Avian Papilloma and Squamous Cell Carcinoma: a Histopathological, Immunohistochemical and Virological study.

In this retrospective study, we describe the histopathological findings in seven papillomas and 45 squamous cell carcinomas (SCCs) from psittacine birds, raptors and domestic fowl. The age of affected birds ranged from 3 to 40 years, with median age significantly higher in psittacines (P = 0.014). The majority of tumours were located in the skin (24/52, 46.2%) or uropygial gland (10/52, 19.2%). Thirty of the SCCs (66.7%) were well differentiated and 15 (33.3%) were poorly-differentiated. SCCs exhibited a significantly higher degree of nuclear pleomorphism (P = 0.005) and a greater proportion were ulcerated (P = 0.001) compared with papillomas; however, there was no significant difference in mitotic count (MC) or inflammation score. The expression of cyclo-oxygenase (COX)-2 and E-cadherin was investigated by immunohistochemistry. The COX-2 total score (TS) was significantly higher in SCCs compared with papillomas (P = 0.002), but the difference between COX-2 TS of well- and poorly-differentiated SCCs was not significant. COX-2 labelling was predominantly cytoplasmic, but some tumours had concurrent membranous and/or perinuclear labelling. SCCs with membranous labelling had a significantly higher MC (P = 0.028). A significantly higher proportion of SCCs were negative for E-cadherin compared with papillomas (P = 0.042), but there was no significant difference between well- and poorly-differentiated SCCs. Fourteen papillomas and SCCs from psittacines were also tested by polymerase chain reaction for the presence of Psittacus erithacus papillomavirus 1 and Psittacid herpesvirus 1, but all samples tested negative. We demonstrate for the first time the expression of COX-2 and E-cadherin in avian tissues, and suggest that these markers may be useful in differentiating papillomas from SCCs, particularly when sample size is small.

Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.

WITHDRAWN: Clinical Signs, Neuroanatomical Distribution and Histopathological Characterisation of Meningoencephalitis in Wild Red Foxes (Vulpes vulpes) Associated with a Novel fox Circovirus.

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Malocclusion model of temporomandibular joint osteoarthritis in mice with and without receptor for advanced glycation end products.

OBJECTIVE: This study has two aims: 1. Validate a non-invasive malocclusion model of mouse temporomandibular joint (TMJ) osteoarthritis (OA) that we developed and 2. Confirm role of inflammation in TMJ OA by comparing the disease in the presence and absence of the receptor for advanced glycation end products (RAGE). DESIGN: The malocclusion procedure was performed on eight week old mice, either wild type (WT) or without RAGE. RESULTS: We observed TMJ OA at two weeks post-misalignment/malocclusion. The modified Mankin score used for the semi-quantitative assessment of OA showed an overall significantly higher score in mice with malocclusion compared to control mice at all times points (2, 4, 6 and 8 weeks). Mice with malocclusion showed a decrease in body weight by the first week after misalignment but returned to normal weight for their ages during the following weeks. The RAGE knock out (KO) mice had statistically lower modified Mankin scores compared to WT mice of the same age. The RAGE KO mice had statistically lower levels of Mmp-13 and HtrA1 but higher Tgf-ß1, as measured by immunohistochemistry, compared to WT mice at eight weeks post malocclusion. CONCLUSIONS: We demonstrate an inexpensive, efficient, highly reproducible and non-invasive model of mouse TMJ OA. The mechanical nature of the malocclusion resembles the natural development of TMJ OA in humans, making this an ideal model in future studies that aim to elucidate the pathogenesis of the disease leading to the discovery of a treatment. The RAGE plays a role in mouse TMJ OA.

Detection of non-primate hepaciviruses in UK dogs.

Non-primate hepacivirus (NPHV) has been identified in dogs, horses, bats and wild rodents. The presence of NPHV in dogs outside of the USA however is yet to be established. Here we describe for the first time the detection of NPHV in the UK dog population (described throughout the manuscript as CnNPHV). We examined tissues collected from dogs housed in a rehoming kennel where respiratory disease was endemic. CnNPHV RNA was detected in the tracheal tissues of 48/210 dogs by RT-PCR, and in the liver, lung and/or tracheal tissues of 12/20 dogs. The presence of CnNPHV RNA, and its tropism was confirmed by in situ hybridisation. Histopathological examination demonstrated a trend toward higher histopathological scores in CnNPHV RNA positive respiratory tissues, although, this was not statistically significant. Our findings broaden the geographic distribution and our understanding of CnNPHV. Further evidence of CnNPHV replication in canids warrants investigation.

New and emerging pathogens in canine infectious respiratory disease.

Canine infectious respiratory disease is a common, worldwide disease syndrome of multifactorial etiology. This review presents a summary of 6 viruses (canine respiratory coronavirus, canine pneumovirus, canine influenza virus, pantropic canine coronavirus, canine bocavirus, and canine hepacivirus) and 2 bacteria (Streptococcus zooepidemicus and Mycoplasma cynos) that have been associated with respiratory disease in dogs. For some pathogens a causal role is clear, whereas for others, ongoing research aims to uncover their pathogenesis and contribution to this complex syndrome. Etiology, clinical disease, pathogenesis, and epidemiology are described for each pathogen, with an emphasis on recent discoveries or novel findings.

