Canine pseudopregnancy: an evaluation of prevalence and current treatment protocols in the UK

Background: There is a dearth of literature on pseudopregnancy in the bitch, with only a few treatment-based studies published since the 1990s. Pseudopregnancy may be under-recognised in bitches and may account for a proportion of behavioural cases seen in veterinary practices including aggression. Little is known about commonly used treatments for overtly pseudopregnant bitches and it is possible that current regimes may not be prescribed for a sufficient duration to control any clinical signs including, physical and behavioural changes. To investigate current trends in diagnosis and treatment of canine pseudopregnancy, a postal survey was sent to 2000 randomly selected veterinary surgeons in UK veterinary practices. The questionnaire queried how often vets recognise cases of pseudopregnancy in spayed and entire bitches, which physical or behavioural signs are commonly recognised for diagnosis, and which management or treatment protocols are used. Results: The response rate was 19.8% (397/2000). Ninety-six percent of veterinary surgeons reported seeing pseudopregnant bitches showing behavioural changes without any physical changes within the last 12 months. Of those behavioural changes, collecting and mothering objects was the most frequently reported behavioural sign (96%). Ninety-seven percent of vets had seen aggression in pseudopregnant bitches. Nevertheless, only 52% of vets routinely asked owners about behavioural changes during consultations. Forty-nine percent of respondents reported seeing pseudopregnancy in spayed bitches. The most commonly reported physical sign was enlarged mammary glands and/or milk production (89%). Treatment options varied (surgical, medical or none) and depended on duration and severity of physical and behavioural signs, owners’ preference, cost, concurrent disease, drug availability and previous history. Conclusions: This is the largest epidemiological study of canine pseudopregnancy in the UK. The prevalence and severity of clinical signs in dogs with pseudopregnancy are variable and possibly under-estimated. Dogs with overt pseudopregnancy experience diverse physical and behavioural changes and information on standard treatment protocols are lacking. Although, progress on our understanding of diagnosis and treatment of pseudopregnancy in spayed and entire bitches has been made, further studies are warranted

Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

Exploring the usefulness of scenario archetypes in science-policy processes: experience across IPBES assessments

Scenario analyses have been used in multiple science-policy assessments to better understand complex plausible futures. Scenario archetype approaches are based on the fact that many future scenarios have similar underlying storylines, assumptions, and trends in drivers of change, which allows for grouping of scenarios into typologies, or archetypes, facilitating comparisons between a large range of studies. The use of scenario archetypes in environmental assessments foregrounds important policy questions and can be used to codesign interventions tackling future sustainability issues. Recently, scenario archetypes were used in four regional assessments and one ongoing global assessment within the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services (IPBES). The aim of these assessments was to provide decision makers with policy-relevant knowledge about the state of biodiversity, ecosystems, and the contributions they provide to people. This paper reflects on the usefulness of the scenario archetype approach within science-policy processes, drawing on the experience from the IPBES assessments. Using a thematic analysis of (a) survey data collected from experts involved in the archetype analyses across IPBES assessments, (b) notes from IPBES workshops, and (c) regional assessment chapter texts, we synthesize the benefits, challenges, and frontiers of applying the scenario archetype approach in a science-policy process. Scenario archetypes were perceived to allow syntheses of large amounts of information for scientific, practice-, and policy-related purposes, streamline key messages from multiple scenario studies, and facilitate communication of them to end users. In terms of challenges, they were perceived as subjective in their interpretation, oversimplifying information, having a limited applicability across scales, and concealing contextual information and novel narratives. Finally, our results highlight what methodologies, applications, and frontiers in archetype-based research should be explored in the future. These advances can assist the design of future large-scale sustainability-related assessment processes, aiming to better support decisions and interventions for equitable and sustainable futures

Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer

Background:Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC).Methods:We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients ⩾18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety.Results:Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) ⩾8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated.Conclusions:The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival

