Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

Metabolic signatures of human Alzheimer's disease (AD): H-1 NMR analysis of the polar metabolome of post-mortem brain tissue

Brain tissue from so-called Alzheimer's disease (AD) mouse models has previously been examined using H-1 NMR-metabolomics, but comparable information concerning human AD is negligible. Since no animal model recapitulates all the features of human AD we undertook the first H-1 NMR-metabolomics investigation of human AD brain tissue. Human post-mortem tissue from 15 AD subjects and 15 age-matched controls was prepared for analysis through a series of lyophilised, milling, extraction and randomisation steps and samples were analysed using H-1 NMR. Using partial least squares discriminant analysis, a model was built using data obtained from brain extracts. Analysis of brain extracts led to the elucidation of 24 metabolites. Significant elevations in brain alanine (15.4 %) and taurine (18.9 %) were observed in AD patients (p ≤ 0.05). Pathway topology analysis implicated either dysregulation of taurine and hypotaurine metabolism or alanine, aspartate and glutamate metabolism. Furthermore, screening of metabolites for AD biomarkers demonstrated that individual metabolites weakly discriminated cases of AD [receiver operating characteristic (ROC) AUC <0.67; p < 0.05]. However, paired metabolites ratios (e.g. alanine/carnitine) were more powerful discriminating tools (ROC AUC = 0.76; p < 0.01). This study further demonstrates the potential of metabolomics for elucidating the underlying biochemistry and to help identify AD in patients attending the memory clinic

AgriSense: Multichannel disposable sensors for animal health disease diagnostics

Rapid and sensitive detection of viral infections associated with Bovine Respiratory Disease (BRD) in live animals is recognized as key to minimizing the impact of this disease. ELISA-based testing is limited as it typically relies on the detection of a single viral antibody subtype within an individual test sample and testing is relatively slow and expensive. We have recently initiated a new project entitled AgriSense to develop a novel low-cost and label-free, integrated bimodal electronic biosensor system for BRD. The biosensor system will consist of an integrated multichannel thin-film-transistor biosensor and an electrochemical impedance spectroscopy biosensor, interfaced with PDMS-based microfluidic sample delivery channels. By using both sensors in tandem, nonspecific binding biomolecules must have the same mass to charge ratio as the target analyte to elicit equivalent responses from both sensors. The system will target simultaneous multiplexed sensing of the four primary viral agents involved in the development of BRD: bovine herpesvirus-1 (BHV-1), bovine parainfluenza virus-3 (BPIV-3), bovine respiratory syncytial virus (BRSV), and bovine viral diarrhea (BVD). Optimized experimental conditions derived through model antigen-antibody studies will be applied to the detection of serological markers of BRD-related infections based on IgG interaction with a panel of sensor-immobilized viral proteins. This rapid, “cowside” multiplex sensor capability presents a major step forward in disease diagnosis, helping to ensure the integrity of the agri-food supply chain by reducing the risk of disease spread during animal movement and transport.

Ultraviolet irradiation for the prevention of graft-versus-host disease and graft rejection in bone marrow transplantation

This review describes an approach to the prevention of graft-versus-host disease (GVHD) and graft rejection following allogeneic BMT that differs from conventional methods. Ultraviolet (UV) irradiation inhibits the proliferative responses of lymphoid cells to mitogens and alloantigens by inactivation of T lymphocytes and dendritic cells, and in animal models this can prevent both GVHD and graft rejection. It is important that the marrow repopulating capacity of haemopoietic stem cells is not damaged by the irradiation process. We have found that polymorphic microsatellite markers are a sensitive way of assessing the impact of UV irradiation on chimerism after BMT in rodents.

Mis-measure of animal contests.

