our approach was validated by analyzing dose- and time-dependent changes in beat patterns induced by known proarrhythmic compounds and screening a cardiotoxicity library to rank order compounds based on their proarrhythmic potential. We demonstrate a strong correlation for dose-dependent beat irregularity monitored by electrical impedance and quantified by autocorrelation analysis to traditional manual patch clamp potency values for hERG blockers. In addition, our platform identifies non-hERG blockers known to cause clinical arrhythmia. Our method provides a novel suite of medium-throughput quantitative tools for assessing compound effects on cardiac contractility and predicting compounds with potential proarrhythmia and may be applied to in vitro paradigms for pre-clinical cardiac safety evaluation. - Highlights: • Impedance-based monitoring of human iPSC-derived cardiomyocyte contractility • Limit cycle analysis of impedance data identifies aberrant oscillation patterns. • Nonlinear autocorrelation function quantifies beat irregularity. • Identification of hERG and non-hERG inhibitors with known risk of arrhythmia • Automated software processes limit cycle and autocorrelation analyses of 96w data

  3. SIS - Fish Assessment

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Fish Assessment data set within the Species Information System (SIS) constraints information related to fishery stock assessments, including assessment meta-data...

  4. Patient Assessment File (PAF)

    Data.gov (United States)

    Department of Veterans Affairs — The Patient Assessment File (PAF) database compiles the results of the Patient Assessment Instrument (PAI) questionnaire filled out for intermediate care Veterans...

  5. Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

    Science.gov (United States)

    Merchant, Hamid A; McConnell, Emma L; Liu, Fang; Ramaswamy, Chandrasekaran; Kulkarni, Rucha P; Basit, Abdul W; Murdan, Sudaxshina

    2011-01-18

    Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pigpig). The lymphoid tissue distribution (lymphoid follicles, Peyer's patches and long strips) along the length of the gut in these animals is presented; in particular, an abundance of lymphoid tissue was found in pig's stomach, small intestine and caecum, and rabbit's appendix. Their ample presence indicated the potential utility of these animal species in oral and colonic vaccination. These differences in the gastrointestinal parameters of the guinea pig, rabbit and pig reiterates the crucial importance of correctly selecting animal models for pre-clinical studies. Copyright © 2010 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    Jones, Anne; Sheppard, Lorraine

    2012-01-01

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

  7. Challenges in Risk Assessment: Quantitative Risk Assessment

    OpenAIRE

    Jacxsens, Liesbeth; Uyttendaele, Mieke; De Meulenaer, Bruno

    2016-01-01

    The process of risk analysis consists out of three components, risk assessment, risk management and risk communication. These components are internationally well spread by Codex Alimentarius Commission as being the basis for setting science based standards, criteria on food safety hazards, e.g. setting maximum limits of mycotoxins in foodstuffs. However, the technical component risk assessment is hard to elaborate and to understand. Key in a risk assessment is the translation of biological or...

  8. Energy and environmental assessment

    DEFF Research Database (Denmark)

    Lund, Henrik; Sukkumnoed, Decharut

    2004-01-01

    The paper introduce and discuss strategic environmental assessment (SEA) and economic assessment for energy innovation and suggests approach to influence support for sustainable energy development in Thailand.......The paper introduce and discuss strategic environmental assessment (SEA) and economic assessment for energy innovation and suggests approach to influence support for sustainable energy development in Thailand....

  9. Issues in Assessment: Implementation.

    Science.gov (United States)

    Malinowski, Patricia A., Ed.

    This collection of articles is the third in a series on assessment produced by Finger Lakes Community College (New York). It deals with classroom assessment as an ongoing process that can be of significant value to teachers as well as to students. Assessment at the college and assessment in the classroom in general are explored. Articles include:…

  10. Assessing Assessment: In Pursuit of Meaningful Learning

    Science.gov (United States)

    Rootman-le Grange, Ilse; Blackie, Margaret A. L.

    2018-01-01

    The challenge of supporting the development of meaningful learning is prevalent in chemistry education research. One of the core activities used in the learning process is assessments. The aim of this paper is to illustrate how the semantics dimension of Legitimation Code Theory can be a helpful tool to critique the quality of assessments and…

  11. An assessment of health-care students’ attitudes toward patients with or at high risk for HIV: implications for education and cultural competency

    Science.gov (United States)

    Jin, Harry; Earnshaw, Valerie A.; Wickersham, Jeffrey A.; Kamarulzaman, Adeeba; Desai, Mayur M.; John, Jacob; Altice, Frederick L.

    2014-01-01

    Stigma perpetuated by health-care providers has been found to be a barrier to care for vulnerable populations, including HIV-infected, people who inject drugs (PWIDs), and men who have sex with men (MSM) in multiple clinical contexts and remains unexamined among professional health-care students in Malaysia. This cross-sectional, anonymous, and Internet-based survey assessed the attitudes of medical and dental students toward HIV-infected, PWID, and MSM patients. Survey invitation was emailed to 3191 students at 8 professional schools; 1296 (40.6%) responded and scored their attitudes toward these patient groups using a feeling thermometer, indicating their attitudes on a sliding scale from 0 (most negative) to 100 (most positive). Compared to general patients (mean = 76.50), the mean scores for HIV-infected (mean = 54.04; p religion, ethnicity, and personally knowing someone from these populations were associated with significant differences in attitudes. No differences were noted between pre-clinical and clinical year of training. Health-care students represent the next generation of clinicians who will be responsible for future HIV prevention and treatment efforts. Our findings suggest alarmingly negative attitudes toward these patients, especially MSM, necessitating prompt and effective interventions designed to ameliorate the negative attitudes of health-care students toward vulnerable populations, specifically HIV-infected, PWID, and MSM patients in Malaysia. PMID:24625279

  12. An assessment of health-care students' attitudes toward patients with or at high risk for HIV: implications for education and cultural competency.

    Science.gov (United States)

    Jin, Harry; Earnshaw, Valerie A; Wickersham, Jeffrey A; Kamarulzaman, Adeeba; Desai, Mayur M; John, Jacob; Altice, Frederick L

    2014-01-01

    Stigma perpetuated by health-care providers has been found to be a barrier to care for vulnerable populations, including HIV-infected, people who inject drugs (PWIDs), and men who have sex with men (MSM) in multiple clinical contexts and remains unexamined among professional health-care students in Malaysia. This cross-sectional, anonymous, and Internet-based survey assessed the attitudes of medical and dental students toward HIV-infected, PWID, and MSM patients. Survey invitation was emailed to 3191 students at 8 professional schools; 1296 (40.6%) responded and scored their attitudes toward these patient groups using a feeling thermometer, indicating their attitudes on a sliding scale from 0 (most negative) to 100 (most positive). Compared to general patients (mean = 76.50), the mean scores for HIV-infected (mean = 54.04; p religion, ethnicity, and personally knowing someone from these populations were associated with significant differences in attitudes. No differences were noted between pre-clinical and clinical year of training. Health-care students represent the next generation of clinicians who will be responsible for future HIV prevention and treatment efforts. Our findings suggest alarmingly negative attitudes toward these patients, especially MSM, necessitating prompt and effective interventions designed to ameliorate the negative attitudes of health-care students toward vulnerable populations, specifically HIV-infected, PWID, and MSM patients in Malaysia.

  13. Implementation and assessment of an animal management system for small-animal micro-CT / micro-SPECT imaging

    Science.gov (United States)

    Holdsworth, David W.; Detombe, Sarah A.; Chiodo, Chris; Fricke, Stanley T.; Drangova, Maria

    2011-03-01

    Advances in laboratory imaging systems for CT, SPECT, MRI, and PET facilitate routine micro-imaging during pre-clinical investigations. Challenges still arise when dealing with immune-compromised animals, biohazardous agents, and multi-modality imaging. These challenges can be overcome with an appropriate animal management system (AMS), with the capability for supporting and monitoring a rat or mouse during micro-imaging. We report the implementation and assessment of a new AMS system for mice (PRA-3000 / AHS-2750, ASI Instruments, Warren MI), designed to be compatible with a commercial micro-CT / micro-SPECT imaging system (eXplore speCZT, GE Healthcare, London ON). The AMS was assessed under the following criteria: 1) compatibility with the imaging system (i.e. artifact generation, geometric dimensions); 2) compatibility with live animals (i.e. positioning, temperature regulation, anesthetic supply); 3) monitoring capabilities (i.e. rectal temperature, respiratory and cardiac monitoring); 4) stability of co-registration; and 5) containment. Micro-CT scans performed using a standardized live-animal protocol (90 kVp, 40 mA, 900 views, 16 ms per view) exhibited low noise (+/-19 HU) and acceptable artifact from high-density components within the AMS (e.g. ECG pad contacts). Live mice were imaged repeatedly (with removal and replacement of the AMS) and spatial registration was found to be stable to within +/-0.07 mm. All animals tolerated enclosure within the AMS for extended periods (i.e. > one hour) without distress, based on continuous recordings of rectal temperature, ECG waveform and respiratory rate. A sealed AMS system extends the capability of a conventional micro-imaging system to include immune-compromised and biosafety level 2 mouse-imaging protocols.

  14. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  15. Distributed road assessment system

    Science.gov (United States)

    Beer, N. Reginald; Paglieroni, David W

    2014-03-25

    A system that detects damage on or below the surface of a paved structure or pavement is provided. A distributed road assessment system includes road assessment pods and a road assessment server. Each road assessment pod includes a ground-penetrating radar antenna array and a detection system that detects road damage from the return signals as the vehicle on which the pod is mounted travels down a road. Each road assessment pod transmits to the road assessment server occurrence information describing each occurrence of road damage that is newly detected on a current scan of a road. The road assessment server maintains a road damage database of occurrence information describing the previously detected occurrences of road damage. After the road assessment server receives occurrence information for newly detected occurrences of road damage for a portion of a road, the road assessment server determines which newly detected occurrences correspond to which previously detected occurrences of road damage.

  16. Risk assessment research and technology assessment

    International Nuclear Information System (INIS)

    Albach, H.; Schade, D.; Sinn, H.

    1991-01-01

    The concepts and approaches for technology assessment, the targets and scientific principles, as well as recognizable deficits and recommendations concerning purposeful strategies for the promotion of this research field require a dialog between those concerned. Conception, deficits, and the necessary measures for risk assessment research and technology assessment were discussed as well as ethical aspects. The problematic nature of using organisms altered through genetic engineering in the open land, traffic and transport, site restoration, nuclear energy, and isotope applications were subjects particularly dealt with. (DG) [de

  17. Life Cycle Assessment and Risk Assessment

    DEFF Research Database (Denmark)

    Olsen, Stig Irving

    Life Cycle Assessment (LCA) is a tool for environmental assessment of product and systems – over the whole life cycle from acquisition of raw materials to the end-of-life of the product – and encompassing all environmental impacts of emissions and resource usage, e.g. global warming, acidification...... cycle. The models for assessing toxic impacts in LCA are to a large extent based on those developed for RA, e.g. EUSES, and require basic information about the inherent properties of the emissions like solubility, LogKow,ED50 etc. Additionally, it is a prerequisite to know how to characterize...

  18. Does academic assessment system type affect levels of academic stress in medical students? A cross-sectional study from Pakistan

    Directory of Open Access Journals (Sweden)

    Madiha Ali

    2015-06-01

    Full Text Available Introduction: Stress among medical students induced by academic pressures is on the rise among the student population in Pakistan and other parts of the world. Our study examined the relationship between two different systems employed to assess academic performance and the levels of stress among students at two different medical schools in Karachi, Pakistan. Methods: A sample consisting of 387 medical students enrolled in pre-clinical years was taken from two universities, one employing the semester examination system with grade point average (GPA scores (a tiered system and the other employing an annual examination system with only pass/fail grading. A pre-designed, self-administered questionnaire was distributed. Test anxiety levels were assessed by The Westside Test Anxiety Scale (WTAS. Overall stress was evaluated using the Perceived Stress Scale (PSS. Results: There were 82 males and 301 females while four did not respond to the gender question. The mean age of the entire cohort was 19.7±1.0 years. A total of 98 participants were from the pass/fail assessment system while 289 were from the GPA system. There was a higher proportion of females in the GPA system (85% vs. 59%; p<0.01. Students in the pass/fail assessment system had a lower score on the WTAS (2.4±0.8 vs. 2.8±0.7; p=0.01 and the PSS (17.0±6.7 vs. 20.3±6.8; p<0.01, indicating lower levels of test anxiety and overall stress than in students enrolled in the GPA assessment system. More students in the pass/fail system were satisfied with their performance than those in the GPA system. Conclusion: Based on the present study, we suggest governing bodies to revise and employ a uniform assessment system for all the medical colleges to improve student academic performance and at the same time reduce stress levels. Our results indicate that the pass/fail assessment system accomplishes these objectives.

  19. Assessing the assessments: Pharmaceuticals in the environment

    International Nuclear Information System (INIS)

    Enick, O.V.; Moore, M.M.

    2007-01-01

    The relatively new issue of pharmaceutical contamination of the environment offers the opportunity to explore the application of values to the construction, communication and management of risk. The still-developing regulatory policies regarding environmental contamination with pharmaceuticals provide fertile ground for the introduction of values into the definition and management of risk. In this report, we summarize the current knowledge regarding pharmaceutical contamination of the environment and discuss specific attributes of pharmaceuticals that require special consideration. We then present an analysis showing that if values are incorporated into assessing, characterizing and managing risk, the results of risk assessments will more accurately reflect the needs of various stakeholders. Originating from an acknowledgement of the inherent uncertainty and value-laden nature of risk assessment, the precautionary principle (and later, the multi-criteria, integrated risk assessment), provides a direction for further research and policy development

  20. Solar Resource Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Renne, D.; George, R.; Wilcox, S.; Stoffel, T.; Myers, D.; Heimiller, D.

    2008-02-01

    This report covers the solar resource assessment aspects of the Renewable Systems Interconnection study. The status of solar resource assessment in the United States is described, and summaries of the availability of modeled data sets are provided.

  1. Life cycle assessment (LCA)

    DEFF Research Database (Denmark)

    Thrane, Mikkel; Schmidt, Jannick Andresen

    2004-01-01

    The chapter introduces Life Cycle Assessment (LCA) and its application according to the ISO 1404043 standards.......The chapter introduces Life Cycle Assessment (LCA) and its application according to the ISO 1404043 standards....

  2. Role of assessment

    African Journals Online (AJOL)

    User

    skills valued by employers such as problem solving, communication skills, and working effectively with ... structured. Performance assessment, portfolios, authentic assessment and student self ...... damaging the self-esteem of low achievers.

  3. National Assessment Database

    Data.gov (United States)

    U.S. Environmental Protection Agency — The National Assessment Database stores and tracks state water quality assessment decisions, Total Maximum Daily Loads (TMDLs) and other watershed plans designed to...

  4. Hepatitis Risk Assessment

    Science.gov (United States)

    ... please visit this page: About CDC.gov . Hepatitis Risk Assessment Recommend on Facebook Tweet Share Compartir Viral Hepatitis. Are you at risk? Take this 5 minute Hepatitis Risk Assessment developed ...

  5. The Structured Assessment Dialogue

    DEFF Research Database (Denmark)

    Dolin, Jens; Bruun, Jesper; Nielsen, Sanne Schnell

    2018-01-01

    The two key purposes of assessment, formative and summative, are often in a contradictory position if they are used concurrently. The summative assessment of learning will often prevent the formative assessment for learning to be realised (Butler, J Educ Psychol 79(4):474, 1987), meaning...... assessment method involving three distinct phases: A 5-min student-teacher dialogue, a 5-min peer feedback phase and finally 2–3-min of student self-reflection. We describe the rationales for the SAD and analyse results from classroom implementations in Denmark and Finland. First, using focus group interview...... that the learning potential of the assessment will often be minimal. It is therefore a central challenge to find ways to combine the dual use of assessment. The structured assessment dialogue (SAD) is a candidate for such a combination. This chapter introduces the structured assessment dialogue – a short ritualised...

