Cross-Sectional Study of Characteristics of Owners and Nonowners Surrendering Cats to Four Australian Animal Shelters

Unwanted cats surrendered to nonhuman animal shelters are generally categorized as either “owned” or “stray.” This classification is misleading because “stray” cats may include many “semiowned” cats, for which people provide care but who are not perceived as being owned. This differentiation is important because effective strategies designed to reduce cat admissions to, and euthanasia rates in, shelters rely on accurate information about cat populations contributing to shelter intake; cat semiowners will likely respond to different strategies than people with no relationship with the cats they surrender. People surrendering cats to four Australian animal shelters were surveyed to identify factors associated with perception of ownership. Many self-classified nonowners had fed the cats they surrendered, often for a considerable period of time. The factor most strongly associated with ownership perception was an increasing association time with the cat. These findings confirm that enduring relationships between surrenderers and cats, consistent with cat semiownership, are common for cats surrendered to Australian animal shelters. This finding should be taken into account when planning education messages and cat population management strategies aimed at reducing cat admissions.     

Tree diversity is key for promoting the diversity and abundance of forest-associated taxa in Europe

Plant diversity is an important driver of diversity at other trophic levels, suggesting that cascading extinctions could reduce overall biodiversity. Most evidence for positive effects of plant diversity comes from grasslands. Despite the fact that forests are hotspots of biodiversity, the importance of tree diversity, in particular its relative importance compared to other management related factors, in affecting forest-associated taxa is not well known. To address this, we used data from 183 plots, located in different forest types, from Mediterranean to Boreal, and established along a climatic gradient across six European countries (FunDivEUROPE project). We tested the influence of tree diversity, tree functional composition (i.e. functional trait values), forest structure, climate and soil on the diversity and abundance/activity of nine taxa (bats, birds, spiders, microorganisms, earthworms, ungulates, foliar fungal pathogens, defoliating insects and understorey plants) and on their overall diversity and abundance/activity (multidiversity, multiabundance/activity). Tree diversity was a key driver of taxon-level and overall forest-associated biodiversity, along with tree functional composition, forest structure, climate and soil. Both tree species richness and functional diversity (variation in functional trait values) were important. The effects of tree diversity on the abundance/activity of forest-associated taxa were less consistent. Nonetheless, spiders, ungulates and foliar fungal pathogens were all more abundant/active in diverse forests. Tree functional composition and structure were also important drivers of abundance/activity: conifer stands had lower overall multidiversity (although the effect was driven by defoliating insects), while stands with potentially tall trees had lower overall multiabundance/activity. We found more synergies than tradeoffs between diversity and abundance/activity of different taxa, suggesting that forest management can promote high diversity across taxa. Our results clearly show the high value of mixed forest stands for multiple forest-associated taxa and indicate that multiple dimensions of tree diversity (taxonomic and functional) are important.     

Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine

Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP-BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1, suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy.     

Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor,in Patients with Metastatic Gastric Cancer

Purpose

The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma.

Patients and Methods

Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity.

Results

From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25–88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9–7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment.

Conclusion

These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00725712","term_id":"NCT00725712"}}NCT00725712     

A Cross Sectional Analysis of the Role of the Antimicrobial Peptide Cathelicidin in Lung Function Impairment within the ALIVE Cohort

Background

Vitamin D deficiency is associated with reduced lung function. Cathelicidin, an antimicrobial peptide regulated by vitamin D, plays a role within the innate immune system. The association of cathelicidin with lung function decrement and respiratory infection is undefined.We determined the independent relationship of cathelicidin with lung function.

Methods

In a cross-sectional analysis of 650 participants in an urban observational cohort with high smoking prevalence, plasma 25(OH)-vitamin D and cathelicidin levels were measured from stored samples obtained within 6 months of spirometry study visits. Multivariable linear regression was used to determine the independent association between low cathelicidin (defined as the lowest quartile of the cohort) and absolute forced expiratory volume in 1 second (FEV1).

Results

The mean age of the cohort was 49 years; 91% were black, 35% female and 41% HIV-infected. Participants with low cathelicidin had a 183 mL lower FEV1 compared to higher cathelicidin (p = 0.009); this relationship was maintained (115 ml lower; p = 0.035) after adjusting for demographics, BMI, and smoking. Neither HIV serostatus, heavy smoking history, nor 25(OH)-vitamin D levels were associated with cathelicidin levels. Participants with low cathelicidin had a greater prevalence of prior bacterial pneumonia (21% versus 14%; p = 0.047). Inclusion of pneumonia in adjusted models did not substantially reduce the FEV1 decrement observed with low cathelicidin (104 mL lower FEV1; p = 0.05). Lung function decrements associated with low cathelicidin were greatest among individuals with lower 25(OH)-vitamin D levels.

Conclusions

In a cohort at risk for airflow obstruction, low cathelicidin was independently associated with lower FEV1. These clinical data support a mechanistic link between 25(OH)-vitamin D deficiency and lung function impairment, independent of pneumonia risk.     

Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.     

