Taking tissue seriously means taking communities seriously

<p>Abstract</p> <p>Background</p> <p>Health research is increasingly being conducted on a global scale, particularly in the developing world to address leading causes of morbidity and mortality. While research interest has increased, building scientific capacity in the developing world has not kept pace. This often leads to the export of human tissue (defined broadly) from the developing to the developed world for analysis. These practices raise a number of important ethical issues that require attention.</p> <p>Discussion</p> <p>In the developed world, there is great heterogeneity of regulatory practices regarding human tissues. In this paper, we outline the salient ethical issues raised by tissue exportation, review the current ethical guidelines and norms, review the literature on what is known empirically about perceptions and practices with respect to tissue exportation from the developing to the developed world, set out what needs to be known in terms of a research agenda, and outline what needs to be done immediately in terms of setting best practices. We argue that the current status of tissue exportation is ambiguous and requires clarification lest problems that have plagued the developed world occur in the context of global heath research with attendant worsening of inequities. Central to solutions to current ethical concerns entail moving beyond concern with individual level consent and embracing a robust interaction with communities engaged in research.</p> <p>Conclusion</p> <p>Greater attention to community engagement is required to understand the diverse issues associated with tissue exportation.</p

Structural Insights from Binding Poses of CCR2 and CCR5 with Clinically Important Antagonists: A Combined In Silico Study

Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å), we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2) and Glu283 (CCR5) are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design

Cytokine Combination Therapy with Erythropoietin and Granulocyte Colony Stimulating Factor in a Porcine Model of Acute Myocardial Infarction

PurposeErythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model.MethodsMI was induced in pigs by a 90&nbsp;min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6&nbsp;weeks post-MI. Histopathology was performed 6&nbsp;weeks post-MI.ResultsAt week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p &lt; 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy.ConclusionOur findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF

Apelin Enhances Directed Cardiac Differentiation of Mouse and Human Embryonic Stem Cells

Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors

Bone Is Not Essential for Osteoclast Activation

Background: The mechanism whereby bone activates resorptive behavior in osteoclasts, the cells that resorb bone, is unknown. It is known that avb3 ligands are important, because blockade of avb3 receptor signaling inhibits bone resorption, but this might be through inhibition of adhesion or migration rather than resorption itself. Nor is it known whether avb3 ligands are sufficient for resorption the consensus is that bone mineral is essential for the recognition of bone as the substrate appropriate for resorption. Methodology/Principal Findings: Vitronectin- but not fibronectin-coated coverslips induced murine osteoclasts to secrete tartrate-resistant acid phosphatase, as they do on bone. Osteoclasts incubated on vitronectin, unlike fibronectin, formed podosome belts on glass coverslips, and these were modulated by resorption-regulating cytokines. Podosome belts formed on vitronectin-coated surfaces whether the substrates were rough or smooth, rigid or flexible. We developed a novel approach whereby the substrate-apposed surface of cells can be visualized in the scanning electron microscope. With this approach, supported by transmission electron microscopy, we found that osteoclasts on vitronectin-coated surfaces show ruffled borders and clear zones characteristic of resorbing osteoclasts. Ruffles were obscured by a film if cells were incubated in the cathepsin inhibitor E64, suggesting that removal of the film represents substrate-degrading behavior. Analogously, osteoclasts formed resorption-like trails on vitronectin-coated substrates. Like bone resorption, these trails were dependent upon resorbogenic cytokines and were inhibited by E64. Bone mineral induced actin rings and surface excavation only if first coated with vitronectin. Fibronectin could not substitute in any of these activities, despite enabling adhesion and cell spreading. Conclusions/Significance: Our results show that ligands avb3 are not only necessary but sufficient for the induction of resorptive behavior in osteoclasts; and suggest that bone is recognized through its affinity for these ligands, rather than by its mechanical or topographical attributes, or through a putative ‘mineral receptor’

An agent-based model of the response to angioplasty and bare-metal stent deployment in an atherosclerotic blood vessel

Purpose: While animal models are widely used to investigate the development of restenosis in blood vessels following an intervention, computational models offer another means for investigating this phenomenon. A computational model of the response of a treated vessel would allow investigators to assess the effects of altering certain vessel- and stent-related variables. The authors aimed to develop a novel computational model of restenosis development following an angioplasty and bare-metal stent implantation in an atherosclerotic vessel using agent-based modeling techniques. The presented model is intended to demonstrate the body's response to the intervention and to explore how different vessel geometries or stent arrangements may affect restenosis development. Methods: The model was created on a two-dimensional grid space. It utilizes the post-procedural vessel lumen diameter and stent information as its input parameters. The simulation starting point of the model is an atherosclerotic vessel after an angioplasty and stent implantation procedure. The model subsequently generates the final lumen diameter, percent change in lumen cross-sectional area, time to lumen diameter stabilization, and local concentrations of inflammatory cytokines upon simulation completion. Simulation results were directly compared with the results from serial imaging studies and cytokine levels studies in atherosclerotic patients from the relevant literature. Results: The final lumen diameter results were all within one standard deviation of the mean lumen diameters reported in the comparison studies. The overlapping-stent simulations yielded results that matched published trends. The cytokine levels remained within the range of physiological levels throughout the simulations. Conclusion: We developed a novel computational model that successfully simulated the development of restenosis in a blood vessel following an angioplasty and bare-metal stent deployment based on the characteristics of the vessel crosssection and stent. A further development of this model could ultimately be used as a predictive tool to depict patient outcomes and inform treatment options. © 2014 Curtin, Zhou

Family physicians\u27 professional identity formation: a study protocol to explore impression management processes in institutional academic contexts.

BACKGROUND: Despite significant differences in terms of medical training and health care context, the phenomenon of medical students\u27 declining interest in family medicine has been well documented in North America and in many other developed countries as well. As part of a research program on family physicians\u27 professional identity formation initiated in 2007, the purpose of the present investigation is to examine in-depth how family physicians construct their professional image in academic contexts; in other words, this study will allow us to identify and understand the processes whereby family physicians with an academic appointment seek to control the ideas others form about them as a professional group, i.e. impression management. METHODS/DESIGN: The methodology consists of a multiple case study embedded in the perspective of institutional theory. Four international cases from Canada, France, Ireland and Spain will be conducted; the \u22case\u22 is the medical school. Four levels of analysis will be considered: individual family physicians, interpersonal relationships, family physician professional group, and organization (medical school). Individual interviews and focus groups with academic family physicians will constitute the main technique for data generation, which will be complemented with a variety of documentary sources. Discourse techniques, more particularly rhetorical analysis, will be used to analyze the data gathered. Within- and cross-case analysis will then be performed. DISCUSSION: This empirical study is strongly grounded in theory and will contribute to the scant body of literature on family physicians\u27 professional identity formation processes in medical schools. Findings will potentially have important implications for the practice of family medicine, medical education and health and educational policies