  6. GM Risk Assessment

    Science.gov (United States)

    Sparrow, Penny A. C.

    GM risk assessments play an important role in the decision-making process surrounding the regulation, notification and permission to handle Genetically Modified Organisms (GMOs). Ultimately the role of a GM risk assessment will be to ensure the safe handling and containment of the GMO; and to assess any potential impacts on the environment and human health. A risk assessment should answer all ‘what if’ scenarios, based on scientific evidence.

  7. Dutch Risk Assessment tools

    NARCIS (Netherlands)

    Venema, A.

    2015-01-01

    The ‘Risico- Inventarisatie- en Evaluatie-instrumenten’ is the name for the Dutch risk assessment (RA) tools. A RA tool can be used to perform a risk assessment including an evaluation of the identified risks. These tools were among the first online risk assessment tools developed in Europe. The

  8. Dynamic Speaking Assessments

    Science.gov (United States)

    Hill, Kent; Sabet, Mehran

    2009-01-01

    This article describes an attempt to adopt dynamic assessment (DA) methods in classroom speaking assessments. The study reported in this article focused on four particular applications of dynamic speaking assessment (DSA). The first, "mediated assistance" (MA), involves interaction between an assistor and a learner to reveal problems in…

  9. Georgia's Teacher Performance Assessment

    Science.gov (United States)

    Fenton, Anne Marie; Wetherington, Pamela

    2016-01-01

    Like most states, Georgia until recently depended on an assessment of content knowledge to award teaching licenses, along with a licensure recommendation from candidates' educator preparation programs. While the content assessment reflected candidates' grasp of subject matter, licensure decisions did not hinge on direct, statewide assessment of…

  10. Financial Sector Assessment : Turkey

    OpenAIRE

    World Bank

    2007-01-01

    A joint International Monetary Fund-World Bank team conducted an assessment of Turkey's financial system in connection with the Financial Sector Assessment Program (FSAP) through missions in April, August-September 2006 and March, 2007. This report provides a summary of the main findings of the assessment and the policy priorities identified. The main objective of the FSAP is to assist the...

  11. Prior Knowledge Assessment Guide

    Science.gov (United States)

    2014-12-01

    assessment in a reasonable amount of time. Hands-on assessments can be extremely diverse in makeup and administration depending on the subject matter...DEVELOPING AND USING PRIOR KNOWLEDGE ASSESSMENTS TO TAILOR TRAINING D-3 ___ Brush and scrub ___ Orchards ___ Rice

  12. 75 FR 72581 - Assessments, Assessment Base and Rates

    Science.gov (United States)

    2010-11-24

    ... Part III Federal Deposit Insurance Corporation 12 CFR Part 327 Assessments, Assessment Base and... Assessments, Assessment Base and Rates AGENCY: Federal Deposit Insurance Corporation. ACTION: Notice of... Consumer Protection Act regarding the definition of an institution's deposit insurance assessment base...

  13. Assessment of Students Projects

    DEFF Research Database (Denmark)

    Kofoed, Lise B.; Stachowicz, Marian S.

    2012-01-01

    The evaluation and assessment of engineering programmes is a big issue, and there exist many concepts and methods. This paper deals with the assessment methods which can be used when assessing the knowledge, skills and competences developed in projects using PBL (problem based and project organized...... learning) pedagogical approaches. The experience of assessing first year projects from the Medialogy education at Aalborg University and third year projects from the Electrical and Computer Engineering Department at University of Minnesota, Duluth are presented, and the different methods discussed....... The conclusion is that process as well as product has to be assessed in a way which evaluates all aspects of students’ learning outcomes....

  14. Practical Privacy Assessment

    DEFF Research Database (Denmark)

    Peen, Søren; Jansen, Thejs Willem; Jensen, Christian D.

    2008-01-01

    This chapter proposes a privacy assessment model called the Operational Privacy Assessment Model that includes organizational, operational and technical factors for the protection of personal data stored in an IT system. The factors can be evaluated in a simple scale so that not only the resulting...... graphical depiction can be easily created for an IT system, but graphical comparisons across multiple IT systems are also possible. Examples of factors presented in a Kiviat graph are also presented. This assessment tool may be used to standardize privacy assessment criteria, making it less painful...... for the management to assess privacy risks on their systems....

  15. Human reliability assessment and probabilistic risk assessment

    International Nuclear Information System (INIS)

    Embrey, D.E.; Lucas, D.A.

    1989-01-01

    Human reliability assessment (HRA) is used within Probabilistic Risk Assessment (PRA) to identify the human errors (both omission and commission) which have a significant effect on the overall safety of the system and to quantify the probability of their occurrence. There exist a variey of HRA techniques and the selection of an appropriate one is often difficult. This paper reviews a number of available HRA techniques and discusses their strengths and weaknesses. The techniques reviewed include: decompositional methods, time-reliability curves and systematic expert judgement techniques. (orig.)

  16. SPECAL ISSUE Assessing the Assessment Procedures and ...

    African Journals Online (AJOL)

    Community Based Education/CBE Courses at Jimma. University .... Develop policies and strategies for the CBE courses with high levels of ... practices to enhance successful performance and sustainability of the philosophy in ... Thus, descriptive method was used in this study to assess and describe the existing condition of ...

  17. GCSE Assessment Notes: Six GCSE Assessment Assignments.

    Science.gov (United States)

    Graham, Stephen

    1988-01-01

    Provided are copy masters, instructions for use, and grading criteria for six problems used as part of the practical assessment for a modular science course. Each problem gives a narrative and a list of materials necessary to complete the problem. (CW)

  18. Assessing the information in the Summaries of Product Characteristics for the use of medicines in pregnancy and lactation

    Science.gov (United States)

    Arguello, Blanca; Salgado, Teresa M; Fernandez-Llimos, Fernando

    2015-01-01

    Aims To assess the completeness and applicability of information for the use of medicines in pregnancy and lactation contained in European Summaries of Product Characteristics (SmPCs). Methods SmPCs available on the EMA website in April 2011 were retrieved, and information on the use of medicines during pregnancy and lactation was analyzed. A form was designed to extract information regarding drug concentrations crossing the placenta, excretion of the drug in milk, the existence of pre-clinical and clinical studies and clinical experience describing the use of the medicine in pregnancy and lactation, medicine effects on human fertility, medicines use in women of child-bearing potential and specific recommendations for use during pregnancy and breastfeeding. SmPCs were classified as containing ‘conclusive’ or ‘ambiguous’ information depending on whether (or not) they provided clear instructions regarding medicine use in pregnancy and lactation. Results Of the 534 SmPCs, 89.3% did not mention whether the drug crossed the placenta, 67.6% indicated that there was no clinical experience during pregnancy and in 61.4% it was unknown whether the medicine was excreted in human milk. Recommendations for medicine use during pregnancy and breastfeeding were ambiguous in 57.0% and 16.5% of the SmPCs, respectively, and medicine use was restricted in over 90% SmPCs for both pregnancy and breastfeeding, despite no information supporting these restrictions being reported. The time elapsed since a SmPCs first approval was not associated with an increase in information quality. Conclusions Important information deficits on the use of medicines during pregnancy and breastfeeding were found in European SmPCs. PMID:25224071

  19. Conceptualising sustainability assessment

    International Nuclear Information System (INIS)

    Pope, Jenny; Annandale, David; Morrison-Saunders, Angus

    2004-01-01

    Sustainability assessment is being increasingly viewed as an important tool to aid in the shift towards sustainability. However, this is a new and evolving concept and there remain very few examples of effective sustainability assessment processes implemented anywhere in the world. Sustainability assessment is often described as a process by which the implications of an initiative on sustainability are evaluated, where the initiative can be a proposed or existing policy, plan, programme, project, piece of legislation, or a current practice or activity. However, this generic definition covers a broad range of different processes, many of which have been described in the literature as 'sustainability assessment'. This article seeks to provide some clarification by reflecting on the different approaches described in the literature as being forms of sustainability assessment, and evaluating them in terms of their potential contributions to sustainability. Many of these are actually examples of 'integrated assessment', derived from environmental impact assessment (EIA) and strategic environmental assessment (SEA), but which have been extended to incorporate social and economic considerations as well as environmental ones, reflecting a 'triple bottom line' (TBL) approach to sustainability. These integrated assessment processes typically either seek to minimise 'unsustainability', or to achieve TBL objectives. Both aims may, or may not, result in sustainable practice. We present an alternative conception of sustainability assessment, with the more ambitious aim of seeking to determine whether or not an initiative is actually sustainable. We term such processes 'assessment for sustainability'. 'Assessment for sustainability' firstly requires that the concept of sustainability be well-defined. The article compares TBL approaches and principles-based approaches to developing such sustainability criteria, concluding that the latter are more appropriate, since they avoid many

  20. Assessment in Cognitive Therapy

    OpenAIRE

    Brown, Gary P.; Clark, David A.

    2015-01-01

    This volume brings together leading experts to explore the state of the art of cognitive clinical assessment and identify cutting-edge approaches of interest to clinicians and researchers. The book highlights fundamental problems concerning the validity of assessments that are widely used in cognitive-behavioral therapy (CBT). Key directions for further research and development are identified. Updated cognitive assessment methods are described in detail, with particular attention to transdiag...

  1. Biology Reflective Assessment Curriculum

    Science.gov (United States)

    Bayley, Cheryl Ann

    Often students and educators view assessments as an obligation and finality for a unit. In the current climate of high-stakes testing and accountability, the balance of time, resources and emphasis on students' scores related to assessment have been slanted considerably toward the summative side. This tension between assessment for accountability and assessment to inform teaching strains instruction and educators' ability to use that information to design learning opportunities that help students develop deeper conceptual understanding. A substantive body of research indicates that formative and reflective assessment can significantly improve student learning. Biology Reflective Assessment Curriculum (BRAC) examines support provided for high school science students through assessment practices. This investigation incorporates the usage of reflective assessments as a guiding practice for differentiated instruction and student choice. Reflective assessment is a metacognitive strategy that promotes self-monitoring and evaluation. The goals of the curriculum are to promote self-efficacy and conceptual understanding in students learning biology through developing their metacognitive awareness. BRAC was implemented in a high school biology classroom. Data from assessments, metacognitive surveys, self-efficacy surveys, reflective journals, student work, a culminating task and field notes were used to evaluate the effectiveness of the curriculum. The results suggest that students who develop their metacognitive skills developed a deeper conceptual understanding and improved feelings of self-efficacy when they were engaged in a reflective assessment unit embedded with student choice. BRAC is a tool for teachers to use assessments to assist students in becoming metacognitive and to guide student choice in learning opportunities.

  2. Transforming Assessment Research

    DEFF Research Database (Denmark)

    Nielsen, Jan Alexis; Dolin, Jens; Tidemand, Sofie

    2018-01-01

    This chapter will identify and outline current gaps in research into assessment practice and tie the results of the ASSIST-ME project onto this outline. In this way, the chapter will present concrete research vistas that are still needed in international assessment research. The chapter concludes...... with a key theme that appears across many of the chapters in this volume, namely, issues concerning the operationalisation of complex learning goals into teaching and assessment activities....

  3. Nutritional assessment of athletes

    National Research Council Canada - National Science Library

    Driskell, Judy A; Wolinsky, Ira

    2011-01-01

    "Evaluating dietary intake, determining energy metabolism, and conducting other nutritional assessments are essential in understanding the relationships between diet, exercise, health, and physical...

  4. Process of performance assessment

    International Nuclear Information System (INIS)

    King, C.M.; Halford, D.K.

    1987-01-01

    Performance assessment is the process used to evaluate the environmental consequences of disposal of radioactive waste in the biosphere. An introductory review of the subject is presented. Emphasis is placed on the process of performance assessment from the standpoint of defining the process. Performance assessment, from evolving experience at DOE sites, has short-term and long-term subprograms, the components of which are discussed. The role of mathematical modeling in performance assessment is addressed including the pros and cons of current approaches. Finally, the system/site/technology issues as the focal point of this symposium are reviewed

  5. Ecological risk assessment

    National Research Council Canada - National Science Library

    Suter, Glenn W; Barnthouse, L. W. (Lawrence W)

    2007-01-01

    Ecological risk assessment is commonly applied to the regulation of chemicals, the remediation of contaminated sites, the monitoring of importation of exotic organisms, the management of watersheds...

  6. Assessment of Innovation Competency

    DEFF Research Database (Denmark)

    Nielsen, Jan Alexis

    2015-01-01

    competency, and communication competency) as well as assessment criteria for a number of skills relevant to these subcompetencies. These assessment criteria, it is argued, largely resonate with existing literature and they provide a detailed glimpse into how assessment of innovation competency could...... of the recorded talk in interaction that occurred in teacher group discussion sessions at 5 upper secondary schools. Based on the analysis, it was possible to extrapolate assessment criteria for 5 subcompetencies relevant to innovation (creative competency, collaboration competency, navigation competency, action...

  7. Systems dependability assessment

    CERN Document Server

    Aubry, Jean-François

    2015-01-01

    Presents recent developments of probabilistic assessment of systems dependability based on stochastic models, including graph theory, finite state automaton and language theory, for both dynamic and hybrid contexts.

  8. Performance assessment - risk assessment vive la differences

    International Nuclear Information System (INIS)

    Nitschke, R.L.

    1997-01-01

    In the sister worlds of radioactive waste management disposal and environmental restoration, there are two similar processes and computational approaches for determining the acceptability of the proposed activities. While similar, these two techniques can lead to confusion and misunderstanding if the differences are not recognized and appreciated. In the case of radioactive waste management, the performance assessment process is used to determine compliance with certain prescribed 'performance objectives'. These objectives are designed to ensure that the disposal of radioactive (high-level, low-level, and/or transuranic) waste will be protective of human health and the environment. The environmental link is primarily through assuring protection of the groundwater as a resource. In the case of environmental restoration, the risk assessment process is used to determine the proper remedial action response, if any, for a past hazardous waste release. The process compares the 'no action' or 'leave as is' option with both carcinogenic and noncarcinogenic values for human health to determine the need for any action and to help to help determine just what the appropriate action would need to be. The impacts to the ecological system are evaluated in a slightly, different but similar fashion. Now the common objectives between these two processes notwithstanding. There are some key and fundamental differences that need to be answered that make direct comparisons or a common approach inappropriate. Failure to recognize this can lead to confusion and misunderstanding. This can be particularly problematic when one is faced with an active disposal facility located within the boundaries of an environmental restoration site as is the case at the Idaho National Engineering Laboratory (INEL). Through a critical evaluation of the performance assessment and risk assessment processes, highlighting both similarities and differences, it is hoped that greater understanding and appreciation

  9. Assessment on the net

    Directory of Open Access Journals (Sweden)

    Joaquín GARCÍA CARRASCO

    2016-03-01

    Full Text Available Evaluation assesses the teaching-learning process, so that there can not be teaching and learning if there are not some defined objectives to be assessed. Currently, there are many virtual learning environments developed, mainly supported by the web, but most of them do not incorporate evaluation modules. Besides, the lack of learning technology standards limits system interoperability and resource reuse.