Contests between rivals placing similar value on the resource at stake are commonly won by the rival having greater 'resource holding potential' (RHP). Mutual assessment of RHP difference between rivals is usually expected as an economical means of resolution; weaker rivals can retreat when they detect their relative inferiority, thereby avoiding costly, futile persistence. Models of contest resolution that entail retreat decisions based on estimates of RHP difference predict that contest duration diminishes as RHP difference between rivals increases because the asymmetry is more readily detected. This prediction appears to have been fulfilled in contests of diverse taxa, generating widespread support for assessment of RHP differences in contests. But few studies have considered alternatives in which each rival simply persists in accord with its own RHP ('own RHP-dependent persistence'). In contests decided by own RHP-dependent persistence, in which costs accrue only through each rival's own actions, weaker rivals retreat first because they are inherently less persistent, and contest duration depends primarily on the weaker (losing) rival's RHP rather than RHP difference between the rivals. We show here that the analyses most commonly used to detect effects of RHP difference cannot discriminate between these alternatives. Because RHP difference between rivals tends to be correlated with RHP of the weaker rival in a pair, a negative relation between RHP difference and contest duration may be generated even when decisions of retreat are not based on estimated RHP difference. Many studies purporting to show a negative relation between RHP difference and contest duration may actually reflect an incidental association between weaker rival RHP and RHP difference. We suggest statistical and experimental approaches that may help to discriminate between effects of weaker rival RHP and true effects of RHP difference. We also discuss whether 'true' negative effects of RHP difference on contest duration always reflect retreat decisions based on estimated RHP differences. Copyright 2003 Published by Elsevier Science Ltd on behalf of The Association for the Study of Animal Behaviour.

Models of open populations with space-limited recruitment: extension of theory and application to the barnacle Chthamalus montagui.

1. Barnacles are a good model organism for the study of open populations with space-limited recruitment. These models are applicable to other species with open supply of new individuals and resource limitation. The inclusion of space in models leads to reductions in recruitment with increasing density, and thus predictions of population size and stability are possible. 2. Despite the potential generality of a demographic theory for open space-limited populations, the models currently have a narrow empirical base. In this study, a model for an open population with space-limited recruitment was extended to include size-specific survival and promotions to any size class. The assumptions of this model were tested using data from a pan-European study of the barnacle Chthamalus montagui Southward. Two models were constructed: a 6-month model and a periodic annual model. Predicted equilibria and their stabilities were compared between shores. 3. Tests of model assumptions supported the extension of the theory to include promotions to any size class. Mortality was found to be size-specific and density independent. Studied populations were open, with recruitment proportional to free space. 4. The 6-month model showed a significant interaction between time and location for equilibrium free space. This may have been due to contrasts in the timing of structuring processes (i.e. creating and filling space) between Mediterranean and Atlantic systems. Integration of the 6-month models into a periodic annual model removed the differences in equilibrium-free space between locations. 5. Model predictions show a remarkable similarity between shores at a European scale. Populations were persistent and all solutions were stable. This reflects the apparent absence of density-dependent mortality and a high adult survivorship in C. montagui. As populations are intrinsically stable, observations of fluctuations in density are directly attributable to variations in the environmental forcing of recruitment or mortality

Non-invasive in vivo imaging in small animal research

Non-invasive real time in vivo molecular imaging in small animal models has become the essential bridge between in vitro data and their translation into clinical applications. The tremendous development and technological progress, such as tumour modelling, monitoring of tumour growth and detection of metastasis, has facilitated translational drug development. This has added to our knowledge on carcinogenesis. The modalities that are commonly used include Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), bioluminescence imaging, fluorescence imaging and multi-modality imaging systems. The ability to obtain multiple images longitudinally provides reliable information whilst reducing animal numbers. As yet there is no one modality that is ideal for all experimental studies. This review outlines the instrumentation available together with corresponding applications reported in the literature with particular emphasis on cancer research. Advantages and limitations to current imaging technology are discussed and the issues concerning small animal care during imaging are highlighted.

