Effect of dietary treatment with dimethylarsinous acid (DMA\u3csup\u3eIII\u3c/sup\u3e) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAV, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMAIII was shown to be the likely urinary metabolite of DMAV inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMAIII-induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMAIII, 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1–5, with higher rating indicating greater extent of cytotoxicity visualized. DMAIII significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMAIII induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMAIII induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMAV does not induce hyperplasia in mice, suggesting that urinary concentrations of DMAIII do not reach cytotoxic levels in DMAV-treated mice

Effect of dietary treatment with dimethylarsinous acid (DMA\u3csup\u3eIII\u3c/sup\u3e) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAV, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMAIII was shown to be the likely urinary metabolite of DMAV inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMAIII-induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMAIII, 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1–5, with higher rating indicating greater extent of cytotoxicity visualized. DMAIII significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMAIII induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMAIII induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMAV does not induce hyperplasia in mice, suggesting that urinary concentrations of DMAIII do not reach cytotoxic levels in DMAV-treated mice

Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells

AbstractChronic exposure to high levels of inorganic arsenic (iAs) has been associated with cancerous and non-cancerous health effects, including cardiovascular effects. However, the mechanism for a presumed toxic effect of arsenic on vascular tissue is not clear. Our working hypothesis is that inorganic trivalent arsenic and its methylated metabolites react with cysteine-containing cellular proteins and alter their function leading to adverse events such as cytotoxicity or proliferation. In this study, human microvascular endothelial cells (HMEC1) and mouse microvascular endothelial cells (MFP-MVEC) were exposed to arsenite (iAsIII), monomethylarsonous acid (MMAIII), or dimethylarsinous acid (DMAIII) for 72h to evaluate cytotoxicity, and for 24, 48 or 72h to evaluate cell proliferation. Both cell lines showed similar LC50 values, from 0.1 to 2.4μM, for all three trivalent arsenicals. The endothelial cells treated with1nM to 1μM concentrations of the three trivalent arsenicals did not show increased cell proliferation at 24, 48 or 72h or increased rate of proliferation at 72h of exposure. Overall, cytotoxicity of trivalent arsenicals to microvascular endothelial cells is similar to their cytotoxicity to epithelial cells, and that these compounds are not mitogenic

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery

Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo.

The apicomplexan parasite Neospora caninum is an important causative agent of congenital neosporosis, resulting in abortion, birth of weak offspring and neuromuscular disorders in cattle, sheep, and many other species. Among several compound classes that are currently being developed, two have been reported to limit the effects of congenital neosporosis: (i) bumped kinase inhibitors (BKIs) target calcium dependent protein kinase 1 (CDPK1), an enzyme that is encoded by an apicoplast-derived gene and found only in apicomplexans and plants. CDPK1 is essential for host cell invasion and egress; (ii) endochin-like quinolones (ELQs) are inhibitors of the cytochrome bc1 complex of the mitochondrial electron transport chain and thus inhibit oxidative phosphorylation. We here report on the in vitro and in vivo activities of BKI-1748, and of ELQ-316 and its respective prodrugs ELQ-334 and ELQ-422, applied either as single-compounds or ELQ-BKI-combinations. In vitro, BKI-1748 and ELQ-316, as well as BKI-1748 and ELQ-334, acted synergistically, while this was not observed for the BKI-1748/ELQ-422 combination treatment. In a N. caninum-infected pregnant BALB/c mouse model, the synergistic effects observed in vitro were not entirely reproduced, but 100% postnatal survival and 100% inhibition of vertical transmission was noted in the group treated with the BKI-1748/ELQ-334 combination. In addition, the combined drug applications resulted in lower neonatal mortality compared to treatments with single drugs

Engaging with History after Macpherson

The Race Relations Amendment Act (2000) identifies a key role for education, and more specifically history, in promoting ‘race equality’ in Britain. In this article Ian Grosvenor and Kevin Myers consider the extent of young people’s current engagement with the history of ‘diversity, change and immigration’ which underpins the commitment to ‘race equality’. Finding that in many of Britain’s schools and universities a singular and exclusionary version of history continues to dominate the curriculum, they go on to consider the reasons for the neglect of multiculturalism. The authors identify the development of an aggressive national identity that depends on the past for its legitimacy and argue that this sense of the past is an important obstacle to future progress

C5 Palsy After Cervical Spine Surgery: A Multicenter Retrospective Review of 59 Cases.