  10. Sudan Investment Climate Assessment

    OpenAIRE

    World Bank

    2009-01-01

    This report on Sudan's Investment Climate Assessment (ICA) provides a baseline assessment of challenges to productivity, diversification and inclusion. Chapter 1 describes some of the questions underlying the three issues of competitiveness, diversification and broad-based growth. Chapter 2 analyzes firm performance and competitiveness. Chapter 3 discusses markets and trust. Chapter 4 des...

  11. Educational Assessment in Norway

    Science.gov (United States)

    Tveit, Sverre

    2014-01-01

    Norway has seen major changes in the field of educational assessment over the past decade, following the 2001 '"PISA shock" that stimulated reform of the entire primary and secondary education systems: new outcome-based curricula with cross-disciplinary basic skills were accompanied by major revision of assessment regulations,…

  12. Calculus Courses' Assessment Data

    Science.gov (United States)

    Pauna, Matti

    2017-01-01

    In this paper we describe computer-aided assessment methods used in online Calculus courses and the data they produce. The online learning environment collects a lot of time-stamped data about every action a student makes. Assessment data can be harnessed into use as a feedback, predictor, and recommendation facility for students and instructors.…

  13. Functional Assessment Inventory Manual.

    Science.gov (United States)

    Crewe, Nancy M.; Athelstan, Gary T.

    This manual, which provides extensive new instructions for administering the Functional Assessment Inventory (FAI), is intended to enable counselors to begin using the inventory without undergoing any special training. The first two sections deal with the need for functional assessment and issues in the development and use of the inventory. The…

  14. Change Agents & Impact Assessment

    DEFF Research Database (Denmark)

    Kørnøv, Lone; Larsen, Sanne Vammen; Hansen, Anne Merrild

    2010-01-01

    One of the challenges facing impact assessment is finding ways to work in research and practice that allow appropriate action and critical interrogation og action to enable and support sustainable change.......One of the challenges facing impact assessment is finding ways to work in research and practice that allow appropriate action and critical interrogation og action to enable and support sustainable change....

  15. Assessment Hotspots, 2000.

    Science.gov (United States)

    Ahearn, Charles, Ed.; Nalley, Donna, Ed.; Marsh, Corinda, Ed.; Casbon, Christy, Ed.

    2000-01-01

    SouthEastern Regional Vision for Education (SERVE) is one of the federally funded regional educational laboratories. This annual publication captures and shares the experiences of SERVE school districts that have volunteered to share their efforts at assessment reform. This issue contains the following articles: (1) "Classroom Assessment: A…

  16. Assessment, surgeon, and society.

    Science.gov (United States)

    Norcini, John; Talati, Jamsheer

    2009-08-01

    An increasing public demand to monitor and assure the quality of care provided by physicians and surgeons has been accompanied by a deepening appreciation within the profession of the demands of self-regulation and the need for accountability. To respond to these developments, the public and the profession have turned increasingly to assessment, both to establish initial competence and to ensure that it is maintained throughout a career. Fortunately, this comes at a time when there have been significant advances in the breadth and quality of the assessment tools available. This article provides an overview of the drivers of change in assessment which includes the educational outcomes movement, the development of technology, and advances in assessment. It then outlines the factors that are important in selecting assessment devices as well as a system for classifying the methods that are available. Finally, the drivers of change have spawned a number of trends in the assessment of competence as a surgeon. Three of them are of particular note, simulation, workplace-based assessment, and the assessment of new competences, and each is reviewed with a focus on its potential.

  17. Assessing Second Language Speaking

    Science.gov (United States)

    Fulcher, Glenn

    2015-01-01

    While the viva voce (oral) examination has always been used in content-based educational assessment (Latham 1877: 132), the assessment of second language (L2) speaking in performance tests is relatively recent. The impetus for the growth in testing speaking during the 19th and 20th centuries is twofold. Firstly, in educational settings the…

  18. Competencies and Their Assessment

    Science.gov (United States)

    Drisko, James W.

    2014-01-01

    This article explores competencies and methods for their assessment in higher education and in social work's accreditation standards. Many contemporary policy and educational accreditation efforts employ the model of competency assessment. The current emphasis on accountability in higher education, including the Council on Social Work…

  19. TIMSS 2015 Assessment Frameworks

    Science.gov (United States)

    Mullis, Ina V. S., Ed.; Martin, Michael O., Ed.

    2013-01-01

    Now entering into its 20th year of data collection, Trends in International Mathematics and Science Study, (TIMSS) is an international assessment of mathematics and science at the fourth and eighth grades. TIMSS 2015 is the most recent in the TIMSS series, which began with the first assessments in 1995 and has continued every four years--1999,…

  20. Presentation on ecoenergetic assessment

    International Nuclear Information System (INIS)

    Fournelle, C.

    1998-01-01

    The development of a tool to assess the quality of indoor air for buildings in the residential and commercial sector was presented. The computer software program was designed to allow a building operator to set an optimal target to reflect the greatest economies in energy consumption. Air quality was assessed in terms of carbon dioxide, volatile organic compounds, and other common indoor pollutants

  1. Assessment of human exposures

    Energy Technology Data Exchange (ETDEWEB)

    Lebret, E [RIVM-National Inst. of Public Health and Environmental Protection (Netherlands)

    1996-12-31

    This article describes some of the features of the assessment of human exposure to environmental pollutants in epidemiological studies. Since exposure assessment in air pollution epidemiology studies typically involve professionals from various backgrounds, interpretation of a concepts like `exposure` may vary. A brief descriptions is therefore given by way of introduction

  2. Chemical Risk Assessment

    Science.gov (United States)

    This course is aimed at providing an overview of the fundamental guiding principles and general methods used in chemical risk assessment. Chemical risk assessment is a complex and ever-evolving process. These principles and methods have been organized by the National Research Cou...

  3. Discourse and Assessment.

    Science.gov (United States)

    McNamara, Tim; Hill, Kathryn; May, Lynette

    2002-01-01

    Focuses on the increase in discourse-based studies of oral proficiency assessment techniques. Discusses research carried out on a number of factors in the assessment setting, including the role of interlocutor, candidate, and rater, and the impact of tasks, task performance conditions, and rating criteria. (Author/VWL)

  4. Assessment of human exposures

    Energy Technology Data Exchange (ETDEWEB)

    Lebret, E. [RIVM-National Inst. of Public Health and Environmental Protection (Netherlands)

    1995-12-31

    This article describes some of the features of the assessment of human exposure to environmental pollutants in epidemiological studies. Since exposure assessment in air pollution epidemiology studies typically involve professionals from various backgrounds, interpretation of a concepts like `exposure` may vary. A brief descriptions is therefore given by way of introduction

  5. Competencies, skills and assessment

    DEFF Research Database (Denmark)

    Højgaard, Tomas

    2009-01-01

    This paper is an analysis of the challenge of assessing student learning and how that is affected by using descriptions of competencies as a core element when describing the aims of the learning process. Assessment is modelled as a three step process; characterising, identifying and judging, to a...

  6. Environmental Workplace Assessment.

    Science.gov (United States)

    Bernier, Jacques; And Others

    1994-01-01

    Describes environmental workplace assessments as tools in developing customized training, highlighting the group process and individual interview techniques. Suggests that, by assessing the cultural climate of an organization, education providers can gather essential baseline information on an organization and thereby provide a guide for further…

  7. WATER CHEMISTRY ASSESSMENT METHODS

    Science.gov (United States)

    This section summarizes and evaluates the surfce water column chemistry assessment methods for USEPA/EMAP-SW, USGS-NAQA, USEPA-RBP, Oho EPA, and MDNR-MBSS. The basic objective of surface water column chemistry assessment is to characterize surface water quality by measuring a sui...

  8. Comprehensive neurotoxicity assessment

    NARCIS (Netherlands)

    Kulig, B.M.

    1996-01-01

    Significant progress has been made in recent years in terms of both the conceptualization of neurotoxicity assessment strategies as well as in the development of behavioral techniques for evaluating neurotoxic exposures. A tiered approach, for example, has been advocated as an assessment strategy in

  9. Lesion activity assessment

    DEFF Research Database (Denmark)

    Ekstrand, K R; Zero, D T; Martignon, S

    2009-01-01

    in response to cariogenic plaque as well as lesion arrest. Based on this understanding, different clinical scoring systems have been developed to assess the severity/depth and activity of lesions. A recent system has been devised by the International Caries Detection and Assessment System Committee...

  10. NRC performance assessment program

    International Nuclear Information System (INIS)

    Coplan, S.M.

    1986-01-01

    The U.S. Nuclear Regulatory Commission's (NRC) performance assessment program includes the development of guidance to the U.S. Department of Energy (DOE) on preparation of a license application and on conducting the studies to support a license application. The nature of the licensing requirements of 10 CFR Part 60 create a need for performance assessments by the DOE. The NRC and DOE staffs each have specific roles in assuring the adequacy of those assessments. Performance allocation is an approach for determining what testing and analysis will be needed during site characterization to assure that an adequate data base is available to support the necessary performance assessments. From the standpoint of establishing is implementable methodology, the most challenging performance assessment needed for licensing is the one that will be used to determine compliance with the U.S. Environmental Protection Agency's (EPA) containment requirement

  11. Breastfeeding assessment tools

    International Nuclear Information System (INIS)

    Bizouerne, Cécile; Kerac, Marko; Macgrath, Marie

    2014-01-01

    Full text: Breastfeeding plays a major role in reducing the global burden of child mortality and under-nutrition. Whilst many programmes aim to support breastfeeding and prevent feeding problems occurring, interventions are also needed once they have developed. In this situation, accurate assessment of a problem is critical to inform prognosis and enables tailored, appropriate treatment. The presentation will present a review, which aims to identify breastfeeding assessment tools/checklists for use in assessing malnourished infants in poor resource settings. The literature review identified 24 breastfeeding assessment tools, and 41 validation studies. Evidence underpinning most of the tools was mainly low quality, and conducted in high-income countries and hospital settings. The presentation will describe the main findings of the literature review and propose recommendations for improving existing tools in order to appropriately assess malnourished infants and enable early, appropriate intervention and treatment of malnutrition. (author)

  12. Environmental impact assessment report

    Energy Technology Data Exchange (ETDEWEB)

    Jung, K. J.; Paik, S. T.; Chung, U. S.; Jung, K. H.; Park, S. K.; Lee, D. G.; Kim, H. R.; Kim, J. K.; Yang, S. H.; Lee, B. J.; Kim, E. H.; Choi, K. S

    2000-10-01

    This report is the revised Environmental Impact Assessment Report which was made and submitted as one of the license documents for TRIGA Research Reactor D and D Project. The Environmental Impact Assessment Report includes introduction of decommissioning plan, status of reactors and environmental impact of surroundings. Also it was assessed and analyzed on radioactivity for environment, and the plan was established to minimize radioactive material release. Finally environmental monitoring plan was established to confirm whether contaminated or not from radioactivity during decommissioning period. According to the assessment results, the risk of excess exposure will be not on environment and public. The first Environmental Impact Assessment Report was submitted to the government for the license and reviewed by Korea Institute of Nuclear Safety. The first Report was revised including answers for the questions arising from review process.

  13. SPAT 15 - Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Bartley, J.C. (Coordinator)

    1998-08-01

    In the Spring of 1997, the Department of Energy's Department Standards Committee (DSC) convened a Standards Process Action Team (SPAT-15) to evaluate assessment processes within the DOE complex. If time and resources permitted, the team was also to evaluate assessment processes used by private industry conducting similar work and activities. The specific task statement was as follows: "Define the attributes of assessment programs that effectively support organizational feedback and improvement of safety systems at all the different levels of contractor and Department organizations." The team gathered information on existing assessment programs through surveys and presentations by representatives from national laboratories, processing facilities, and remediation sites. Examples of assessment programs described in this report encompass site-wide, individual facility, and task level applications within the DOE compIex

  14. SPAT 15 - Assessment

    International Nuclear Information System (INIS)

    Bartley, J.C.

    1998-01-01

    In the Spring of 1997, the Department of Energy's Department Standards Committee (DSC) convened a Standards Process Action Team (SPAT-15) to evaluate assessment processes within the DOE complex. If time and resources permitted, the team was also to evaluate assessment processes used by private industry conducting similar work and activities. The specific task statement was as follows: ''Define the attributes of assessment programs that effectively support organizational feedback and improvement of safety systems at all the different levels of contractor and Department organizations.'' The team gathered information on existing assessment programs through surveys and presentations by representatives from national laboratories, processing facilities, and remediation sites. Examples of assessment programs described in this report encompass site-wide, individual facility, and task level applications within the DOE compIex

  15. 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.

  16. Is enteral administration of fluorine-18-fluorodeoxyglucose (F-18 FDG) a palatable alternative to IV injection? Pre-clinical evaluation in normal rodents

    Energy Technology Data Exchange (ETDEWEB)

    Higashi, T. E-mail: higashi@kuhp.kyoto-u.ac.jp; Fisher, S.J.; Nakada, K.; Romain, D.J.; Wahl, R.L

    2002-04-01

    To establish effective methods of enteral 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) administration, the efficiency of FDG absorption in the gastrointestinal tracts following enteral administrations was evaluated using the FDG biodistribution in normal rodents, in combination with various fasting conditions and FDG diluents. The blood FDG curve using hypotonic solution showed a rapid increase, while that in iso- and hypertonic groups showed slow rises. Brain FDG uptake had a close positive correlation with blood AUC (area under curve) and an inverse relationship with the stomach contents.

  17. Boosted Regeneration and Reduced Denervated Muscle Atrophy by NeuroHeal in a Pre-clinical Model of Lumbar Root Avulsion with Delayed Reimplantation.

    Science.gov (United States)

    Romeo-Guitart, David; Forés, Joaquim; Navarro, Xavier; Casas, Caty

    2017-09-20

    The "gold standard" treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.

  18. 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.

  19. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.

    Science.gov (United States)

    Camerino, Giulia Maria; Cannone, Maria; Giustino, Arcangela; Massari, Ada Maria; Capogrosso, Roberta Francesca; Cozzoli, Anna; De Luca, Annamaria

    2014-11-01

    Weakness and fatigability are typical features of Duchenne muscular dystrophy patients and are aggravated in dystrophic mdx mice by chronic treadmill exercise. Mechanical activity modulates gene expression and muscle plasticity. Here, we investigated the outcome of 4 (T4, 8 weeks of age) and 12 (T12, 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in the gastrocnemius muscle of mdx and wild-type (WT) mice using quantitative real-time PCR. Basal expression of the exercise-sensitive genes peroxisome-proliferator receptor γ coactivator 1α (Pgc-1α) and Sirtuin1 (Sirt1) was higher in mdx versus WT mice at both ages. Exercise increased Pgc-1α expression in WT mice; Pgc-1α was downregulated by T12 exercise in mdx muscles, along with Sirt1, Pparγ and the autophagy marker Bnip3. Sixteen weeks old mdx mice showed a basal overexpression of the slow Mhc1 isoform and Serca2; T12 exercise fully contrasted this basal adaptation as well as the high expression of follistatin and myogenin. Conversely, T12 exercise was ineffective in WT mice. Damage-related genes such as gp91-phox (NADPH-oxidase2), Tgfβ, Tnfα and c-Src tyrosine kinase were overexpressed in mdx muscles and not affected by exercise. Likewise, the anti-inflammatory adiponectin was lower in T12-exercised mdx muscles. Chronic exercise with minor adaptive effects in WT muscles leads to maladaptation in mdx muscles with a disequilibrium between protective and damaging signals. Increased understanding of the pathways involved in the altered mechanical-metabolic coupling may help guide appropriate physical therapies while better addressing pharmacological interventions in translational research. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Factors associated with consumption of caffeinated-beverage among Siriraj pre-clinical year medical students, A 2-year consecutive survey.

