Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Knowledge dynamics in the tourism-social entrepreneurship nexus

Tourism is often employed as a vehicle for facilitating social-economic development, however its usefulness has been somewhat limited in relation to addressing social issues, and in particular, those issues relating to poverty. This is partly due to the lack of cross-sectoral interactions and knowledge exchange between private, public and third sectors that are needed to create effective and appropriate initiatives to leverage tourism for social benefits. Such traditional sectoral boundaries can be broken down through social entrepreneurship approaches which concomitantly, facilitate the creation and synergizing of social innovation that addresses persistent social issues. Yet to date, the utility of cross-sectoral knowledge dynamics still remains largely under-researched in both the social entrepreneurship and tourism literature. This chapter introduces readers to the concept of knowledge dynamics and discusses knowledge dynamics in the tourism and social entrepreneurship nexus via a case study of community-based tourism in Mai Hich, Vietnam. We argue that by gaining an enhanced understanding of cross-sectoral knowledge dynamics, we can strengthen the overall praxis of tourism and social entrepreneurship, and in particular, assist policymakers in fostering conditions that generate increased innovation.Griffith Business School, Department of Tourism, Sport and Hotel ManagementNo Full Tex

Antipsychotic withdrawal symptoms: Phenomenology and pathophysiology

The authors review the literature discribing non-dyskinetic antipsychotic withdrawal phenomena. Withdrawal of these agents can cause nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness and insomnia, but the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65190/1/j.1600-0447.1988.tb05116.x.pd

Interaction between Coastal and Oceanic Ecosystems of the Western and Central Pacific Ocean through Predator-Prey Relationship Studies

The Western and Central Pacific Ocean sustains the highest tuna production in the world. This province is also characterized by many islands and a complex bathymetry that induces specific current circulation patterns with the potential to create a high degree of interaction between coastal and oceanic ecosystems. Based on a large dataset of oceanic predator stomach contents, our study used generalized linear models to explore the coastal-oceanic system interaction by analyzing predator-prey relationship. We show that reef organisms are a frequent prey of oceanic predators. Predator species such as albacore (Thunnus alalunga) and yellowfin tuna (Thunnus albacares) frequently consume reef prey with higher probability of consumption closer to land and in the western part of the Pacific Ocean. For surface-caught-predators consuming reef prey, this prey type represents about one third of the diet of predators smaller than 50 cm. The proportion decreases with increasing fish size. For predators caught at depth and consuming reef prey, the proportion varies with predator species but generally represents less than 10%. The annual consumption of reef prey by the yellowfin tuna population was estimated at 0.8±0.40CV million tonnes or 2.17×1012±0.40CV individuals. This represents 6.1%±0.17CV in weight of their diet. Our analyses identify some of the patterns of coastal-oceanic ecosystem interactions at a large scale and provides an estimate of annual consumption of reef prey by oceanic predators

State history and economic development: evidence from six millennia

The presence of a state is one of the most reliable historical predictors of social and economic development. In this article, we complete the coding of an extant indicator of state presence from 3500 BCE forward for almost all but the smallest countries of the world today. We outline a theoretical framework where accumulated state experience increases aggregate productivity in individual countries but where newer or relatively inexperienced states can reach a higher productivity maximum by learning from the experience of older states. The predicted pattern of comparative development is tested in an empirical analysis where we introduce our extended state history variable. Our key finding is that the current level of economic development across countries has a hump-shaped relationship with accumulated state history

Learning to Use Illumination Gradients as an Unambiguous Cue to Three Dimensional Shape

The luminance and colour gradients across an image are the result of complex interactions between object shape, material and illumination. Using such variations to infer object shape or surface colour is therefore a difficult problem for the visual system. We know that changes to the shape of an object can affect its perceived colour, and that shading gradients confer a sense of shape. Here we investigate if the visual system is able to effectively utilise these gradients as a cue to shape perception, even when additional cues are not available. We tested shape perception of a folded card object that contained illumination gradients in the form of shading and more subtle effects such as inter-reflections. Our results suggest that observers are able to use the gradients to make consistent shape judgements. In order to do this, observers must be given the opportunity to learn suitable assumptions about the lighting and scene. Using a variety of different training conditions, we demonstrate that learning can occur quickly and requires only coarse information. We also establish that learning does not deliver a trivial mapping between gradient and shape; rather learning leads to the acquisition of assumptions about lighting and scene parameters that subsequently allow for gradients to be used as a shape cue. The perceived shape is shown to be consistent for convex and concave versions of the object that exhibit very different shading, and also similar to that delivered by outline, a largely unrelated cue to shape. Overall our results indicate that, although gradients are less reliable than some other cues, the relationship between gradients and shape can be quickly assessed and the gradients therefore used effectively as a visual shape cue

