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Asad A.B.A.,Merck And Co. | Seah S.,Merck And Co. | Baumgartner R.,Merck And Co. | Feng D.,Merck And Co. | And 7 more authors.
PLoS ONE | Year: 2016

Background Approximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored. Methodology Here we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42° C; OFF:40 s/35° C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42° C or 48° C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail).Principal Findings Group comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the 'pain matrix', including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures. Conclusions These findings provide insights into the specific brain regions involved with aversive, 'painlike', responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics. © 2016 Asad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Dahiya P.,Food and Veterinary Administration | Ogden B.E.,Maccine Pte Ltd
Frontiers in Bioscience - Scholar | Year: 2010

It is well recognized that animals play a vital role and are indispensable to scientific and medical research. Over the years, a number of non-animal procedures have been developed. However, despite all the advances in science, as yet, no system has been evolved which can completely replace a living system to conduct basic research. There is still a need to test food, drugs, medical devices, treatment regimes etc. on some animals before they can be tested and used (if found suitable) in human beings. Even the most sophisticated technology models have failed to mimic completely the complex cellular interactions occurring in a living system. The search for a complete alternative to animal research is still on and in the mean time we can all help play our part by conducting animal research in a humane and responsible fashion. This chapter discusses the ethical issues in animal research highlighting the need to use animals conscientiously. Source


Sampath S.,Merck And Co. | Klimas M.,Merck And Co. | Feng D.,Merck And Co. | Baumgartner R.,Merck And Co. | And 5 more authors.
PLoS ONE | Year: 2015

Pre-clinical animal models are important to study the fundamental biological and functional mechanisms involved in the longitudinal evolution of heart failure (HF). Particularly, large animal models, like nonhuman primates (NHPs), that possess greater physiological, biochemical, and phylogenetic similarity to humans are gaining interest. To assess the translatability of these models into human diseases, imaging biomarkers play a significant role in non-invasive phenotyping, prediction of downstream remodeling, and evaluation of novel experimental therapeutics. This paper sheds insight into NHP cardiac function through the quantification of magnetic resonance (MR) imaging biomarkers that comprehensively characterize the spatiotemporal dynamics of left ventricular (LV) systolic pumping and LV diastolic relaxation. MR tagging and phase contrast (PC) imaging were used to quantify NHP cardiac strain and flow. Temporal inter-relationships between rotational mechanics, myocardial strain and LV chamber flow are presented, and functional biomarkers are evaluated through test-retest repeatability and inter subject variability analyses. The temporal trends observed in strain and flow was similar to published data in humans. Our results indicate a dominant dimension based pumping during early systole, followed by a torsion dominant pumping action during late systole. Early diastole is characterized by close to 65% of untwist, the remainder of which likely contributes to efficient filling during atrial kick. Our data reveal that moderate to good intra-subject repeatability was observed for peak strain, strain-rates, E/circumferential strain-rate (CSR) ratio, E/longitudinal strain-rate (LSR) ratio, and deceleration time. The inter-subject variability was high for strain dyssynchrony, diastolic strain-rates, peak torsion and peak untwist rate. We have successfully characterized cardiac function in NHPs using MR imaging. Peak strain, average systolic strain-rate, diastolic E/CSR and E/LSR ratios, and deceleration time were identified as robust biomarkers that could potentially be applied to future pre-clinical drug studies. © 2015 Sampath et al. Source


Connolly B.M.,Merck And Co. | Vanko A.,Merck And Co. | McQuade P.,Merck And Co. | Guenther I.,Merck And Co. | And 8 more authors.
Molecular Imaging and Biology | Year: 2012

Purpose: The purpose of this study was to evaluate the binding specificity of the radiolabeled glucagon-like peptide 1 receptor (GLP-1R) agonist (Lys 40(DOTA)NH 2)Exendin-4 in the pancreas using a combination of ex vivo autoradiography and immunohistochemistry. Procedures: Sprague-Dawley rats were administered [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 i.v. with or without unlabeled Exendin (9-39) to determine binding specificity. Similar experiments were performed using Zucker diabetic fatty (ZDF) and Zucker lean (ZLC) rats. Animals were euthanized and the pancreas was extracted, immediately frozen, and sectioned. The sections were apposed to phosphor imaging plates, scanned, and immunostained for insulin. Results: Co-registration of the autoradiographic and immunohistochemical images revealed that [ 64Cu] (Lys 40(DOTA)NH 2)Exendin-4 specific binding was restricted to islet cells. This binding was blocked by the co-administration of Exendin(9-39) indicating that the radiotracer uptake is mediated by GLP-1R. Uptake of [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 was greatly decreased in the pancreas of ZDF rats. Conclusions: Ex vivo autoradiography results using [ 64Cu](Lys 40(DOTA)NH 2)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the in vivo determination of β-cell mass. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011. Source


Wang Z.,University of Pittsburgh | Wang Z.,Maccine Pte Ltd | Song Q.,Nanyang Technological University | Soh Y.C.,Nanyang Technological University | Sim K.,Institute of Mental Health
Computer Vision and Image Understanding | Year: 2013

This paper presents an adaptive spatial information-theoretic fuzzy clustering algorithm to improve the robustness of the conventional fuzzy c-means (FCM) clustering algorithms for image segmentation. This is achieved through the incorporation of information-theoretic framework into the FCM-type algorithms. By combining these two concepts and modifying the objective function of the FCM algorithm, we are able to solve the problems of sensitivity to noisy data and the lack of spatial information, and improve the image segmentation results. The experimental results have shown that this robust clustering algorithm is useful for MRI brain image segmentation and it yields better segmentation results when compared to the conventional FCM approach. © 2013 Elsevier Inc. All rights reserved. Source

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