    Science.gov (United States)

    Pandejpong, Denla; Paisansudhi, Supalerg; Udompunthurak, Suthipol

    2014-03-01

    Previous studies showed that significant proportion of medical students consumed caffeine to face sleep-deprived daily schedules. To monitor the trend of caffeinated-beverage consumption among Siriraj medical students as well as to study possible factors associated with caffeine dependency. The questionnaire was distributed to a class of medical students for 2 consecutive years. Statistical analysis was performed for descriptive purpose. 269 (89.7%) and 225 (74.5%) questionnaires were returned in year 1 and year 2, respectively 16.2% refused to take caffeine-beverages totally. 13% of those who consumed caffeinated-beverages developed caffeine dependence. From logistical analysis, positive history of smoking-family member and female sex were the only other two factors associated with caffeine dependency (OR 2.19, 95% CI 1.04-4.61 and 1.76, 95% CI 1.01-3.07, respectively). Other investigated factors included: exercise (p = 0.08); sleep hours (p = 0.24); reading beverage labels (p = 0.87); alcohol consumption (p = 0.59); class performance (p = 0.87); family member coffee-drinking habits (p = 0.66);family member alcohol-drinking habits (p = 0.18); and family income (p = 0.06). Caffeinated-beverage consumption was common among Siriraj medical students. No significant change was detected in the pattern of caffeinated-beverage consumption within the study period. Positive history of smoking family members and female sex were found as the only other two factors correlated with caffeine dependency.

  1. Pre-clinical evaluation of eight DOTA coupled gastrin-releasing peptide receptor (GRP-R) ligands for in vivo targeting of receptor-expressing tumors.

    Science.gov (United States)

    Accardo, Antonella; Galli, Filippo; Mansi, Rosalba; Del Pozzo, Luigi; Aurilio, Michela; Morisco, Anna; Ringhieri, Paola; Signore, Alberto; Morelli, Giancarlo; Aloj, Luigi

    2016-12-01

    Overexpression of the gastrin-releasing peptide receptor (GRP-R) has been documented in several human neoplasms such as breast, prostate, and ovarian cancer. There is growing interest in developing radiolabeled peptide-based ligands toward these receptors for the purpose of in vivo imaging and radionuclide therapy of GRP-R-overexpressing tumors. A number of different peptide sequences, isotopes, and labeling methods have been proposed for this purpose. The aim of this work is to perform a direct side-by-side comparison of different GRP-R binding peptides utilizing a single labeling strategy to identify the most suitable peptide sequence. Solid-phase synthesis of eight derivatives (BN1-8) designed based on literature analysis was carried out. Peptides were coupled to the DOTA chelator through a PEG4 spacer at the N-terminus. Derivatives were characterized for serum stability, binding affinity on PC-3 human prostate cancer cells, biodistribution in tumor-bearing mice, and gamma camera imaging at 1, 6, and 24 h after injection. Serum stability was quite variable among the different compounds with half-lives ranging from 16 to 400 min at 37 °C. All compounds tested showed K d values in the nanomolar range with the exception of BN3 that showed no binding. Biodistribution and imaging studies carried out for compounds BN1, BN4, BN7, and BN8 showed targeting of the GRP-R-positive tumors and the pancreas. The BN8 compound (DOTA-PEG-DPhe-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) showed high affinity, the longest serum stability, and the highest target-to-background ratios in biodistribution and imaging experiments among the compounds tested. Our results indicate that the NMeGly for Gly substitution and the Sta-Leu substitution at the C-terminus confer high serum stability while maintaining high receptor affinity, resulting in biodistribution properties that outperform those of the other peptides.

  2. A pre-clinical evaluation of silver, iodine and Manuka honey based dressings in a model of traumatic extremity wounds contaminated with Staphylococcus aureus.

    Science.gov (United States)

    Guthrie, Hugo C; Martin, Kevin R; Taylor, Christopher; Spear, Abigail M; Whiting, Rachel; Macildowie, Sara; Clasper, Jonathan C; Watts, Sarah A

    2014-08-01

    Prevention of extremity war wound infection remains a clinical challenge. Staphylococcus aureus is the most common pathogen in delayed infection. We hypothesised that choice of wound dressings may affect bacterial burden over 7 days reflecting the current practice of delayed primary closure of wounds within this timeframe. A randomised controlled trial of 3 commercially available dressings (Inadine(®) (Johnson & Johnson, NJ, USA), Acticoat(®) (Smith & Nephew, Hull, UK), Activon Tulle (Advancis Medical, Nottingham, UK)) was conducted in a rabbit model of contaminated forelimb muscle injury. A positive control group treated with antibiotics was included. Groups were compared to a saline soaked gauze control. The primary outcome was a statistically significant reduction (p injury. Secondary outcome measurements included bacteraemias, observational data, whole blood determination, ELISA for plasma biomarkers, PCR array analysis of wound healing gene expression and muscle/lymph node histopathology. Antibiotic, Inadine and Acticoat groups had statistically significant lower bacterial counts (mean 7.13 [95% CI 0.00-96.31]×10(2); 1.66 [0.94-2.58]×10(5); 8.86 [0.00-53.35]×10(4)cfu/g, respectively) and Activon Tulle group had significantly higher counts (2.82 [0.98-5.61]×10(6)cfu/g) than saline soaked gauze control (7.58 [1.65-17.83]×10(5)cfu/g). There were no bacteraemias or significant differences in observational data or whole blood determination. There were no significant differences in muscle/loss or pathology and lymph node cross-sectional area or morphology. There were some significant differences between treatment groups in the plasma cytokines IL-4, TNFα and MCP-1 in comparison to the control. PCR array data demonstrated more general changes in gene expression in the muscle tissue from the Activon Tulle group than the Inadine or Acticoat dressings with a limited number of genes showing significantly altered expression compared to control. This study has demonstrated that both Acticoat(®) and Inadine(®) dressings can reduce the bacteria burden in a heavily contaminated soft tissue wound and so they may offer utility in the clinical setting particularly where surgical treatment is delayed. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  3. 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, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials. Keywords: nanoparticles, flurbiprofen, polyethylene glycol 3350, d-(+-trehalose, freeze-drying, γ-irradiation

  4. Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme (GBM) cells due to c-Myc silencing.

    Science.gov (United States)

    Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam; Bradner, James E

    2014-10-01

    Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

  5. 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 pericarditis or macroscopic signs of inflammation at the site of the device were found. All pigs were in good condition with normal weight gain and no other clinical symptoms.This novel 3D printed left atrial appendage closure technique with a novel holdfast device was proven to be safe and feasible in all pigs. A benign healing process without inflammation and damage to the surrounding structures or evidence of new thrombi formation was observed. Moreover, the uncomplicated survival and full LAA exclusion in all animals demonstrate the efficacy of this novel and relatively cheap device. Further clinical evaluation and implementation studies should be performed to introduce this new technology into clinical practice.

  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. Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model

    Science.gov (United States)

    Al-Ghobashy, Medhat A.; Elmeshad, Aliaa N.; Abdelsalam, Rania M.; Nooh, Mohammed M.; Al-Shorbagy, Muhammad; Laible, Götz

    2017-04-01

    Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ɛ-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation. In conclusion: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

  8. Investigation of a pre-clinical mandibular bone notch defect model in miniature pigs: clinical computed tomography, micro-computed tomography, and histological evaluation.

    Science.gov (United States)

    Carlisle, Patricia L; Guda, Teja; Silliman, David T; Lien, Wen; Hale, Robert G; Brown Baer, Pamela R

    2016-02-01

    To validate a critical-size mandibular bone defect model in miniature pigs. Bilateral notch defects were produced in the mandible of dentally mature miniature pigs. The right mandibular defect remained untreated while the left defect received an autograft. Bone healing was evaluated by computed tomography (CT) at 4 and 16 weeks, and by micro-CT and non-decalcified histology at 16 weeks. In both the untreated and autograft treated groups, mineralized tissue volume was reduced significantly at 4 weeks post-surgery, but was comparable to the pre-surgery levels after 16 weeks. After 16 weeks, CT analysis indicated that significantly greater bone was regenerated in the autograft treated defect than in the untreated defect (P=0.013). Regardless of the treatment, the cortical bone was superior to the defect remodeled over 16 weeks to compensate for the notch defect. The presence of considerable bone healing in both treated and untreated groups suggests that this model is inadequate as a critical-size defect. Despite healing and adaptation, the original bone geometry and quality of the pre-injured mandible was not obtained. On the other hand, this model is justified for evaluating accelerated healing and mitigating the bone remodeling response, which are both important considerations for dental implant restorations.

  9. H5N2 Highly Pathogenic Avian Influenza Viruses from the US 2014-2015 outbreak have an unusually long pre-clinical period in turkeys

    OpenAIRE

    Spackman, Erica; Pantin-Jackwood, Mary J.; Kapczynski, Darrell R.; Swayne, David E.; Suarez, David L.

    2016-01-01

    Background From December 2014 through June 2015, the US experienced the most costly highly pathogenic avian influenza (HPAI) outbreak to date. Most cases in commercial poultry were caused by an H5N2 strain which was a reassortant with 5 Eurasian lineage genes, including a clade 2.3.4.4 goose/Guangdong/1996 lineage hemagglutinin, and 3 genes from North American wild waterfowl low pathogenicity avian influenza viruses. The outbreak primarily affected turkeys and table-egg layer type chickens. T...

  10. High-resolution harmonics ultrasound imaging for non-invasive characterization of wound healing in a pre-clinical swine model.

    Directory of Open Access Journals (Sweden)

    Surya C Gnyawali

    Full Text Available This work represents the first study employing non-invasive high-resolution harmonic ultrasound imaging to longitudinally characterize skin wound healing. Burn wounds (day 0-42, on the dorsum of a domestic Yorkshire white pig were studied non-invasively using tandem digital planimetry, laser speckle imaging and dual mode (B and Doppler ultrasound imaging. Wound depth, as measured by B-mode imaging, progressively increased until day 21 and decreased thereafter. Initially, blood flow at the wound edge increased up to day 14 and subsequently regressed to baseline levels by day 21, when the wound was more than 90% closed. Coinciding with regression of blood flow at the wound edge, there was an increase in blood flow in the wound bed. This was observed to regress by day 42. Such changes in wound angiogenesis were corroborated histologically. Gated Doppler imaging quantitated the pulse pressure of the primary feeder artery supplying the wound site. This pulse pressure markedly increased with a bimodal pattern following wounding connecting it to the induction of wound angiogenesis. Finally, ultrasound elastography measured tissue stiffness and visualized growth of new tissue over time. These studies have elegantly captured the physiological sequence of events during the process of wound healing, much of which is anticipated based on certain dynamics in play, to provide the framework for future studies on molecular mechanisms driving these processes. We conclude that the tandem use of non-invasive imaging technologies has the power to provide unprecedented insight into the dynamics of the healing skin tissue.

  11. {sup 99m}Tc-NC100668, a new tracer for imaging venous thromboemboli: pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, David [Grove Centre, Research and Development, GE Healthcare Bio-Sciences, Little Chalfont (United Kingdom); Uppsala University Hospital, Institution of Oncology, Radiology and Clinical Immunology, Section of Radiology, Uppsala (Sweden); Lewis, Joanne; Battle, Mark; Lear, Rochelle; Farrar, Gill; Barnett, D.J.; Godden, Vanessa; Oliveira, Alexandra; Coombes, Catherine [Grove Centre, Research and Development, GE Healthcare Bio-Sciences, Little Chalfont (United Kingdom); Ahlstroem, Haakan [Uppsala University Hospital, Institution of Oncology, Radiology and Clinical Immunology, Section of Radiology, Uppsala (Sweden)

    2006-11-15

    {sup 99m}Tc-NC100668 is a new radiotracer being developed to aid the diagnosis of thromboembolism. The structure of NC100668 is similar to a region of human {alpha}{sub 2}-antiplasmin, which is a substrate for factor XIIIa (FXIIIa). The purpose of this study was to confirm the uptake of {sup 99m}Tc-NC100668 into forming plasma clot and to establish the biodistribution of {sup 99m}Tc-NC100668 in Wistar rats. The in vitro plasma clot uptake of {sup 99m}Tc-NC100668 and other compounds with known affinities to FXIIIa was measured using a plasma clot assay. The biodistribution and blood clot uptake of radioactivity of {sup 99m}Tc-NC100668 in normal Wistar rats and those bearing experimentally induced deep vein thrombi were investigated. The in vitro uptake of {sup 99m}Tc-NC100668 was greater than that for [{sup 14}C]dansyl cadaverine, a known substrate of FXIIIa in the plasma clot assay. The biodistribution of {sup 99m}Tc-NC100668 in male and female Wistar rats up to 24 h p.i. showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention. In vivo the uptake and retention of {sup 99m}Tc-NC100668 into the blood clot was greater than could be accounted for by non-specific accumulation of the radiotracer within the blood clot. {sup 99m}Tc-NC100668 was retained by plasma clots in vitro and blood clots in vivo. No significant tissue retention which could interfere with the ability to image thrombi in vivo was observed. This evidence suggests that {sup 99m}Tc-NC100668 might be useful in the detection of thromboembolism. (orig.)

  12. 99mTc-NC100668, a new tracer for imaging venous thromboemboli: pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro

    International Nuclear Information System (INIS)

    Edwards, David; Lewis, Joanne; Battle, Mark; Lear, Rochelle; Farrar, Gill; Barnett, D.J.; Godden, Vanessa; Oliveira, Alexandra; Coombes, Catherine; Ahlstroem, Haakan

    2006-01-01

    99m Tc-NC100668 is a new radiotracer being developed to aid the diagnosis of thromboembolism. The structure of NC100668 is similar to a region of human α 2 -antiplasmin, which is a substrate for factor XIIIa (FXIIIa). The purpose of this study was to confirm the uptake of 99m Tc-NC100668 into forming plasma clot and to establish the biodistribution of 99m Tc-NC100668 in Wistar rats. The in vitro plasma clot uptake of 99m Tc-NC100668 and other compounds with known affinities to FXIIIa was measured using a plasma clot assay. The biodistribution and blood clot uptake of radioactivity of 99m Tc-NC100668 in normal Wistar rats and those bearing experimentally induced deep vein thrombi were investigated. The in vitro uptake of 99m Tc-NC100668 was greater than that for [ 14 C]dansyl cadaverine, a known substrate of FXIIIa in the plasma clot assay. The biodistribution of 99m Tc-NC100668 in male and female Wistar rats up to 24 h p.i. showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention. In vivo the uptake and retention of 99m Tc-NC100668 into the blood clot was greater than could be accounted for by non-specific accumulation of the radiotracer within the blood clot. 99m Tc-NC100668 was retained by plasma clots in vitro and blood clots in vivo. No significant tissue retention which could interfere with the ability to image thrombi in vivo was observed. This evidence suggests that 99m Tc-NC100668 might be useful in the detection of thromboembolism. (orig.)

  13. Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

    Directory of Open Access Journals (Sweden)

    Ju Huang

    2017-06-01

    Full Text Available Fabry disease is a rare lysosomal storage disorder (LSD. We designed multiple recombinant lentivirus vectors (LVs and tested their ability to engineer expression of human α-galactosidase A (α-gal A in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.

  14. Evaluation of the effect of carnosine, its novel derivative trolox-carnosine and trolox in a pre-clinical study focussing on the regulation of immunity

    Directory of Open Access Journals (Sweden)

    Slovák L.