STUDY DESIGN: A multicenter, retrospective review of C5 palsy after cervical spine surgery. OBJECTIVE: Postoperative C5 palsy is a known complication of cervical decompressive spinal surgery. The goal of this study was to review the incidence, patient characteristics, and outcome of C5 palsy in patients undergoing cervical spine surgery. METHODS: We conducted a multicenter, retrospective review of 13 946 patients across 21 centers who received cervical spine surgery (levels C2 to C7) between January 1, 2005, and December 31, 2011, inclusive. P values were calculated using 2-sample t test for continuous variables and χ(2) tests or Fisher exact tests for categorical variables. RESULTS: Of the 13 946 cases reviewed, 59 patients experienced a postoperative C5 palsy. The incidence rate across the 21 sites ranged from 0% to 2.5%. At most recent follow-up, 32 patients reported complete resolution of symptoms (54.2%), 15 had symptoms resolve with residual effects (25.4%), 10 patients did not recover (17.0%), and 2 were lost to follow-up (3.4%). CONCLUSION: C5 palsy occurred in all surgical approaches and across a variety of diagnoses. The majority of patients had full recovery or recovery with residual effects. This study represents the largest series of North American patients reviewed to date

Numerical Simulation of Bolide Entry with Ground Footprint Prediction

As they decelerate through the atmosphere, meteors deposit mass, momentum and energy into the surrounding air at tremendous rates. Trauma from the entry of such bolides produces strong blast waves that can propagate hundreds of kilometers and cause substantial terrestrial damage even when no ground impact occurs. We present a new simulation technique for airburst blast prediction using a fully-conservative, Cartesian mesh, finite-volume solver and investigate the ability of this method to model far- field propagation over hundreds of kilometers. The work develops mathematical models for the deposition of mass, momentum and energy into the atmosphere and presents verification and validation through canonical problems and the comparison of surface overpressures, and blast arrival times with actual results in the literature for known bolides. The discussion also examines the effects of various approximations to the physics of bolide entry that can substantially decrease the computational expense of these simulations. We present parametric studies to quantify the influence of entry-angle, burst-height and other parameters on the ground footprint of the airburst, and these values are related to predictions from analytic and handbook-methods

The antisaccade task as an index of sustained goal activation in working memory: modulation by nicotine

The antisaccade task provides a laboratory analogue of situations in which execution of the correct behavioural response requires the suppression of a more prepotent or habitual response. Errors (failures to inhibit a reflexive prosaccade towards a sudden onset target) are significantly increased in patients with damage to the dorsolateral prefrontal cortex and patients with schizophrenia. Recent models of antisaccade performance suggest that errors are more likely to occur when the intention to initiate an antisaccade is insufficiently activated within working memory. Nicotine has been shown to enhance specific working memory processes in healthy adults. MATERIALS AND METHODS: We explored the effect of nicotine on antisaccade performance in a large sample (N = 44) of young adult smokers. Minimally abstinent participants attended two test sessions and were asked to smoke one of their own cigarettes between baseline and retest during one session only. RESULTS AND CONCLUSION: Nicotine reduced antisaccade errors and correct antisaccade latencies if delivered before optimum performance levels are achieved, suggesting that nicotine supports the activation of intentions in working memory during task performance. The implications of this research for current theoretical accounts of antisaccade performance, and for interpreting the increased rate of antisaccade errors found in some psychiatric patient groups are discussed

Climate-smart agriculture global research agenda: Scientific basis for action

Background: Climate-smart agriculture (CSA) addresses the challenge of meeting the growing demand for food, fibre and fuel, despite the changing climate and fewer opportunities for agricultural expansion on additional lands. CSA focuses on contributing to economic development, poverty reduction and food security; maintaining and enhancing the productivity and resilience of natural and agricultural ecosystem functions, thus building natural capital; and reducing trade-offs involved in meeting these goals. Current gaps in knowledge, work within CSA, and agendas for interdisciplinary research and science-based actions identified at the 2013 Global Science Conference on Climate-Smart Agriculture (Davis, CA, USA) are described here within three themes: (1) farm and food systems, (2) landscape and regional issues and (3) institutional and policy aspects. The first two themes comprise crop physiology and genetics, mitigation and adaptation for livestock and agriculture, barriers to adoption of CSA practices, climate risk management and energy and biofuels (theme 1); and modelling adaptation and uncertainty, achieving multifunctionality, food and fishery systems, forest biodiversity and ecosystem services, rural migration from climate change and metrics (theme 2). Theme 3 comprises designing research that bridges disciplines, integrating stakeholder input to directly link science, action and governance. Outcomes: In addition to interdisciplinary research among these themes, imperatives include developing (1) models that include adaptation and transformation at either the farm or landscape level; (2) capacity approaches to examine multifunctional solutions for agronomic, ecological and socioeconomic challenges; (3) scenarios that are validated by direct evidence and metrics to support behaviours that foster resilience and natural capital; (4) reductions in the risk that can present formidable barriers for farmers during adoption of new technology and practices; and (5) an understanding of how climate affects the rural labour force, land tenure and cultural integrity, and thus the stability of food production. Effective work in CSA will involve stakeholders, address governance issues, examine uncertainties, incorporate social benefits with technological change, and establish climate finance within a green development framework. Here, the socioecological approach is intended to reduce development controversies associated with CSA and to identify technologies, policies and approaches leading to sustainable food production and consumption patterns in a changing climate