The effects of patient characteristics on ADHD diagnosis and treatment: a factorial study of family physicians

<p>Abstract</p> <p>Background</p> <p>Attention Deficit Hyperactivity Disorder (ADHD) is a costly and prevalent disorder in the U.S., especially among youth. However, significant disparities in diagnosis and treatment appear to be predicted by the race and insurance status of patients.</p> <p>Methods</p> <p>This study employed a web-based factorial survey with four ADHD cases derived from an ADHD clinic, two diagnosed with ADHD in actual evaluation, and two not. Randomized measures included race and insurance status of the patients. Participants N = (187) included clinician members of regional and national practice-based research networks and the U.S. clinical membership of the Society of Teachers of Family Medicine. The main outcomes were decisions to 1) diagnose and 2) treat the cases, based upon the information presented, analyzed via binary logistic regression of the randomized factors and case indicators on diagnosis and treatment.</p> <p>Results</p> <p>ADHD-positive cases were 8 times more likely to be diagnosed and 12 times more likely to be treated, and the male ADHD positive case was more likely to be diagnosed and treated than the female ADHD positive case. Uninsured cases were significantly more likely to be treated overall, but male cases that were uninsured were about half as likely to be diagnosed and treated with ADHD. Additionally, African-American race appears to increase the likelihood of medicinal treatment for ADHD and being both African-American and uninsured appears to cut the odds of medicinal treatment in half, but not significantly.</p> <p>Conclusions</p> <p>Family physicians were competent at discerning between near-threshold ADHD-negative and ADHD positive cases. However, insurance status and race, as well as gender, appear to affect the likelihood of diagnosis and treatment for ADHD in Family Medicine settings.</p

Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth

Does rapid HIV disease progression prior to combination antiretroviral therapy hinder optimal CD4 + T-cell recovery once HIV-1 suppression is achieved?

Objective: This article compares trends in CD4+ T-cell recovery and proportions achieving optimal restoration (>=500 cells/µl) after viral suppression following combination antiretroviral therapy (cART) initiation between rapid and nonrapid progressors. Methods: We included HIV-1 seroconverters achieving viral suppression within 6 months of cART. Rapid progressors were individuals experiencing at least one CD4+ less than 200 cells/µl within 12 months of seroconverters before cART. We used piecewise linear mixed models and logistic regression for optimal restoration. Results: Of 4024 individuals, 294 (7.3%) were classified as rapid progressors. At the same CD4+ T-cell count at cART start (baseline), rapid progressors experienced faster CD4+ T-cell increases than nonrapid progressors in first month [difference (95% confidence interval) in mean increase/month (square root scale): 1.82 (1.61; 2.04)], which reversed to slightly slower increases in months 1–18 [-0.05 (-0.06; -0.03)] and no significant differences in 18–60 months [-0.003 (-0.01; 0.01)]. Percentage achieving optimal restoration was significantly lower for rapid progressors than nonrapid progressors at months 12 (29.2 vs. 62.5%) and 36 (47.1 vs. 72.4%) but not at month 60 (70.4 vs. 71.8%). These differences disappeared after adjusting for baseline CD4+ T-cell count: odds ratio (95% confidence interval) 0.86 (0.61; 1.20), 0.90 (0.38; 2.17) and 1.56 (0.55; 4.46) at months 12, 36 and 60, respectively. Conclusion: Among people on suppressive antiretroviral therapy, rapid progressors experience faster initial increases of CD4+ T-cell counts than nonrapid progressors, but are less likely to achieve optimal restoration during the first 36 months after cART, mainly because of lower CD4+ T-cell counts at cART initiation

The scale, governance, and sustainability of central places in pre-Hispanic Mesoamerica

Examinations of the variation and relative successes or failures of past large-scale societies have long involved attempts to reconcile efforts at generalization and the identification of specific factors with explanatory value for regional trajectories. Although historical particulars are critical to understanding individual cases, there are both scholarly and policy rationales for drawing broader implications regarding the growing corpus of cross-cultural data germane to understanding variability in the constitution of human societies, past and present. Archaeologists have recently highlighted how successes and failures in communal-resource management can be studied over the long term through the material record to both engage and enhance transdisciplinary research on cooperation and collective action. In this article we consider frameworks that have been traditionally employed in studies of the rise, diversity, and fall of preindustrial urban aggregations. We suggest that a comparative theoretical perspective that foregrounds collective-action problems, unaligned individual and group interests, and the social mechanisms that promote or hamper cooperation advances our understanding of variability in these early cooperative arrangements. We apply such a perspective to an examination of pre-Hispanic Mesoamerican urban centers to demonstrate tendencies for more collective systems to be larger and longer lasting than less collective ones, likely reflecting greater sustainability in the face of the ecological and cultural perturbations specific to the region and era.Accepted manuscrip