    2016-09-01

    Full Text Available The neuroprotective or neurotoxic effects of the products of the kynurenine pathway of tryptophan metabolism highly depend on the action of kynurenine-3-monooxygenase (KMO. The present results show increased concentrations of the KMO in the plasma of rats repeatedly exposed to an immune challenge. Increased concentrations of this key enzyme are likely to cause a shift of kynurenine pathway towards enhanced production of neurotoxic metabolites.

  15. Pre-clinical test of the virtual wedge option of a PRIMUS linear accelerator and verification of the calculation algorithm in the treatment planning system HEAX-TMS

    International Nuclear Information System (INIS)

    Gesheva-Atanassova, N.; Balabanova, A.

    2006-01-01

    Full text: The purpose of the study is to check the long-time stability of the wedge angle and the wedge factor (WF) of Virtual Wedges for 6 and 18 MV photon beams, and the accuracy of the TPS HELAX-TMS, in order to accept the virtual wedge technique for patient treatment. All measurements - dose profiles, central axis dose distributions and applied dose for pre-calculated monitor units, have been performed in water, applying a calibrated 0.3 cm 3 ion chamber, 47 ion chamber array LA48 and the beam analyzing system MP3. The measured data has been compared with the corresponding planned data. During a four years time period the long time stability checking revealed no changes in the central axis distributions and variations of the wedge angles are within ± 2 deg. The values of WFs and the differences between calculated and measured dose values are in the acceptable limits, except for the 6 MV beam with wedge angle 60 deg and field size 20x20 cm 2 , where the deviation reaches 6.5%. The dose profile for depth up to 10 cm showed a good coincidence. Non acceptable deviations have been found for beam profiles at depth 20 cm and field size 20x20 cm 2 for both 6 and 18 MV. The Virtual Wedge Option of PRIMUS in combination with HELAX-TMS can be applied with confidence for radiotherapy with wedged beams except for the combination of field 20x20 cm 2 and angle 60 deg

  16. Optimised and rapid pre-clinical screening in the SOD1(G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS.

    Directory of Open Access Journals (Sweden)

    Richard J Mead

    Full Text Available The human SOD1(G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS. In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6 SOD1(G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  17. 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.

  18. The relationship between retinal damage and current intensity in a pre-clinical suprachoroidal-transretinal stimulation model using a laser-formed microporous electrode

    Science.gov (United States)

    Kanda, Hiroyuki; Nakano, Yukari; Terasawa, Yasuo; Morimoto, Takeshi; Fujikado, Takashi

    2017-10-01

    Objective. Suprachoroidal-transretinal stimulation (STS) is a stimulation method for retinal prostheses. For STS-type retinal prostheses, we developed a new type of stimulating electrode called a femtosecond laser-induced porous electrode (FLiP electrode). To verify the safety of the FLiP electrode for STS, we investigated the characteristics of STS-induced retinal injury. Approach. Sixteen eyes of pigmented rabbits were studied in this in vivo study. For each examined eye, we implanted a single-channel FLiP electrode (diameter, 0.5 mm height, 0.3 mm geometric surface area, 0.43 mm2) in a scleral pocket created at the posterior pole of the eye. A return electrode (diameter, 0.5 mm length, 3 mm) was inserted into the vitreous cavity. The eyes were divided into five groups, and each group was stimulated with a different current intensity. The stimulus intensities and the number of eyes in each group were as follows: 1.0 mA (n  =  2), 1.5 mA (n  =  3), 2.0 mA (n  =  3), 2.5 mA (n  =  4), and 3.0 mA (n  =  2). Continuous biphasic pulses (0.5 ms/phase) were applied under general anesthesia at a frequency of 20 Hz for 48 h. Fundus photography, fluorescein angiography (FA), and optical coherence tomography were performed before and after applying the electrical stimulation to evaluate the retinal injury. Main results. The 1.0 mA and 1.5 mA groups showed little or no retinal damage. Fluorescent dye leakage in FA and punctate pigmentation in the fundus were observed around the stimulation site with stimulation of 2.0 mA (1/3), 2.5 mA (1/4), and 3.0 mA (2/2). Significance. Our findings indicate that the threshold current for inducing retinal damage is greater than that for eliciting electrical phosphenes (<1 mA) with STS observed in human trials. Therefore, STS by the FLiP electrode is a safe and feasible stimulation method for retinal prostheses as long as it is used with these pulse parameters.

  19. Accelerated production of antigen-specific T-cells for pre-clinical and clinical applications using Gas-permeable Rapid Expansion cultureware (G-Rex)

    Science.gov (United States)

    Vera, Juan F.; Brenner, Lara J.; Gerdemann, Ulrike; Ngo, Minhtran C.; Sili, Uluhan; Liu, Hao; Wilson, John; Dotti, Gianpietro; Heslop, Helen E.; Leen, Ann M.; Rooney, Cliona M.

    2009-01-01

    The clinical manufacture of antigen-specific cytotoxic T lymphocytes (CTL) for adoptive immunotherapy is limited by the complexity and time required to produce large numbers with the desired function and specificity. The culture conditions required are rigorous, and in some cases only achieved in 2cm2 wells in which cell growth is limited by gas exchange, nutrients and waste accumulation. Bioreactors developed to overcome these issues tend to be complex, expensive and not always conducive to CTL growth. We observed that antigen-specific CTL undergo seven to ten divisions post-stimulation. However the expected CTL numbers were achieved only in the first week of culture. By recreating the culture conditions present during this first week - low frequency of antigen-specific T-cells and high frequency of feeder cells - we were able to increase CTL expansion to expected levels which could be sustained for several weeks without affecting phenotype or function. However, the number of 24-well plates needed was excessive and cultures required frequent media changes, increasing complexity and manufacturing costs. Therefore, we evaluated novel gas-permeable culture devices (G-Rex) with a silicone membrane at the base allowing gas exchange to occur uninhibited by depth of medium above. This system effectively supports the expansion of CTL and actually increases output by up to 20-fold while decreasing required technician time. Importantly, this amplified cell expansion is not due to more cell divisions but to reduced cell death. This bioprocess optimization increased T-cell output while decreasing the complexity and cost of CTL manufacture, making cell therapy more accessible. PMID:20445351

  20. 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.

  1. Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).

    Science.gov (United States)

    Mead, Richard J; Bennett, Ellen J; Kennerley, Aneurin J; Sharp, Paul; Sunyach, Claire; Kasher, Paul; Berwick, Jason; Pettmann, Brigitte; Battaglia, Guiseppe; Azzouz, Mimoun; Grierson, Andrew; Shaw, Pamela J

    2011-01-01

    The human SOD1(G93A) transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1(G93A) transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  2. Is enteral administration of fluorine-18-fluorodeoxyglucose (F-18 FDG) a palatable alternative to IV injection? Pre-clinical evaluation in normal rodents

    International Nuclear Information System (INIS)

    Higashi, T.; Fisher, S.J.; Nakada, K.; Romain, D.J.; Wahl, R.L.

    2002-01-01

    To establish effective methods of enteral 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) administration, the efficiency of FDG absorption in the gastrointestinal tracts following enteral administrations was evaluated using the FDG biodistribution in normal rodents, in combination with various fasting conditions and FDG diluents. The blood FDG curve using hypotonic solution showed a rapid increase, while that in iso- and hypertonic groups showed slow rises. Brain FDG uptake had a close positive correlation with blood AUC (area under curve) and an inverse relationship with the stomach contents

  3. Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

    Directory of Open Access Journals (Sweden)

    Bart eVaes

    2012-11-01

    Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  4. Radiosynthesis and pre-clinical evaluation of [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Graham [Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Zhao Yongjun [MDx Discovery (part of GE Healthcare) at Hammersmith Imanet, Ltd., Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Leyton, Julius [Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Shan Bo [MDx Discovery (part of GE Healthcare) at Hammersmith Imanet, Ltd., Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Nguyen, Quang-de; Perumal, Meg [Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Turton, David [GE-Imanet, Hammersmith Hospital, Du Cane Road, London, W12 0NN (United Kingdom); Arstad, Erik; Luthra, Sajinder K.; Robins, Edward G. [MDx Discovery (part of GE Healthcare) at Hammersmith Imanet, Ltd., Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom); Aboagye, Eric O., E-mail: eric.aboagye@imperial.ac.u [Comprehensive Cancer Imaging Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN (United Kingdom)

    2011-01-15

    Introduction: Choline radiotracers are widely used for clinical PET diagnosis in oncology. [{sup 11}C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[{sup 18}F]fluoro-2-deoxy-D-glucose ('FDG') shows high background uptake. More recently we have extended the clinical utility of [{sup 11}C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline, was synthesized and evaluated as a potential PET imaging probe. Methods: [{sup 18}F]Fluorocholine, [{sup 18}F]fluoro-[1-{sup 2}H{sub 2}]choline and [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline were synthesized by alkylation of the relevant precursor with [{sup 18}F]fluorobromomethane or [{sup 18}F]fluoromethyl tosylate. Radiosynthesis of [{sup 18}F]fluoromethyl tosylate required extensive modification of the existing method. [{sup 18}F]Fluorocholine and [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline were then subjected to in vitro oxidative stability analysis in a chemical oxidation model using potassium permanganate and an enzymatic model using choline oxidase. The two radiotracers, together with the corresponding di-deuterated compound, [{sup 18}F]fluoro-[1-{sup 2}H{sub 2}]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice. Results: Alkylation with [{sup 18}F]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [{sup 18}F]fluorocholine. The distribution of the three radiotracers, [{sup 18}F]fluorocholine, [{sup 18}F]fluoro-[1-{sup 2}H{sub 2}]choline and [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline was significantly increased at late time points compared to [{sup 18}F]fluorocholine and [{sup 18}F]fluoro-[1-{sup 2}H{sub 2}]choline. Conclusions: Stability analysis and biodistribution suggest that [{sup 18}F]fluoro-[1,2-{sup 2}H{sub 4}]choline warrants further in vivo investigation as a PET probe of choline metabolism.

  5. Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

    Czech Academy of Sciences Publication Activity Database

    Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 9-10 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

  6. 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.

  7. Comparison of three experimental protocols in pre clinical studies for thyroid cancer treatment using sodium butyrate in combination with boron neutron capture therapy (BNCT)

    International Nuclear Information System (INIS)

    Perona, M; Rodriguez, C; Carpano, M; Majdalani E; Nievas, S; Olivera, M; Pisarev, M; Cabrini, R; Juvenal, G; Dagrosa A

    2012-01-01

    Background: We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC). However new strategies are being assayed in order to optimize its application. Histone de acetylase inhibitors (HDAC-I) like sodium butyrate (NaB), are emerging as a new class of chemotherapeutic agents which target the epigenome. Since histone hyper acetylation mediates changes in chromatin conformation, HDAC-I are involved in different epigenetically controlled activities like apoptosis, proliferation, cell differentiation, induction of cell cycle arrest and motility. The purpose of the present studies was to analyze different treatment regimens of combination of NaB and boronophenylalanine (BPA) uptake in animals bearing transplants of a human thyroid carcinoma Methods: NIH nude mice of 6-8 weeks were implanted (s.c.) with 10 6 of human follicular thyroid carcinoma cells (WRO). Three regimens were evaluated in 48 animals after 15 days when tumors had a size between 50 and 100 mm 3 . Group 1 (n=10): BPA and NaB (50 mM) via i.p. at a dose of 110 mg/kg b.w. 24 h before boron compound administration; group 2 (n=10): BPA and NaB 3.4% in the water ad libitum during a month after 15 days post-implantation; group 3 (n=10): BPA alone. In all the groups BPA was injected at a dose of 350 mg/Kg b.w. (i.p.) and the animals were sacrificed at 2 h post-administration. Boron measurements in tissues and blood were performed by ICP-OES. A control group without NaB (n=6) for each regimen was included. The tumor growth and the body weight were determined twice a week during a month. Results: The administration of NaB 3.4% during a month previous to BNCT did not modify the body weight of the mice and decreased the tumor growth compared to its control group (p<0.01). The biodistribution studies showed a tumor boron concentration of 32.6 ± 1.4 ppm for group 1 (NaB 50 mM plus BPA), of 16.9 ± 3.7 ppm for group 2 (NaB 3.4% plus BPA) and of 22.5 ± 0.9 ppm for the group which received BPA alone. The tumor/blood and tumor/surrounding skin ratios were 6.93 and 2.85 for group 1; 6.22 and 2.49 for group 2 and 4.25 and 2.12 for group 3. Conclusions: The chronic administration of sodium butyrate in the water ad libitum did not affect the body weight and decreased the tumor volume showing an antitumoral compound activity by itself. However the BPA uptake was lower in this group than in the BPA group alone, which could be due to a decrease of the proliferative rate. The group which received NaB 24 h before BPA administration showed an increase in the tumor boron uptake that could be attributed to an increase in the expression of the BPA transporter. The sodium butyrate could be combined to BNCT for optimization of the treatment of thyroid carcinoma (author)

  8. Integrated assessment briefs

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-04-01

    Integrated assessment can be used to evaluate and clarify resource management policy options and outcomes for decision makers. The defining characteristics of integrated assessment are (1) focus on providing information and analysis that can be understood and used by decision makers rather than for merely advancing understanding and (2) its multidisciplinary approach, using methods, styles of study, and considerations from a broader variety of technical areas than would typically characterize studies produced from a single disciplinary standpoint. Integrated assessment may combine scientific, social, economic, health, and environmental data and models. Integrated assessment requires bridging the gap between science and policy considerations. Because not everything can be valued using a single metric, such as a dollar value, the integrated assessment process also involves evaluating trade-offs among dissimilar attributes. Scientists at Oak Ridge National Laboratory (ORNL) recognized the importance and value of multidisciplinary approaches to solving environmental problems early on and have pioneered the development of tools and methods for integrated assessment over the past three decades. Major examples of ORNL`s experience in the development of its capabilities for integrated assessment are given.

  9. Assessing Resource Assessment for MRE (Invited)

    Science.gov (United States)

    Hanson, H. P.; Bozec, A.; Duerr, A. S.; Rauchenstein, L. T.

    2010-12-01

    The Southeast National Marine Renewable Energy Center at Florida Atlantic University is concerned with marine renewable energy (MRE) recovery from the Florida Current using marine hydrokinetic technology and, in the future, from the thermocline in the Florida Straits via ocean thermal energy conversion. Although neither concept is new, technology improvements and the evolution of policy now warrant optimism for the future of these potentially rich resources. In moving toward commercial-scale deployments of energy-generating systems, an important first step is accurate and unembellished assessment of the resource itself. In short, we must ask: how much energy might be available? The answer to this deceptively simple question depends, of course, on the technology itself - system efficiencies, for example - but it also depends on a variety of other limiting factors such as deployment strategies, environmental considerations, and the overall economics of MRE in the context of competing energy resources. While it is universally agreed that MRE development must occur within a framework of environmental stewardship, it is nonetheless inevitable that there will be trade-offs between absolute environmental protection and realizing the benefits of MRE implementation. As with solar-energy and wind-power technologies, MRE technologies interact with the environment in which they are deployed. Ecological, societal, and even physical resource concerns all require investigation and, in some cases, mitigation. Moreover, the converse - how will the environment affect the equipment? - presents technical challenges that have confounded the seagoing community forever. Biofouling, for example, will affect system efficiency and create significant maintenance and operations issues. Because this will also affect the economics of MRE, nonlinear interactions among the limiting factors complicate the overall issue of resource assessment significantly. While MRE technology development is

  10. Characterisation of a behavioural protocol for the assessment of nociception in normal and inflamed porcine skin

    DEFF Research Database (Denmark)

    di Giminiani, Pierpaolo

    2012-01-01

    The study of pain has been historically based on the investigation of human clinical conditions with the purpose of identifying the direct causes of pain to develop suitable analgesic treatments. The need to comprehend the mechanisms behind the processes of pain ignited the rapid development of pre......-clinical research, based on the investigation of experimental models designed to reproduce painful conditions or parts thereof. Animals play a fundamental role, since they provide the platform to reproduce human conditions in order to study the mechanisms behind pain processes, and during the last three decades...... increasing scepticism because a large proportion of emerging pharmaceutical products never reached marketing approval due to poor correlations between preclinical therapeutic findings and the eventual efficacy of these compounds in clinical trials. Thus, the behavioural component of pre-clinical studies...

