A guide to chemokines and their receptors

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G‐protein coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behaviour, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many non‐leukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localisation and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarises the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focussing particularly on their ability to direct leukocyte migration

Prehospital Randomised Assessment of a Mechanical Compression Device In Cardiac Arrest (PaRAMeDIC) Trial Protocol

BACKGROUND Survival after out-of-hospital cardiac arrest is closely linked to the quality of CPR, but in real life, resuscitation during prehospital care and ambulance transport is often suboptimal. Mechanical chest compression devices deliver consistent chest compressions, are not prone to fatigue and could potentially overcome some of the limitations of manual chest compression. However, there is no high-quality evidence that they improve clinical outcomes, or that they are cost effective. The Prehospital Randomised Assessment of a Mechanical Compression Device In Cardiac Arrest (PARAMEDIC) trial is a pragmatic cluster randomised study of the LUCAS-2 device in adult patients with non-traumatic out-of-hospital cardiac arrest. METHODS/DESIGN The primary objective of this trial is to evaluate the effect of chest compression using LUCAS-2 on mortality at 30 days post out-of-hospital cardiac arrest, compared with manual chest compression. Secondary objectives of the study are to evaluate the effects of LUCAS-2 on survival to 12 months, cognitive and quality of life outcomes and cost-effectiveness. METHODS Ambulance service vehicles will be randomised to either manual compression (control) or LUCAS arms. Adult patients in out-of-hospital cardiac arrest, attended by a trial vehicle will be eligible for inclusion. Patients with traumatic cardiac arrest or who are pregnant will be excluded. The trial will recruit approximately 4000 patients from England, Wales and Scotland. A waiver of initial consent has been approved by the Research Ethics Committees. Consent will be sought from survivors for participation in the follow-up phase. CONCLUSION The trial will assess the clinical and cost effectiveness of the LUCAS-2 mechanical chest compression device. TRIAL REGISTRATION The trial is registered on the International Standard Randomised Controlled Trial Number Registry (ISRCTN08233942)

How do undergraduate medical students perceive social accountability?

Aim: The concept of social accountability within undergraduate training is embedded within the remit of medical schools. Little is known of how medical students perceive social accountability, recognize aspects of their training contributing to the development of this concept and cultivate the underpinning values. Methods: Students nearing graduation were recruited to participate in focus groups designed to explore their perceptions of social accountability, which curricular aspects had contributed to their understanding, and to investigate the implications of individual variations in training. Results: Students expressed limited appreciation of the concept of social accountability and acknowledged little explicit teaching around underpinning core concepts such as awareness of local health needs, advocacy and nurturing of altruism. However, participants recognized numerous aspects of the course and learning initiatives as impacting on their attitudes towards this concept implicitly. Conclusion: This study highlights areas of their undergraduate training that students recognize as having the greatest impact on their development into socially accountable professionals. It poses some significant challenges for health care educators in addressing unintended consequences, including an outcome-driven educational approach, in reducing students’ capacity or willingness to engage in curricular challenges often designed to embed this concept

Discourses of student orientation to medical education programs

Background: Although medical students’ initial orientation is an important point of transition in medical education, there is a paucity of literature on the subject and major variations in the ways that different institutions orient incoming medical students to their programs. Methods: We conducted a discourse analysis of medical education orientation in the literature and on data from a survey of peer institutions’ approaches to orientation. Results: These two discourses of orientation had clear similarities, in particular, the critical role of ceremony and symbols, and the focus on developing professionalism and physician identities. There were also differences between them, in particular, in the way that the discourse in the literature focused on the symbolic and professional aspects of orientation; something we have called ‘cultural orientation’. Meanwhile, those who were responsible for orientation in their own institutions tended to focus on the practical and social dimensions. Conclusion: By examining how orientation has been described and discussed, we identify three domains of orientation: cultural, social, and practical. These domains are relatively distinct in terms of the activities associated with them, and in terms of who is involved in organizing and running these activities. We also describe orientation as a liminal activity system on the threshold of medical school where incoming students initially cross into the profession. Interestingly, this state of ambiguity also extends to the scholarship of orientation with only some of its aspects attracting formal enquiry, even though there is a growing interest in transitions in medical education as a whole. We hope, therefore, that this study can help to legitimize enquiry into orientation in all its forms and that it can begin to situate the role of orientation more firmly within the firmament of medical education practice and research