Moderate-to-vigorous physical activity is associated with decreases in body mass index from ages 9 to 15 years.

OBJECTIVE: The purpose of this study is to determine whether time spent in objectively measured physical activity is associated with change in body mass index (BMI) from ages 9 to 15. DESIGN AND METHODS: The participants were enrolled in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (n = 938). At ages 9, 11, 12, and 15 the time spent in moderate-to-vigorous physical activity (MVPA) was objectively measured, and BMI was calculated (kg/m(2) ). Longitudinal quantile regression was used to analyze the data. The 10th, 25th, 50th, 75th, and 90th BMI percentiles were modeled as the dependent variables with age and MVPA (h/day) modeled as predictors. Adjustment was also made for gender, race, sleep, healthy eating score, maternal education, and sedentary behavior. RESULTS: A negative association between MVPA and change in BMI was observed at the 90th BMI percentile (-3.57, 95% CI -5.15 to -1.99 kg/m(2) per hour of MVPA). The negative association between time spent in MVPA and change in BMI was progressively weaker toward the 10th BMI percentile (-0.27, 95% CI -0.62 to 0.07 kg/m(2) per hour of MVPA). The associations remained similar after adjusting for the covariates, and when the analyses were stratified by gender. CONCLUSION: Time spent in MVPA was negatively associated with change in BMI from age 9 to 15. The association was strongest at the upper tail of the BMI distribution, and increasing time spent in MVPA could help reduce the prevalence of childhood obesity.

Time spent in sedentary behavior and changes in childhood BMI: a longitudinal study from ages 9 to 15 years.

OBJECTIVE: To determine if time spent in objectively measured sedentary behavior is associated with a change in body mass index (BMI) between ages 9 and 15 years, adjusting for moderate-to-vigorous physical activity (MVPA). DESIGN: Prospective observational study of children at ages 9 (2000), 11 (2002), 12 (2003) and 15 years (2006). Longitudinal quantile regression was used to model the influence of predictors on changes at the 10th, 25th, 50th, 75th and 90th BMI percentiles over time. SUBJECTS: Participants were enrolled in the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development and include both boys and girls (n=789). MEASUREMENTS: Objectively measured BMI (kg m(-2)) was the outcome variable and objectively measured sedentary behavior was the main predictor. Adjustment was also made for MVPA, gender, race, maternal education, hours of sleep and healthy eating index. RESULTS: Increases in BMI were observed at all percentiles, with the greatest increase observed at the 90th BMI percentile. Spending more time in sedentary behavior (h per day) was associated with additional increases in BMI at the 90th, 75th and 50th BMI percentiles, independent of MVPA and the other covariates (90th percentile=0.59, 95% confidence interval (95% CI): 0.19-0.98 kg m(-2); 75th percentile=0.48, 95% CI: 0.25-0.72 kg m(-2); and 50th percentile=0.19, 95% CI: 0.05-0.33 kg m(-2)). No associations were observed between sedentary behavior and changes at the 25th and 10th BMI percentiles. CONCLUSION: Sedentary behavior was associated with greater increases in BMI at the 90th, 75th and 50th BMI percentiles between ages 9 and 15 years, independent of MVPA. Preventing an increase in sedentary behavior from childhood to adolescence may contribute to reducing the number of children classified as obese.

Nanoinformatics: developing new computing applications for nanomedicine.

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.

Pharmacology and therapeutic potential of pattern recognition receptors.

Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.

50 years of informatics research on decision support: what's next.

OBJECTIVES: To reflect on the history, status, and future trends of decision support in health and biomedical informatics. To highlight the new challenges posed by the complexity and diversity of genomic and clinical domains. To examine the emerging paradigms for supporting cost-effective, personalized decision making. METHODS: A group of international experts in health and biomedical informatics presented their views and discussed the challenges and issues on decision support at the Methods of Information in Medicine 50th anniversary symposium. The experts were invited to write short articles summarizing their thoughts and positions after the symposium. RESULTS AND CONCLUSIONS: The challenges posed by the complexity and diversity of the domain knowledge, system infrastructure, and usage pattern are highlighted. New requirements and computational paradigms for representing, using, and acquiring biomedical knowledge and healthcare protocols are proposed. The underlying common themes identified for developing next-generation decision support include incorporating lessons from history, uniform vocabularies, integrative interfaces, contextualized decisions, personalized recommendations, and adaptive solutions.

Aspirin has little additional anti-platelet effect in healthy volunteers receiving prasugrel.

BACKGROUND: Strong P2Y(12) blockade, as can be achieved with novel anti-platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A(2) -mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin. OBJECTIVE: The present study investigated the hypothesis that aspirin provides little additional anti-aggregatory effect in a group of healthy volunteers taking prasugrel. STUDY PARTICIPANTS/METHODS: In all, 9 males, aged 18 to 40 years, enrolled into the 21-day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow and urine samples were collected for quantification of prostanoid metabolites. RESULTS: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP-6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose. CONCLUSIONS: In healthy volunteers, prasugrel produces a strong anti-aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual-therapy with potent P2Y(12) receptor inhibitors warrants further investigation.