  11. CERCLA site assessment workbook

    International Nuclear Information System (INIS)

    1994-08-01

    This contains comments for each chapter of exercises (in Vol. 1) which illustrate how to conduct site assessments for CERCLA regulation. A through analysis of the exercises is provided so that work and solutions from Vol 1 can be critiqued and comments are also included on the strategy of site assessment whereas the exercises illustrate the principles involved. Covered exercises include the following: A preliminary assessment of a ground water site; waste characteristics and characterization of sources; documentation of observed releases and actual contamination of targets; the strategy of an SI at a surface water site; the soil exposure pathway; the air pathway

  12. Wadeable Streams Assessment Data

    Science.gov (United States)

    The Wadeable Streams Assessment (WSA) is a first-ever statistically-valid survey of the biological condition of small streams throughout the U.S. The U.S. Environmental Protection Agency (EPA) worked with the states to conduct the assessment in 2004-2005. Data for each parameter sampled in the Wadeable Streams Assessment (WSA) are available for downloading in a series of files as comma separated values (*.csv). Each *.csv data file has a companion text file (*.txt) that lists a dataset label and individual descriptions for each variable. Users should view the *.txt files first to help guide their understanding and use of the data.

  13. Assessing Big Data

    DEFF Research Database (Denmark)

    Leimbach, Timo; Bachlechner, Daniel

    2015-01-01

    In recent years, big data has been one of the most controversially discussed technologies in terms of its possible positive and negative impact. Therefore, the need for technology assessments is obvious. This paper first provides, based on the results of a technology assessment study, an overview...... of the potential and challenges associated with big data and then describes the problems experienced during the study as well as methods found helpful to address them. The paper concludes with reflections on how the insights from the technology assessment study may have an impact on the future governance of big...... data....

  14. Assessment of inclusive education

    DEFF Research Database (Denmark)

    Miller, Tanja

    2014-01-01

    The focus of this paper is on the way teachers, in teams can work with assessing the inclusive practice in their own classes. In 2012 a joint effort between CEPRA, teachers and school administrators from the municipality of Hjørring developed a dialog based model for continually assessing...... the quality of the learning environment in regard to inclusion – this model draws heavily on the logic and mindset of ECERS (Early child environment program). This article will relate the rationale of the assessment model called “Dialoger om Kvalitet” (dialogues on quality) to LSP’s definition of inclusion...

  15. Assessing Knowledge in Dialogue

    DEFF Research Database (Denmark)

    Tackney, Charles T.; Strømgren, Ole; Sato, Toyoko

    2013-01-01

    The Synopsis–Based Oral Examination (S–BOE) is described as deployed in international management education programs in a Danish business school. It assesses students in light of specified learning objectives through time–constrained presentation and dialogue. The format is premised on prior...... submission of a synopsis, although the synopsis has no bearing on grade assessment. Practitioner experience and student feedback suggest that students experience this type of examination as an important learning experience, in itself, in addition to testing course–related knowledge. We reviewed the current...... epistemological basis for grading, providing a critical realism corrective to enhance assessment and appropriation of this exam format....

  16. Crowdsourced emphysema assessment

    DEFF Research Database (Denmark)

    Ørting, Silas Nyboe; Cheplygina, Veronika; Petersen, Jens

    2017-01-01

    Classification of emphysema patterns is believed to be useful for improved diagnosis and prognosis of chronic obstructive pulmonary disease. Emphysema patterns can be assessed visually on lung CT scans. Visual assessment is a complex and time-consuming task performed by experts, making...... it unsuitable for obtaining large amounts of labeled data. We investigate if visual assessment of emphysema can be framed as an image similarity task that does not require expert. Substituting untrained annotators for experts makes it possible to label data sets much faster and at a lower cost. We use crowd...... annotators to gather similarity triplets and use t-distributed stochastic triplet embedding to learn an embedding. The quality of the embedding is evaluated by predicting expert assessed emphysema patterns. We find that although performance varies due to low quality triplets and randomness in the embedding...

  17. Assessing intravascular fluid status

    African Journals Online (AJOL)

    The assessment of intravascular fluid volume is a difficult undertaking in both the intensive care unit and theatre situation ... equally applicable to pulmonary capillary wedge pressure. .... airway pressure, the more difficult it becomes to interpret ...

  18. National Lakes Assessment Data

    Data.gov (United States)

    U.S. Environmental Protection Agency — The National Lakes Assessment (NLA) is a first-ever statistically-valid survey of the biological condition of lakes and reservoirs throughout the U.S. The U.S....

  19. Biosafety Risk Assessment Methodology

    Energy Technology Data Exchange (ETDEWEB)

    Caskey, Susan Adele [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). International Biological Threat Reduction Program; Gaudioso, Jennifer M. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). International Biological Threat Reduction Program; Salerno, Reynolds Mathewson [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). International Biological Threat Reduction Program; Wagner, Stefan M. [Public Health Agency of Canada, Winnipeg, MB (Canada). Canadian Science Centre for Human and Animal Health (CSCHAH); Shigematsu, Mika [National Inst. of Infectious Diseases (NIID), Tokyo (Japan); Risi, George [Infectious Disease Specialists, P.C, Missoula, MT (United States); Kozlovac, Joe [US Dept. of Agriculture (USDA)., Beltsville, MD (United States); Halkjaer-Knudsen, Vibeke [Statens Serum Inst., Copenhagen (Denmark); Prat, Esmeralda [Bayer CropScience, Monheim am Rhein (Germany)

    2010-10-01

    Laboratories that work with biological agents need to manage their safety risks to persons working the laboratories and the human and animal community in the surrounding areas. Biosafety guidance defines a wide variety of biosafety risk mitigation measures, which include measures which fall under the following categories: engineering controls, procedural and administrative controls, and the use of personal protective equipment; the determination of which mitigation measures should be used to address the specific laboratory risks are dependent upon a risk assessment. Ideally, a risk assessment should be conducted in a manner which is standardized and systematic which allows it to be repeatable and comparable. A risk assessment should clearly define the risk being assessed and avoid over complication.

  20. Energy consumption assessment methods

    Energy Technology Data Exchange (ETDEWEB)

    Sutherland, K S

    1975-01-01

    The why, what, and how-to aspects of energy audits for industrial plants, and the application of energy accounting methods to a chemical plant in order to assess energy conservation possibilities are discussed. (LCL)

  1. The library assessment cookbook

    CERN Document Server

    Dobbs, Aaron W

    2017-01-01

    The Library Assessment Cookbook features 80 practical, easy-to-implement recipes divided into nine sections. This Cookbook will help librarians of all levels of experience measure and demonstrate their institutional value.

  2. Superconducting Technology Assessment

    National Research Council Canada - National Science Library

    2005-01-01

    This Superconducting Technology Assessment (STA) has been conducted by the National Security Agency to address the fundamental question of a potential replacement for silicon complementary metal oxide semiconductor (CMOS...

  3. Alternative Assessment Techniques.

    Science.gov (United States)

    Lowenthal, Barbara

    1988-01-01

    Maintaining the precision necessary for administering norm referenced tests can be a problem for the special education teacher who is trained to assist the student. Criterion-referenced tests, observations, and interviews are presented as effective alternative assessment techniques. (JDD)

  4. Offsite transportation hazards assessment

    International Nuclear Information System (INIS)

    Burnside, M.E.

    1997-01-01

    This report documents the emergency preparedness Hazards Assessment for the offsite transportation of hazardous material from the Hanford Site. The assessment is required by the US Department of Energy (DOE) Order 151.1. Offsite transportation accidents are categorized using the DOE system to assist communication within the DOE and assure that appropriate assistance is provided to the people in charge at the scene. The assistance will initially include information about the load and the potential hazards. Local authorities will use the information to protect the public following a transportation accident. This Hazards Assessment will focus on the material being transported from the Hanford Site. Shipments coming to Hanford are the responsibility of the shipper and the carrier and, therefore, are not included in this Hazards Assessment, unless the DOE elects to be the shipper of record

  5. RCTA capstone assessment

    Science.gov (United States)

    Lennon, Craig; Bodt, Barry; Childers, Marshal; Dean, Robert; Oh, Jean; DiBerardino, Chip; Keegan, Terence

    2015-05-01

    The Army Research Laboratory's Robotics Collaborative Technology Alliance (RCTA) is a program intended to change robots from tools that soldiers use into teammates with which soldiers can work. This requires the integration of fundamental and applied research in perception, artificial intelligence, and human-robot interaction. In October of 2014, the RCTA assessed progress towards integrating this research. This assessment was designed to evaluate the robot's performance when it used new capabilities to perform selected aspects of a mission. The assessed capabilities included the ability of the robot to: navigate semantically outdoors with respect to structures and landmarks, identify doors in the facades of buildings, and identify and track persons emerging from those doors. We present details of the mission-based vignettes that constituted the assessment, and evaluations of the robot's performance in these vignettes.

  6. Offshore risk assessment

    CERN Document Server

    Vinnem, Jan-Erik

    2014-01-01

      Offshore Risk Assessment was the first book to deal with quantified risk assessment (QRA) as applied specifically to offshore installations and operations. Risk assessment techniques have been used for more than three decades in the offshore oil and gas industry, and their use is set to expand increasingly as the industry moves into new areas and faces new challenges in older regions.   This updated and expanded third edition has been informed by a major R&D program on offshore risk assessment in Norway and summarizes research from 2006 to the present day. Rooted with a thorough discussion of risk metrics and risk analysis methodology,  subsequent chapters are devoted to analytical approaches to escalation, escape, evacuation and rescue analysis of safety and emergency systems.   Separate chapters analyze the main hazards of offshore structures: fire, explosion, collision, and falling objects as well as structural and marine hazards. Risk mitigation and control are discussed, as well as an illustrat...

  7. National Coastal Condition Assessment

    Science.gov (United States)

    The NCCA is a collaborative, statistical survey of the nation's coastal waters and the Great Lakes. It is one of four national surveys that EPA and its partners conduct to assess the condition and health of the nation's water resources.

  8. Assessment and Testing.

    Science.gov (United States)

    Clapham, Caroline

    2000-01-01

    Explores the term "applied linguistics" and discusses the role of language testing within this discipline, the relationship between testing and teaching, and the relationship between testing and assessment (Author/VWL)

  9. Comprehensive geriatric assessment

    African Journals Online (AJOL)

    2007-09-14

    Sep 14, 2007 ... i.e. difficulty performing simple physical and mental tasks necessary for daily life. ... Definition. Comprehensive geriatric assessment (CGA) is a multidimensional .... The formation of a programme of therapy is decided on.

  10. USAID Construction Assessment

    Data.gov (United States)

    US Agency for International Development — The USAID construction assessment is a survey of the character, scope, value and management of construction activities supported by USAID during the period from June...

  11. An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

    Science.gov (United States)

    Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

    2009-09-01

    While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

  12. Risk Assessment Overview

    Science.gov (United States)

    Prassinos, Peter G.; Lyver, John W., IV; Bui, Chinh T.

    2011-01-01

    Risk assessment is used in many industries to identify and manage risks. Initially developed for use on aeronautical and nuclear systems, risk assessment has been applied to transportation, chemical, computer, financial, and security systems among others. It is used to gain an understanding of the weaknesses or vulnerabilities in a system so modification can be made to increase operability, efficiency, and safety and to reduce failure and down-time. Risk assessment results are primary inputs to risk-informed decision making; where risk information including uncertainty is used along with other pertinent information to assist management in the decision-making process. Therefore, to be useful, a risk assessment must be directed at specific objectives. As the world embraces the globalization of trade and manufacturing, understanding the associated risk become important to decision making. Applying risk assessment techniques to a global system of development, manufacturing, and transportation can provide insight into how the system can fail, the likelihood of system failure and the consequences of system failure. The risk assessment can identify those elements that contribute most to risk and identify measures to prevent and mitigate failures, disruptions, and damaging outcomes. In addition, risk associated with public and environment impact can be identified. The risk insights gained can be applied to making decisions concerning suitable development and manufacturing locations, supply chains, and transportation strategies. While risk assessment has been mostly applied to mechanical and electrical systems, the concepts and techniques can be applied across other systems and activities. This paper provides a basic overview of the development of a risk assessment.

  13. Safety Auditing and Assessments

    Science.gov (United States)

    Goodin, James Ronald (Ronnie)

    2005-01-01

    Safety professionals typically do not engage in audits and independent assessments with the vigor as do our quality brethren. Taking advantage of industry and government experience conducting value added Independent Assessments or Audits benefits a safety program. Most other organizations simply call this process "internal audits." Sources of audit training are presented and compared. A relation of logic between audit techniques and mishap investigation is discussed. An example of an audit process is offered. Shortcomings and pitfalls of auditing are covered.

  14. Agile software assessment

    OpenAIRE

    Nierstrasz Oscar; Lungu Mircea

    2012-01-01

    Informed decision making is a critical activity in software development but it is poorly supported by common development environments which focus mainly on low level programming tasks. We posit the need for agile software assessment which aims to support decision making by enabling rapid and effective construction of software models and custom analyses. Agile software assessment entails gathering and exploiting the broader context of software information related to the system at hand as well ...

  15. Inquiries and technological assessment

    International Nuclear Information System (INIS)

    1981-01-01

    The authors examine six Canadian inquiries to determine their values as scientific assessments, their ability to combine scientific data with policy considerations, and their effectiveness in extending public debate on scientific issues. Among the inquiries examined are the environmental assessment hearings into the Point Lepreau nuclear generating station, the Bayda inquiry into the Cluff Lake uranium mine, and the Porter commission on electric power planning in Ontario

  16. Operational risk assessment.

    Science.gov (United States)

    McKim, Vicky L

    2017-06-01

    In the world of risk management, which encompasses the business continuity disciplines, many types of risk require evaluation. Financial risk is most often the primary focus, followed by product and market risks. Another critical area, which typically lacks a thorough review or may be overlooked, is operational risk. This category encompasses many risk exposure types including those around building structures and systems, environmental issues, nature, neighbours, clients, regulatory compliance, network, data security and so on. At times, insurance carriers will assess internal hazards, but seldom do these assessments include more than a cursory look at other types of operational risk. In heavily regulated environments, risk assessments are required but may not always include thorough assessments of operational exposures. Vulnerabilities may linger or go unnoticed, only to become the catalyst for a business disruption at a later time, some of which are so severe that business recovery becomes nearly impossible. Businesses may suffer loss of clients as the result of a prolonged disruption of services. Comprehensive operational risk assessments can assist in identifying such vulnerabilities, exposures and threats so that the risk can be minimised or removed. This paper lays out how an assessment of this type can be successfully conducted.

  17. Assessment in Science Education

    Science.gov (United States)

    Rustaman, N. Y.