Neurogenic inflammation and asthma

Over the past number of decades there has been considerable interest in the role of neurogenic inflammation in asthma with the identification of many biologically active neuropeptides in the lung. Whilst there is convincing evidence of neurogenic inflammation in various animal models of asthma, the evidence in humans is less clear and replicating the experimental approaches in humans has proven difficult with different studies producing conflicting results. In terms of human studies, research has focused on whether pro-inflammatory neuropeptides are elevated in the asthmatic airway, and if so, what their functional effects are. There have also been studies to assess the efficacy of tachykinin receptor antagonists in improving indices of asthma control. Information to date would suggest that neuropeptides are present in human airways and are possibly upregulated in asthma, but this effect does not appear to be specific and may occur in other inflammatory airways conditions (chronic obstructive pulmonary disease (COPD) and smoking). At present there is insufficient evidence to suggest that tachykinin receptor antagonists confer any additional benefit over inhaled corticosteroid regimes for asthmatic patients. © 2007 Bentham Science Publishers Ltd.

Persistently raised C-reactive protein levels are associated with advanced periodontal disease

Objective: The aim was to investigate whether there was an association between periodontitis or tooth loss in a homogeneous group of 60-70-year-old Western European men and either a sustained high or low level of C-reactive protein (CRP).
Material and Methods: Men enrolled in a cohort study of cardiovascular disease in Northern Ireland were screened in 1990-1994 and rescreened in 2001-2004, when a periodontal examination was completed. High-sensitivity CRP was measured from fasting blood samples. There were 806 men with six or more teeth who had either a high level (>3 mg/l) or a lower level of CRP at both time points. Multivariate analysis was carried out using logistic regression with adjustment for possible confounders. Models were constructed with the CRP level as the outcome variable and various measures of periodontal status (low and high threshold periodontitis) or tooth loss as predictor variables. Confounders included in the analysis were known cardiovascular risk factors of age, smoking, diabetes, BMI and socioeconomic status.
Results: There were 67 men who had a high value of CRP (>3 mg/l) and 739 men who had a CRP value =3 mg/l at both time points. The unadjusted odds ratio (OR) for advanced periodontitis to be associated with high CRP was 3.62, p=0.0003. The association was somewhat attenuated but remained significant (OR=2.49, p=0.02) after adjustment for confounders. A high level of tooth loss was also associated with high CRP with an adjusted OR of 2.17, p=0.008. Low threshold periodontitis was not associated with the level of CRP.
Conclusion: There was an association between advanced periodontitis and elevated CRP levels as measured at two time points at a 10-year interval in the 60-70-year-old European males investigated. This association was adjusted for various cardiovascular risk factors. There was also an association between high levels of tooth loss and high CRP in the men studied.

Individual trade-offs between nutrition and risk of interspecific transmission of disease by grazing: cows, badger latrines and bovine tuberculosis

1. We examine whether various measures of herbivore current physiological state (age, breeding and immune status) and genetic potential can be used as indicators of exposure to and risk from disease. We use dairy cattle and the risks of tuberculosis (TB) transmission posed to them by pasture contaminated with badger excreta (via the fecal-oral route) as a model system to address our aim.

Risk of disease from wildlife reservoirs: Badgers, cattle, and bovine tuberculosis

Livestock face complex foraging options associated with optimizing nutrient intake while being able to avoid areas posing risk of parasites or disease. Areas of tall nutrient-rich swards around fecal deposits may be attractive for grazing, but might incur fitness costs from parasites. We use the example of dairy cattle and the risks of tuberculosis transmission posed to them by pastures contaminated with badger excreta to examine this trade-off. A risk may be posed either by aerosolized inhalation through investigation or by ingestion via grazing contaminated swards. We quantified the levels of investigation and grazing of 150 dairy cows at badger latrines (accumulations of feces and urine) and crossing points (urination-only sites). Grazing behavior was compared between strip-grazed and rotation-grazed fields. Strip grazing had fields subdivided for grazing periods of