Phosphatidylinositol mannosides: synthesis and suppression of allergic airway disease

Phosphatidylinositol mannoside (PIM) extracts from mycobacteria have been shown previously to suppress allergic airway inflammation in mice. To help determine the structural requirements for activity, PIM1(2) (1), PIM1(6) (2) and PIM2 (3) were synthesized and tested for their ability to suppress cellular inflammation in a mouse model of allergic asthma. The synthetic PIMs were all effective in suppressing airway eosinophilia in the asthma model, with PIM1(6) being the most effective. Suppression of all inflammatory cells monitored was observed, indicating a general blockade of cellular inflammation. Non-mannosylated phosphatidylinositol (PI) had no suppressive effect, indicating that at least one alpha-d-mannopyranosyl residue is necessary for activity. The suppressive effect of the three PIM compounds indicates that other members of this set may be of value in treatment of a range of diseases driven by infiltration of inflammatory cells.     

"Walking along beside the researcher": how Canadian REBs/IRBs are responding to the needs of community-based participatory research

Research ethics boards and institutional review boards (REBs/IRBs) have been criticized for relying on conceptions of research that privilege biomedical, clinical, and experimental designs, and for penalizing research that deviates from this model. Studies that use a community-based participatory research (CBPR) design have been identified as particularly challenging to navigate through existing ethics review frameworks. However, the voices of REB/IRB members and staff have been largely absent in this debate. The objective of this article is to explore the perspectives of members of Canadian university-based REBs/IRBs regarding their capacity to review CBPR protocols. We present findings from interviews with 24 Canadian REB/IRB members, staff, and other key informants. Participants were asked to describe and contrast their experiences reviewing studies using CBPR and mainstream approaches. Contrary to the perception that REBs/IRBs are inflexible and unresponsive, participants described their attempts to dialogue and negotiate with researchers and to provide guidance. Overall, these Canadian REBs/IRBs demonstrated a more complex understanding of CBPR than is typically characterized in the literature. Finally, we situate our findings within literature on relational ethics and explore the possibility of researchers and REBs/IRBs working collaboratively to find solutions to unique ethical tensions in CBPR.     

Increased PCP removal by <Emphasis Type="Italic">Amylomyces rouxii</Emphasis> transformants with heterologous <Emphasis Type="Italic">Phanerochaete chrysosporium</Emphasis> peroxidases supplementing their natural degradative pathway

Fungal peroxidases and phenoloxidases are widely used in aromatic toxic compounds degradation. Peroxidases, such as lignin peroxidase and manganese peroxidase, as well as laccases are mainly produced by basidiomycetes and to a lower extent by other fungi, such as ascomycetes. Peroxidase-encoding genes have been described and homologous expression has been achieved in basidiomycetes. Heterologous expression has also been achieved in some non-producing peroxidase ascomycetes, like Penicillium and Aspergillus. In this work, heterologous expression of peroxidase-encoding genes, lignin peroxidase, and manganese peroxidase was achieved in a zygomycete producing only phenoloxidases (Amylomyces rouxii), aimed at coupling two different pathways used in nature for PCP removal in only one microbial strain. The ability of PCP removal was assayed with one of the obtained transformants, resulting in increased activity with respect to the ability of the parental strain cultured free of the inducer tyrosine (95% and 45%, respectively, of the initial PCP (12.5 mg L⁻¹) in 120 h, or 100% and 49%, respectively, of the initial PCP after 144 h of liquid culture).     

Placental calcium provision in a lizard with prolonged oviductal egg retention

A prominent scenario for the evolution of viviparity and placentation in reptiles predicts a step-wise pattern with an initial phase of prolonged oviductal egg retention accompanied by progressive reduction in eggshell thickness culminating in viviparity; calcium placentotrophy evolves secondarily to viviparity. Saiphos equalis is an Australian scincid lizard with a reproductive mode that is uncommon for squamates because eggs are retained in the oviduct until late developmental stages, and the embryonic stage at oviposition varies geographically. We studied calcium mobilization by embryos in two populations with different oviductal egg retention patterns to test the hypothesis that the pattern of nutritional provision of calcium is independent of the embryonic stage at oviposition. Females from one population are viviparous and oviposit eggs containing fully formed embryos, whereas embryos in oviposited eggs of the second population are morphologically less mature, and these eggs hatch several days later. The reproductive mode of this population is denoted as prolonged oviductal egg retention. Yolk provided the highest proportion of calcium to hatchlings in both populations. Eggs of both populations were enclosed in calcified eggshells, but shells of the population with prolonged egg retention had twice the calcium content of the viviparous population and embryos recovered calcium from these eggshells. Placental transfer accounted for a substantial amount of calcium in hatchlings in both populations. Hatchling calcium concentration was higher in the population with prolonged egg retention because these embryos mobilized calcium from yolk, the eggshell and the placenta. This pattern of embryonic calcium provision in which both a calcified eggshell and placentotrophy contribute to embryonic nutrition is novel. The reproductive pattern of S. equalis illustrates that calcified eggshells are compatible with prolonged oviductal egg retention and that viviparity is not requisite to calcium placentotrophy.