    2017-09-01

    An analyses study focusing on scientific reasoning literacy was conducted to strengthen the stressing on assessment in science by combining the important of the nature of science and assessment as references, higher order thinking and scientific skills in assessing science learning as well. Having background in developing science process skills test items, inquiry in its many form, scientific and STEM literacy, it is believed that inquiry based learning should first be implemented among science educators and science learners before STEM education can successfully be developed among science teachers, prospective teachers, and students at all levels. After studying thoroughly a number of science researchers through their works, a model of scientific reasoning was proposed, and also simple rubrics and some examples of the test items were introduced in this article. As it is only the beginning, further studies will still be needed in the future with the involvement of prospective science teachers who have interests in assessment, either on authentic assessment or in test items development. In balance usage of alternative assessment rubrics, as well as valid and reliable test items (standard) will be needed in accelerating STEM education in Indonesia.

  18. A framework for combining social impact assessment and risk assessment

    NARCIS (Netherlands)

    Mahmoudi, Hossein; Renn, Ortwin; Vanclay, Frank; Hoffmann, Volker; Karami, Ezatollah

    An increasing focus on integrative approaches is one of the current trends in impact assessment. There is potential to combine impact assessment with various other forms of assessment, such as risk assessment, to make impact assessment and the management of social risks more effective. We identify

  19. Assessment of Working Scientifically--The TAPS Focused Assessment Approach

    Science.gov (United States)

    McMahon, Kendra

    2018-01-01

    The Teacher Assessment in Primary Science (TAPS) Focused Assessment approach embeds assessment within normal classroom science activities. Essentially, a Focused Assessment is a lesson plan for a science inquiry, with an identified focus for assessment and guidance on how to interpret the children's responses in relation to expectations for that…

  20. A framework for combining social impact assessment and risk assessment

    NARCIS (Netherlands)

    Mahmoudi, Hossein; Renn, Ortwin; Vanclay, Frank; Hoffmann, Volker; Karami, Ezatollah

    2013-01-01

    An increasing focus on integrative approaches is one of the current trends in impact assessment. There is potential to combine impact assessment with various other forms of assessment, such as risk assessment, to make impact assessment and the management of social risks more effective. We identify

  1. State of risk assessment

    International Nuclear Information System (INIS)

    Conrad, J.

    1978-03-01

    In view of the growing importance assumed in recent years by scientific work on the calculation, quantification, evaluation and acceptance as well as behavior in the face of risks in general and more specifically, the risks of large industrial plants, the report attempts to provide a survey of the current situation, results and evaluation of this new branch of research, risk assessment. The emphasis of the report is on the basic discussion and criticism of the theoretical and methodological approaches used in the field of risk assessment (section 3). It is concerned above all with - methodical problems of determining and quantifying risks (3.1) - questions of the possibility of risk evaluation and comp arison (3.1, 3.2) - the premises of normative and empirical studies on decision making under risk (3.2, 3.3) - investigations into society's acceptance of risks involved in the introduction of new technologies (3.4) - attempts to combine various aspects of the field of risk assessment in a unified concept (3.5, 3.6, 3.7). Because risk assessment is embedded in the framework of decision theory and technology assessment, it can be implicitly evaluated at a more general level within this framework, as far as its possibilities and weaknesses of method and application are concerned (section 4). Sections 2 and 5 deal with the social context of origin and utilization of risk assessment. Finally, an attempt is made at a summary indicating the possible future development of risk assessment. (orig./HP) [de

  2. Assessment of Mental Status.

    Science.gov (United States)

    Finney, Glen R; Minagar, Alireza; Heilman, Kenneth M

    2016-02-01

    Assessing the mental status of patients with a neurobehavioral disorder is a critical element in the diagnosis and treatment of these patients. This assessment should always be performed after the patient's history it taken and a general physical as well as a neurologic examination is completed. The mental status examination commences with observing the patient's appearance and level of consciousness. The examiner should also pay attention to patient's social behavior, emotional state and mood. There are 3 major means of assessing a patient's mental status. One type attempts to determine if the patient is demented and the severity of the dementia as it pertains to their ability to perform activities of daily living as well as instrumental activities. A second type of assessment utilizes what may be termed as "screening tests" or "omnibus tests". These brief tests are performed independent of the patient's history and examination. The two most frequently used screening tests are the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The third means of assessing a patient's mental status is by using specific neuropsychological tests that focus on specific domains of cognition, such as frontal executive functions, attention, episodic verbal and visuospatial memory, declarative knowledge such as language (speech, reading and writing) and arithmetical, as well as visuospatial and perceptual abilities. These neurobehavioral, neuropsychiatric and neuropsychological assessments of patients with a cognitive decline and behavioral abnormalities should often be accompanied by laboratory tests, and neuroimaging that can help determine the underlying pathologic process so that effective therapeutic and management approaches can be provided. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Safety Assessment for Decommissioning

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-06-15

    In the past few decades, international guidance has been developed on methods for assessing the safety of predisposal and disposal facilities for radioactive waste. More recently, it has been recognized that there is also a need for specific guidance on safety assessment in the context of decommissioning nuclear facilities. The importance of safety during decommissioning was highlighted at the International Conference on Safe Decommissioning for Nuclear Activities held in Berlin in 2002 and at the First Review Meeting of the Joint Convention on the Safety of Spent Fuel Management and on the Safety of Radioactive Waste Management in 2003. At its June 2004 meeting, the Board of Governors of the IAEA approved the International Action Plan on Decommissioning of Nuclear Facilities (GOV/2004/40), which called on the IAEA to: ''establish a forum for the sharing and exchange of national information and experience on the application of safety assessment in the context of decommissioning and provide a means to convey this information to other interested parties, also drawing on the work of other international organizations in this area''. In response, in November 2004, the IAEA launched the international project Evaluation and Demonstration of Safety for Decommissioning of Facilities Using Radioactive Material (DeSa) with the following objectives: -To develop a harmonized approach to safety assessment and to define the elements of safety assessment for decommissioning, including the application of a graded approach; -To investigate the practical applicability of the methodology and performance of safety assessments for the decommissioning of various types of facility through a selected number of test cases; -To investigate approaches for the review of safety assessments for decommissioning activities and the development of a regulatory approach for reviewing safety assessments for decommissioning activities and as a basis for regulatory decision making; -To provide a forum

  4. Information technology resources assessment

    Energy Technology Data Exchange (ETDEWEB)

    Stevens, D.F. [ed.

    1992-01-01

    This year`s Information Technology Resources Assessment (ITRA) is something of a departure from traditional practice. Past assessments have concentrated on developments in fundamental technology, particularly with respect to hardware. They form an impressive chronicle of decreasing cycle times, increasing densities, decreasing costs (or, equivalently, increasing capacity and capability per dollar spent), and new system architectures, with a leavening of operating systems and languages. Past assessments have aimed -- and succeeded -- at putting information technology squarely in the spotlight; by contrast, in the first part of this assessment, we would like to move it to the background, and encourage the reader to reflect less on the continuing technological miracles of miniaturization in space and time and more on the second- and third-order implications of some possible workplace applications of these miracles. This Information Technology Resources Assessment is intended to provide a sense of technological direction for planners in projecting the hardware, software, and human resources necessary to support the diverse IT requirements of the various components of the DOE community. It is also intended to provide a sense of our new understanding of the place of IT in our organizations.

  5. Information technology resources assessment

    Energy Technology Data Exchange (ETDEWEB)

    Stevens, D.F. (ed.)

    1992-01-01

    This year's Information Technology Resources Assessment (ITRA) is something of a departure from traditional practice. Past assessments have concentrated on developments in fundamental technology, particularly with respect to hardware. They form an impressive chronicle of decreasing cycle times, increasing densities, decreasing costs (or, equivalently, increasing capacity and capability per dollar spent), and new system architectures, with a leavening of operating systems and languages. Past assessments have aimed -- and succeeded -- at putting information technology squarely in the spotlight; by contrast, in the first part of this assessment, we would like to move it to the background, and encourage the reader to reflect less on the continuing technological miracles of miniaturization in space and time and more on the second- and third-order implications of some possible workplace applications of these miracles. This Information Technology Resources Assessment is intended to provide a sense of technological direction for planners in projecting the hardware, software, and human resources necessary to support the diverse IT requirements of the various components of the DOE community. It is also intended to provide a sense of our new understanding of the place of IT in our organizations.

  6. Software reliability assessment

    International Nuclear Information System (INIS)

    Barnes, M.; Bradley, P.A.; Brewer, M.A.

    1994-01-01

    The increased usage and sophistication of computers applied to real time safety-related systems in the United Kingdom has spurred on the desire to provide a standard framework within which to assess dependable computing systems. Recent accidents and ensuing legislation have acted as a catalyst in this area. One particular aspect of dependable computing systems is that of software, which is usually designed to reduce risk at the system level, but which can increase risk if it is unreliable. Various organizations have recognized the problem of assessing the risk imposed to the system by unreliable software, and have taken initial steps to develop and use such assessment frameworks. This paper relates the approach of Consultancy Services of AEA Technology in developing a framework to assess the risk imposed by unreliable software. In addition, the paper discusses the experiences gained by Consultancy Services in applying the assessment framework to commercial and research projects. The framework is applicable to software used in safety applications, including proprietary software. Although the paper is written with Nuclear Reactor Safety applications in mind, the principles discussed can be applied to safety applications in all industries

  7. Transdisciplinary knowledge integration : cases from integrated assessment and vulnerability assessment

    NARCIS (Netherlands)

    Hinkel, J.

    2008-01-01

    Keywords: climate change, integrated assessment, knowledge integration, transdisciplinary research, vulnerability, vulnerability assessment.
    This thesis explores how transdisciplinary knowledge integration can be facilitated in the context of integrated assessments and vulnerability

  8. Assessment of cardiovascular risk.

    LENUS (Irish Health Repository)

    Cooney, Marie Therese

    2010-10-01

    Atherosclerotic cardiovascular disease (CVD) is the most common cause of death worldwide. Usually atherosclerosis is caused by the combined effects of multiple risk factors. For this reason, most guidelines on the prevention of CVD stress the assessment of total CVD risk. The most intensive risk factor modification can then be directed towards the individuals who will derive the greatest benefit. To assist the clinician in calculating the effects of these multiple interacting risk factors, a number of risk estimation systems have been developed. This review address several issues regarding total CVD risk assessment: Why should total CVD risk be assessed? What risk estimation systems are available? How well do these systems estimate risk? What are the advantages and disadvantages of the current systems? What are the current limitations of risk estimation systems and how can they be resolved? What new developments have occurred in CVD risk estimation?

  9. Chlorine transportation risk assessment

    International Nuclear Information System (INIS)

    Lautkaski, Risto; Mankamo, Tuomas.

    1977-02-01

    An assessment has been made on the toxication risk of the population due to the bulk rail transportation of liquid chlorine in Finland. Fourteen typical rail accidents were selected and their probability was estimated using the accident file of the Finnish State Railways. The probability of a chlorine leak was assessed for each type of accident separately using four leak size categories. The assessed leakage probability was dominated by station accidents, especially by collisions of a chlorine tanker and a locomotive. Toxication hazard areas were estimated for the leak categories. A simple model was constructed to describe the centring of the densely populated areas along the railway line. A comparison was made between the obtained risk and some other risks including those due to nuclear reactor accidents. (author)

  10. The Research Assessment Exercise

    Directory of Open Access Journals (Sweden)

    Lee-Anne Broadhead

    1998-04-01

    Full Text Available In this article it is argued that the recent Research Assessment Exercise (RAE--undertaken by the United Kingdom's Higher Education Funding Councils (HEFC--is part of a much larger process of assessment in education generally. By taking the RAE as its focus, this article uses a Foucaultian analysis to amplify the nature and practice of disciplinary power in the setting of Higher Education. Foucault's notion of an "integrated system" of control and production, with its routine operation of surveillance and assessment--and its dependence on coercion and consent--is directly applied to the RAE. The impact on research and teaching is discussed. The critical response of academics to the exercise has failed to challenge the process in any fundamental way. it is argued here that this failure is a reflection of the degree to which disciplinary logic is embedded in the academic system.

  11. Assessment of strategy formulation

    DEFF Research Database (Denmark)

    Acur, Nuran; Englyst, Linda

    2006-01-01

    of the success criteria through face-to-face interviews with 46 managers, workshops involving 40 managers, and two in-depth case studies. The success criteria have been slightly modified due to the empirical results, to yield the assessment tool. Findings – The resulting assessment tool integrates three generic...... approaches to strategy assessment, namely the goal-centred, comparative and improvement approaches, as found in the literature. Furthermore, it encompasses three phases of strategy formulation processes: strategic thinking, strategic planning and embedding of strategy. The tool reflects that the different......, but cases and managerial perceptions indicate that the need for accurate and detailed plans might be overrated in the literature, as implementation relies heavily on continuous improvement and empowerment. Concerning embedding, key aspects relate both to the goal-centred and improvement approaches, while...

  12. Overview of risk assessment

    International Nuclear Information System (INIS)

    Rimington, J.D.

    1992-01-01

    The paper begins by defining some terms, and then refer to a number of technical and other difficulties. Finally it attempts to set out why risk assessment is important and what its purposes are. 2) First, risk and risk assessment - what are they?. 3) Risk is a subject of universal significance. Life is very uncertain, and we can achieve no object or benefit in it except by approaching nearer to particular hazards which lie between us and our objects. That approach represents acceptance of risk. 4) Risk assessment is a way of systematising our approach to hazard with a view to determining what is more and what is less risky. It helps us in the end to diminish our exposure while obtaining whatever benefits we have in mind, or to optimise the risks and the benefits

  13. Overview of risk assessment

    Energy Technology Data Exchange (ETDEWEB)

    Rimington, J D [Health and Safety Executive (United Kingdom)

    1992-07-01

    The paper begins by defining some terms, and then refer to a number of technical and other difficulties. Finally it attempts to set out why risk assessment is important and what its purposes are. 2) First, risk and risk assessment - what are they?. 3) Risk is a subject of universal significance. Life is very uncertain, and we can achieve no object or benefit in it except by approaching nearer to particular hazards which lie between us and our objects. That approach represents acceptance of risk. 4) Risk assessment is a way of systematising our approach to hazard with a view to determining what is more and what is less risky. It helps us in the end to diminish our exposure while obtaining whatever benefits we have in mind, or to optimise the risks and the benefits.

  14. Training assessments and assistance

    International Nuclear Information System (INIS)

    Przybylski, J.L.

    1994-07-01

    The Transportation Management Division, Office of Environmental Restoration and Waste Management (TMD/EM-261), United States Department of Energy (DOE), Training Program Manager has established an independent Training Assessment Program, the intent of which is to evaluate, exclusively, transportation and packaging training activities throughout the Department of Energy (DOE) community. The results generated from an application of the Training Assessment Program are intended to be utilized as a management tool for maintaining compliance with applicable regulatory-driven training requirements. In addition, the Transportation Assessment Program can be employed to evaluate training methodologies and, through a pre-arranged, cooperative, technical assistance effort, provide each Department of Energy (DOE) site with the means necessary to enhance it's overall transportation and packaging training capabilities

  15. Patient caries risk assessment

    DEFF Research Database (Denmark)

    Twetman, Svante; Fontana, Margherita

    2009-01-01

    Risk assessment is an essential component in the decision-making process for the correct prevention and management of dental caries. Multiple risk factors and indicators have been proposed as targets in the assessment of risk of future disease, varying sometimes based on the age group at which...... they are targeted. Multiple reviews and systematic reviews are available in the literature on this topic. This chapter focusses primarily on results of reviews based on longitudinal studies required to establish the accuracy of caries risk assessment. These findings demonstrate that there is a strong body...... of evidence to support that caries experience is still, unfortunately, the single best predictor for future caries development. In young children, prediction models which include a variety of risk factors seem to increase the accuracy of the prediction, while the usefulness of additional risk factors...