Beyond Academia: A case for reviews of gray literature for science-policy processes and applied research

Gray literature is increasingly considered to complement evidence and knowledge from peer-reviewed literature for science-policy processes and applied research. On the one hand, science-policy assessments need to both consider a diversity of worldviews, knowledge types and values from a variety of sectors and actor groups, and synthesize policy-relevant findings that are salient, legitimate and credible. On the other hand, practitioners and scholars conducting applied research, especially in environmental and health-related fields, are affected by the time lag and documented biases of academic publication processes. While gray literature holds diverse perspectives that need to be integrated in science-policy processes as well as practical evidence unfiltered by commercial publication processes, its heterogeneity has made it challenging to access through conventional means for a literature review. This paper details one endeavor within the Values Assessment of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) to review gray literature using Google’s Programmable Search Engine. In the absence of a standardized approach, we build on a limited experiential knowledge base for reviewing gray literature and report on the potential applicability of our strategy for future reviews. Our results contrast the findings of our parallel review of academic literature, underlining the importance of mobilizing different knowledge bases in science-policy assessments, evidence-based practices, and applied research

Quiescence: early evolutionary origins and universality do not imply uniformity

Cell cycle investigations have focused on relentless exponential proliferation of cells, an unsustainable situation in nature. Proliferation of cells, whether microbial or metazoan, is interrupted by periods of quiescence. The vast majority of cells in an adult metazoan lie quiescent. As disruptions in this quiescence are at the foundation of cancer, it will be important for the field to turn its attention to the mechanisms regulating quiescence. While often presented as a single topic, there are multiple forms of quiescence each with complex inputs, some of which are tied to conceptually challenging aspects of metazoan regulation such as size control. In an effort to expose the enormity of the challenge, I describe the differing biological purposes of quiescence, and the coupling of quiescence in metazoans to growth and to the structuring of tissues during development. I emphasize studies in the organism rather than in tissue culture, because these expose the diversity of regulation. While quiescence is likely to be a primitive biological process, it appears that in adapting quiescence to its many distinct biological settings, evolution has diversified it. Consideration of quiescence in different models gives us an overview of this diversity

Distilling the role of ecosystem services in the Sustainable Development Goals

Achieving well-being for all, while protecting the environment, is one of the most pressing global challenges of our time, and a central idea in the UN Sustainable Development Goals (SDGs). We believe that integrating ecosystem services, the benefits nature provides to people, into strategies for meeting the SDGs can help achieve this. Many development goals are likely underpinned by the delivery of one or more ecosystem services. Understanding how these services could support multiple development targets will be essential for planning synergistic and cost-effective interventions. Here we present the results of an expert survey on the contributions of 16 ecosystem services to achieving SDG targets linked to environment and human well-being, and review the capacity of modelling tools to evaluate SDG-relevant ecosystem services interactions. Survey respondents judged that individual ecosystem services could make important contributions to achieving 41 targets across 12 SDGs. The provision of food and water, habitat &amp; biodiversity maintenance, and carbon storage &amp; sequestration were perceived to each make contributions to &gt;14 SDG targets, suggesting cross-target interactions are likely, and may present opportunities for synergistic outcomes across multiple SDGs. Existing modelling tools are well-aligned to support SDG-relevant ecosystem service planning. Together, this work identifies entry points and tools to further analyze the role of ecosystem services to support the SDGs.</p

A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement <it>in vitro</it>, independent of the growth factor milieu, and inhibits tumor growth <it>in vivo </it>in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models.</p> <p>Methods</p> <p>We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis <it>in vitro</it>. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models.</p> <p>Results</p> <p>A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC₅₀= 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (<it>p </it>< 0.05) and this inhibition correlates with a concomitant decrease in vessel density.</p> <p>Conclusion</p> <p>The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1 activity and confirms that inhibition of integrin α5β1 impedes angiogenesis and slows tumor growth <it>in vivo</it>.</p