In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation.

BACKGROUND: Aspirin and antagonists of platelet ADP P2Y(12) receptors are often coprescribed for protection against thrombotic events. However, blockade of platelet P2Y(12) receptors can inhibit thromboxane A(2) (TXA(2))-dependent pathways of platelet activation independently of aspirin. OBJECTIVES: To assess in vitro whether aspirin adds additional antiaggregatory effects to strong P2Y(12) receptor blockade. METHODS: With the use of platelet-rich plasma from healthy volunteers, determinations were made in 96-well plates of platelet aggregation, TXA(2) production and ADP/ATP release caused by ADP, arachidonic acid, collagen, epinephrine, TRAP-6 amide and U46619 (six concentrations of each) in the presence of prasugrel active metabolite (PAM; 0.1-10 µmol L(-1)), aspirin (30 µmol L(-1)), PAM + aspirin or vehicle. results: PAM concentration-dependently inhibited aggregation; for example, aggregation in response to all concentrations of ADP and U46619 was inhibited by ≥ 95% by PAM at > 3 µmol L(-1) . In further tests of PAM (3 µmol L(-1)), aspirin (30 µmol L(-1)) and PAM + aspirin, aspirin generally failed to produce more inhibition than PAM or additional inhibition to that caused by PAM. The antiaggregatory effects of PAM were associated with reductions in the platelet release of both TXA(2) and ATP + ADP. Similar effects were found when either citrate or lepirudin were used as anticoagulants, and when traditional light transmission aggregometry was conducted at low stirring speeds. CONCLUSIONS: P2Y(12) receptors are critical to the generation of irreversible aggregation through the TXA(2) -dependent pathway. As a result, strong P2Y(12) receptor blockade alone causes inhibition of platelet aggregation that is little enhanced by aspirin. The clinical relevance of these observations remains to be determined.

International efforts in nanoinformatics research applied to nanomedicine.

BACKGROUND: Nanomedicine and nanoinformatics are novel disciplines facing substantial challenges. Since nanomedicine involves complex and massive data analysis and management, a new discipline named nanoinformatics is now emerging to provide the vision and the informatics methods and tools needed for such purposes. Methods from biomedi-cal informatics may prove applicable with some adaptation despite nanomedicine involving different biophysical and biochemical characteristics of nanomaterials and corresponding differences in information complexity. OBJECTIVES: We analyze recent initiatives and opportunities for research in nanomedicine and nanoinformatics as well as the previous experience of the authors, particularly in the context of a European project named ACTION-Grid. In this project the authors aimed to create a collaborative environment in biomedical and nanomedical research among countries in Europe, Western Balkans, Latin America, North Africa and the USA. METHODS: We review and analyze the rationale and scientific issues behind the new fields of nanomedicine and nanoinformatics. Such a review is linked to actual research projects and achievements of the authors within their groups. RESULTS: The work of the authors at the intersection between these two areas is presented. We also analyze several research initiatives that have recently emerged in the EU and USA context and highlight some ideas for future action at the international level. CONCLUSIONS: Nanoinformatics aims to build new bridges between medicine, nanotechnology and informatics, allowing the application of computational methods in the nano-related areas. Opportunities for world-wide collaboration are already emerging and will be influential in advancing the field.

Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages.

BACKGROUND AND PURPOSE: Gram-negative bacteria contain ligands for Toll-like receptor (TLR) 4 and nucleotide oligomerization domain (NOD) 1 receptors. Lipopolysaccharide (LPS) activates TLR4, while peptidoglycan products activate NOD1. Activation of NOD1 by the specific agonist FK565 results in a profound vascular dysfunction and experimental shock in vivo. EXPERIMENTAL APPROACH: Here, we have analysed a number of pharmacological inhibitors to characterize the role of key signalling pathways in the induction of NOS2 following TLR4 or NOD1 activation. KEY RESULTS: Vascular smooth muscle (VSM) cells expressed NOD1 mRNA and protein, and, after challenge with Escherichia coli or FK565, NOS2 protein and activity were induced. Macrophages had negligible levels of NOD1 and were unaffected by FK565, but responded to E. coli and LPS by releasing increased NO and expression of NOS2 protein. Classic pharmacological inhibitors for NF-kappaB (SC-514) and mitogen-activated protein kinase (SB203580, PD98059) signalling pathways inhibited responses in both cell types regardless of agonist. While TLR4-mediated responses in macrophages were specifically inhibited by the pan-caspase inhibitor z-VAD-fmk and the PKC inhibitor Gö6976, NOD1-mediated responses in VSM cells were inhibited by the Rip2 inhibitor PP2. CONCLUSIONS AND IMPLICATIONS: Our findings suggest a selective role for NOD1 in VSM cells, and highlight NOD1 as a potential novel therapeutic target for the treatment of vascular inflammation.

Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery.

BACKGROUND: The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. OBJECTIVE: The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. RESULTS: By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. CONCLUSION: Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.