  16. Assessment methods for rehabilitation.

    Science.gov (United States)

    Biefang, S; Potthoff, P

    1995-09-01

    Diagnostics and evaluation in medical rehabilitation should be based on methods that are as objective as possible. In this context quantitative methods are an important precondition. We conducted for the German Pensions Insurance Institutions (which are in charge of the medical and vocational rehabilitation of workers and employees) a survey on assessment methods for rehabilitation which included an evaluation of American literature, with the aim to indicate procedures that can be considered for adaptation in Germany and to define further research requirements. The survey identified: (1) standardized procedures and instrumented tests for the assessment of musculoskeletal, cardiopulmonary and neurophysiological function; (2) personality, intelligence, achievement, neuropsychological and alcoholism screening tests for the assessment of mental or cognitive function; (3) rating scales and self-administered questionnaires for the assessment of Activities of Daily Living and Instrumental Activities of Daily Living (ADL/IADL Scales); (4) generic profiles and indexes as well as disease-specific measures for the assessment of health-related quality of life and health status; and (5) rating scales for vocational assessment. German equivalents or German versions exist only for a part of the procedures identified. Translation and testing of Anglo-Saxon procedures should have priority over the development of new German methods. The following procedures will be taken into account: (a) instrumented tests for physical function, (b) IADL Scales, (c) generic indexes of health-related quality of life, (d) specific quality of life and health status measures for disorders of the circulatory system, metabolic system, digestive organs, respiratory tract and for cancer, and (e) vocational rating scales.

  17. HEPA Filter Vulnerability Assessment

    International Nuclear Information System (INIS)

    GUSTAVSON, R.D.

    2000-01-01

    This assessment of High Efficiency Particulate Air (HEPA) filter vulnerability was requested by the USDOE Office of River Protection (ORP) to satisfy a DOE-HQ directive to evaluate the effect of filter degradation on the facility authorization basis assumptions. Within the scope of this assessment are ventilation system HEPA filters that are classified as Safety-Class (SC) or Safety-Significant (SS) components that perform an accident mitigation function. The objective of the assessment is to verify whether HEPA filters that perform a safety function during an accident are likely to perform as intended to limit release of hazardous or radioactive materials, considering factors that could degrade the filters. Filter degradation factors considered include aging, wetting of filters, exposure to high temperature, exposure to corrosive or reactive chemicals, and exposure to radiation. Screening and evaluation criteria were developed by a site-wide group of HVAC engineers and HEPA filter experts from published empirical data. For River Protection Project (RPP) filters, the only degradation factor that exceeded the screening threshold was for filter aging. Subsequent evaluation of the effect of filter aging on the filter strength was conducted, and the results were compared with required performance to meet the conditions assumed in the RPP Authorization Basis (AB). It was found that the reduction in filter strength due to aging does not affect the filter performance requirements as specified in the AB. A portion of the HEPA filter vulnerability assessment is being conducted by the ORP and is not part of the scope of this study. The ORP is conducting an assessment of the existing policies and programs relating to maintenance, testing, and change-out of HEPA filters used for SC/SS service. This document presents the results of a HEPA filter vulnerability assessment conducted for the River protection project as requested by the DOE Office of River Protection

  18. Onsite transportation hazards assessment

    International Nuclear Information System (INIS)

    Burnside, M.E.

    1998-01-01

    This report documents the emergency preparedness Hazards Assessment for the onsite transportation of hazardous material at the Hanford Site. The assessment is required by US Department of Energy (DOE) Order 5500.3A and provides the technical basis for the emergency classification and response procedures. A distinction is made between onsite for the purpose of emergency preparedness and onsite for the purpose of applying US Department of Transportation (DOT) regulations. Onsite for the purpose of emergency preparedness is considered to be within the physical boundary of the entire Hanford Site. Onsite for the purpose of applying DOT regulations is north of the Wye Barricade

  19. Reactor Safety Assessment System

    International Nuclear Information System (INIS)

    Sebo, D.E.; Bray, M.A.; King, M.A.

    1987-01-01

    The Reactor Safety Assessment System (RSAS) is an expert system under development for the United States Nuclear Regulatory Commission (USNRC). RSAS is designed for use at the USNRC Operations Center in the event of a serious incident at a licensed nuclear power plant. RSAS is a situation assessment expert system which uses plant parametric data to generate conclusions for use by the NRC Reactor Safety Team. RSAS uses multiple rule bases and plant specific setpoint files to be applicable to all licensed nuclear power plants in the United States. RSAS currently covers several generic reactor categories and multiple plants within each category

  20. Reactor safety assessment system

    International Nuclear Information System (INIS)

    Sebo, D.E.; Bray, M.A.; King, M.A.

    1987-01-01

    The Reactor Safety Assessment System (RSAS) is an expert system under development for the United States Nuclear Regulatory Commission (USNRC). RSA is designed for use at the USNRC Operations Center in the event of a serious incident at a licensed nuclear power plant. RSAS is a situation assessment expert system which uses plant parametric data to generate conclusions for use by the NRC Reactor Safety Team. RSAS uses multiple rule bases and plant specific setpoint files to be applicable to all licensed nuclear power plants in the United States. RSAS currently covers several generic reactor categories and multiple plants within each category

  1. Dose. Detriment. Limit assessment

    International Nuclear Information System (INIS)

    Breckow, J.

    2015-01-01

    One goal of radiation protection is the limitation of stochastic effects due to radiation exposure. The probability of occurrence of a radiation induced stochastic effect, however, is only one of several other parameters which determine the radiation detriment. Though the ICRP-concept of detriment is a quantitative definition, the kind of detriment weighting includes somewhat subjective elements. In this sense, the detriment-concept of ICRP represents already at the stage of effective dose a kind of assessment. Thus, by comparing radiation protection standards and concepts interconvertible or with those of environment or occupational protection one should be aware of the possibly different principles of detriment assessment.

  2. Acute pain assessment

    LENUS (Irish Health Repository)

    Clear, Elaine

    2016-05-01

    The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” (IASP, 1997). This definition of pain emphasises that it is neither a sensory nor an emotional experience, but a combination of both. It is a subjective experience influenced by physical, psychological and environmental factors that is assessed from a biopsychosocial perspective. The gold standard in assessing pain however is always what the patient says it is.

  3. Impact assessment revisited

    DEFF Research Database (Denmark)

    Thiele, Jan; Kollmann, Johannes Christian; Markussen, Bo

    2010-01-01

    ; and (4) the total invaded range is an inappropriate measure for quantifying regional impact because the habitat area available for invasion can vary markedly among invasive species. Mathematical models and empirical data using an invasive alien plant species (Heracleum mantegazzianum) indicate......The theoretical underpinnings of the assessment of invasive alien species impacts need to be improved. At present most approaches are unreliable to quantify impact at regional scales and do not allow for comparison of different invasive species. There are four basic problems that need...... and we discuss the quantification of the invaded range. These improvements are crucial for impact assessment with the overall aim of prioritizing management of invasive species....

  4. Geothermal industry assessment

    Energy Technology Data Exchange (ETDEWEB)

    1980-07-01

    An assessment of the geothermal industry is presented, focusing on industry structure, corporate activities and strategies, and detailed analysis of the technological, economic, financial, and institutional issues important to government policy formulation. The study is based principally on confidential interviews with executives of 75 companies active in the field. (MHR)

  5. Assessment: The Alternative

    Science.gov (United States)

    FORUM: for promoting 3-19 comprehensive education, 2017

    2017-01-01

    This position statement presents a summative argument against current structures and practices of assessment in England's primary schools, and some key principles for its replacement. The text was agreed by More Than A Score, a broad coalition of professional, curriculum, research and campaigning organisations opposed to the current assessment…

  6. Assessing cataract surgical competency

    NARCIS (Netherlands)

    Lee, Andrew G.; Greenlee, Emily; Oetting, Thomas A.; Beaver, Hilary A.; Johnson, A. Tim; Boldt, H. Culver; Abramoff, Michael; Olson, Richard; Carter, Keith

    2007-01-01

    The Accreditation Council for Graduate Medical Education has mandated that all residency training programs teach and assess 6 general competencies.1 A.G. Lee and K.D. Carter, Managing the new mandate in resident education: A blueprint for translating a national mandate into local compliance,

  7. Assessment of School Image

    Directory of Open Access Journals (Sweden)

    Ludvík Eger

    2018-06-01

    Full Text Available There seems to be a gap in the literature on educational management that focuses on school image and its assessment. This paper addresses this issue by reviewing the state of the art regarding school image and communication with the public.School image can be defined as the overall impression and mosaic synthesised from numerous impressions of individuals of school publics (pupils/students, teachers and deputies of school management, parents, and other stakeholders. School image is not what the headteachers understand it to be, but the feelings and beliefs about the school and its educational programme that exist in the minds of the school publics. The present study contributes to the literature by providing an overview of school image and by providing a practical application of a useful tool for assessing the content of corporate image. Semantic differential scales are used for marketing purposes and as a useful technique for measuring and assessing school image. Communication with publics and the development and sustainability of a positive school image influence not only the marketing of the school but also the educational process in the school. Today, shaping and maintaining a school image is even more important because of the curriculum reform, focusing on higher study process outputs, quality assessments, and accountability. The findings of this study have important implications for school marketing experts and researchers, headteachers, education policymakers, as well as teachers at schools.

  8. Groundwater Assessment Platform

    OpenAIRE

    Podgorski, Joel; Berg, Michael

    2018-01-01

    The Groundwater Assessment Platform is a free, interactive online GIS platform for the mapping, sharing and statistical modeling of groundwater quality data. The modeling allows users to take advantage of publicly available global datasets of various environmental parameters to produce prediction maps of their contaminant of interest.

  9. Hazard waste risk assessment

    International Nuclear Information System (INIS)

    Hawley, K.A.; Napier, B.A.

    1986-01-01

    Pacific Northwest Laboratory continued to provide technical assistance to the Department of Energy (DOE) Office of Operational Safety (OOS) in the area of risk assessment for hazardous and radioactive-mixed waste management. The overall objective is to provide technical assistance to OOS in developing cost-effective risk assessment tools and strategies for bringing DOE facilities into compliance with the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund) and the Resource Conservation and Recovery Act (RCRA). Major efforts during FY 1985 included (1) completing the modification of the Environmental Protection Agency (EPA) Hazard Ranking System (HRS) and developing training manuals and courses to assist in field office implementation of the modified Hazard Ranking System (mHRS); (2) initiating the development of a system for reviewing field office HRS/mHRS evaluations for appropriate use of data and appropriate application of the methodology; (3) initiating the development of a data base management system to maintain all field office HRS/mHRS scoring sheets and to support the master OOS environmental data base system; (4) developing implementation guidance for Phase I of the DOE CERCLA Program, Installation Assessment; (5) continuing to develop an objective, scientifically based methodology for DOE management to use in establishing priorities for conducting site assessments under Phase II of the DOE CERCLA Program, Confirmation; and (6) participating in developing the DOE response to EPA on the proposed listing of three sites on the National Priorities List

  10. Assessing for Technological Literacy

    Science.gov (United States)

    Engstrom, Daniel E.

    2004-01-01

    Designing standards-based assessment is a key component of a quality technology education program. For students to become technologically literate, it is important that the teacher understands how to measure student understandings and abilities in the study of technology. This article is written to help teachers and teacher educators recognize the…

  11. Self Assessment for Socializing

    Science.gov (United States)

    McDonald, Betty

    2011-01-01

    Socializing is an integral part of human relations and auger well for the human development. Defined as "the involvement of students in identifying standards and/or criteria to apply to their work and making judgments about the extent to which they have met these criteria and standards", self assessment by its nature teaches students how to…

  12. Strategic Risk Assessment

    Science.gov (United States)

    Derleth, Jason; Lobia, Marcus

    2009-01-01

    This slide presentation provides an overview of the attempt to develop and demonstrate a methodology for the comparative assessment of risks across the entire portfolio of NASA projects and assets. It includes information about strategic risk identification, normalizing strategic risks, calculation of relative risk score, and implementation options.

  13. Crowdsourced emphysema assessment

    DEFF Research Database (Denmark)

    Ørting, Silas Nyboe; Petersen, Jens; Thomsen, Laura H.

    2017-01-01

    it unsuitable for obtaining large amounts of labeled data. We investigate if visual assessment of emphysema can be framed as an image similarity task that does not require expert. Substituting untrained annotators for experts makes it possible to label data sets much faster and at a lower cost. We use crowd...

  14. Assessment Hotspots, 1998.

    Science.gov (United States)

    Ahearn, Charles, Ed.; Nalley, Donna, Ed.; Casbon, Christy, Ed.

    1998-01-01

    SouthEastern Regional Vision for Education (SERVE) is one of the 10 federally funded regional educational laboratories. This annual publication captures and shares the experiences of SERVE school districts that have volunteered to share their efforts at assessment reform. This issue contains the following: (1) "We Never Get over the Fear of…

  15. Life Cycle Impact Assessment

    DEFF Research Database (Denmark)

    Rosenbaum, Ralph K.; Hauschild, Michael Zwicky; Boulay, Anne-Marie

    2018-01-01

    This chapter is dedicated to the third phase of an LCA study, the Life Cycle Impact Assessment (LCIA) where the life cycle inventory’s information on elementary flows is translated into environmental impact scores. In contrast to the three other LCA phases, LCIA is in practice largely automated...

  16. Health needs assessment

    Directory of Open Access Journals (Sweden)

    Ibrahim A Bani

    2008-01-01

    The findings of the assessment of the health needs of Jazan presented in this review could be utilized as a baseline and reference information for policy formulation, subsequent planning and cost effective intervention programs. It could also be utilized for the curriculum development or review for a community oriented medical schools.

  17. Assessing Scientific Performance.

    Science.gov (United States)

    Weiner, John M.; And Others

    1984-01-01

    A method for assessing scientific performance based on relationships displayed numerically in published documents is proposed and illustrated using published documents in pediatric oncology for the period 1979-1982. Contributions of a major clinical investigations group, the Childrens Cancer Study Group, are analyzed. Twenty-nine references are…

  18. Assessing Intercultural Training Designs

    Science.gov (United States)

    Graf, Andrea

    2004-01-01

    Training designs are critical to the success of intercultural training programmes. A common typology for classifying intercultural training designs distinguishes among the following dimensions: experiential discovery versus didactic expository and culture-specific versus culture-general training. The purpose of this paper is to assess different…

  19. Simply Performance Assessment

    Science.gov (United States)

    McLaughlin, Cheryl A.; McLaughlin, Felecia C.; Pringle, Rose M.

    2013-01-01

    This article presents the experiences of Miss Felecia McLaughlin, a fourth-grade teacher from the island of Jamaica who used the model proposed by Bass et al. (2009) to assess conceptual understanding of four of the six types of simple machines while encouraging collaboration through the creation of learning teams. Students had an opportunity to…

  20. Financial Sector Assessment : Morocco

    OpenAIRE

    World Bank

    2003-01-01

    This Financial Sector Assessment (FSA) provides a summary of the policy priorities, and main findings intended to assist the Moroccan authorities in evaluating the country's financial system. It reviews the uneasy trade-off between concerns for stability, and development, suggesting Morocco's macroeconomic policies and practices as a whole tend to err more on the side of the concerns of pr...