2,454 research outputs found

    Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis

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    Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible

    Strong mass effect on ion beam mixing in metal bilayers

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    Molecular dynamics simulations have been used to study the mechanism of ion beam mixing in metal bilayers. We are able to explain the ion induced low-temperature phase stability and melting behavior of bilayers using only a simple ballistic picture up to 10 keV ion energies. The atomic mass ratio of the overlayer and the substrate constituents seems to be a key quantity in understanding atomic mixing. The critical bilayer mass ratio of δ<0.33\delta < 0.33 is required for the occurrence of a thermal spike (local melting) with a lifetime of τ>0.3\tau > 0.3 ps at low-energy ion irradiation (1 keV) due to a ballistic mechanism. The existing experimental data follow the same trend as the simulated values.Comment: 4 pages, 4 figures, preprin

    Doing more with less: Teacher professional learning communities in resource-constrained primary schools in rural China.

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    Teacher professional learning communities provide environments in which teachers engage in regular research and collaboration. They have been found effective as a means for connecting professional learning to the day-to-day realities faced by teachers in the classroom. In this article, the authors draw on survey data collected in primary schools serving 71 villages in rural Gansu Province as well as transcripts from in-depth interviews with 30 teachers. Findings indicate that professional learning communities penetrate to some of China’s most resource-constrained schools but that their nature and development are shaped by institutional supports, principal leadership, and teachers’ own initiative

    Editor\u27s Special Section-Larry Schnoor: A Celebration of His Impact on Intercollegiate Forensics

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    This panel is honoring Professor Larry Schnoor for his lifelong contribu-tions to Intercollegiate Forensics. National Individual Events Tournaments have continued to flourish under his direction. In addition, his constant mentoring has guaranteed the life of this activity. Panelists will describe Professor Schnoor‘s impact on the AFA-NIET, NFA, IOC and both his mentoring of forensic coaches and programs. Professor Schnoor will help to clarify and add to this oral history

    Analytical solution of a model for complex food webs

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    We investigate numerically and analytically a recently proposed model for food webs [Nature {\bf 404}, 180 (2000)] in the limit of large web sizes and sparse interaction matrices. We obtain analytical expressions for several quantities with ecological interest, in particular the probability distributions for the number of prey and the number of predators. We find that these distributions have fast-decaying exponential and Gaussian tails, respectively. We also find that our analytical expressions are robust to changes in the details of the model.Comment: 4 pages (RevTeX). Final versio

    An unprecedented case of cranial surgery in Longobard Italy (6th–8th century) using a cruciform incision

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    The Longobard necropolis of Castel Trosino dates from the 6th to the 8th century CE. Among the tombs excavated, the skull of an older female shows the first evidence of a cross-shaped bone modification on a living subject. Macroscopic, microscopic, and CT scan analyses revealed signs of at least two sets of scraping marks. Specifically, SEM analysis shows that perimortem bone-scraping traces are present on the skull. Both healed and non-healed defects suggest that the woman has received at least twice intentional bone modifications to address her condition. This is the first evidence of a cross-shaped therapeutic intervention on a living subject

    Ethical and compliance-competence evaluation: a key element of sound corporate governance

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    Motivated by the ongoing post-Enron refocusing on corporate governance and the shift by the Financial Services Authority (FSA) in the UK to promoting compliance- competence within the financial services sector, this paper demonstrates how template analysis can be used as a tool for evaluating compliance-competence. Focusing on the ethical dimension of compliance-competence, we illustrate how this can be subjectively appraised. We propose that this evaluation technique could be utilised as a starting point in informing senior management of corporate governance issues and be used to monitor and demonstrate key compliance and ethical aspects of an institution to external stakeholders and regulators
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