HIV-1 induces cytoskeletal alterations and Rac1 activation during monocyte-blood–brain barrier interactions: modulatory role of CCR5

Abstract Background Most HIV strains that enter the brain are macrophage-tropic and use the CCR5 receptor to bind and infect target cells. Because the cytoskeleton is a network of protein filaments involved in cellular movement and migration, we investigated whether CCR5 and the cytoskeleton are involved in endothelial-mononuclear phagocytes interactions, adhesion, and HIV-1 infection. Results Using a cytoskeleton phospho-antibody microarray, we showed that after co-culture with human brain microvascular endothelial cells (HBMEC), HIV-1 infected monocytes increased expression and activation of cytoskeleton-associated proteins, including Rac1/cdc42 and cortactin, compared to non-infected monocytes co-cultured with HBMEC. Analysis of brain tissues from HIV-1-infected patients validated these findings, and showed transcriptional upregulation of Rac1 and cortactin, as well as increased activation of Rac1 in brain tissues of HIV-1-infected humans, compared to seronegative individuals and subjects with HIV-1-encephalitis. Confocal imaging showed that brain cells expressing phosphorylated Rac1 were mostly macrophages and blood vessels. CCR5 antagonists TAK-799 and maraviroc prevented HIV-induced upregulation and phosphorylation of cytoskeleton-associated proteins, prevented HIV-1 infection of macrophages, and diminished viral-induced adhesion of monocytes to HBMEC. Ingenuity pathway analysis suggests that during monocyte-endothelial interactions, HIV-1 alters protein expression and phosphorylation associated with integrin signaling, cellular morphology and cell movement, cellular assembly and organization, and post-translational modifications in monocytes. CCR5 antagonists prevented these HIV-1-induced alterations. Conclusions HIV-1 activates cytoskeletal proteins during monocyte-endothelial interactions and increase transcription and activation of Rac1 in brain tissues. In addition to preventing macrophage infection, CCR5 antagonists could diminish viral-induced alteration and phosphorylation of cytoskeletal proteins, monocyte adhesion to the brain endothelium and viral entry into the central nervous system. </jats:sec

New Alleles in the Calpastatin Gene Associated with Improved Tenderness in Pork

Suggestive quantitative trait loci (QTL) affecting average Instron force and other tenderness measures were mapped to pig chromosome 2 (SSC 2) by using a three-generation intercross between Berkshire x Yorkshire (B x Y) pigs. Based on the QTL location, the Calpastatin (CAST) gene was considered to be a good candidate for the observed effects. Differences in the CAST gene sequences of the members of the B x Y intercross were analyzed. Two missense substitutions (changes affecting proteins) were identified. To test the hypothesis that at least one of these mutations was associated with differences in tenderness, individuals from F2 B x Y, and from a Duroc x Yorkshire (D x Y) intercross, were genotyped for the candidate gene differences and association studies were performed. The results provide significant support for the presence of new economically important alleles (gene forms) of the CAST gene affecting the Instron/Shear Force and the resulting meat quality. The significant effect of these markers on tenderness measures, will add them to the list of already discovered Halothane and RN markers, as a set of molecular tools developed to improve pork qualit

Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved

Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL

Quantitative and qualitative analysis of individual experiences post botulinum toxin injection ‐ United Kingdom Survey

Data Availability Statement: Data available on request from the authors.Introduction: In the United Kingdom (UK), complications that arise following the administration of Botulinum Toxin are reported to the Medicines and Health Regulatory Agency (MHRA) via the Yellow Card Reporting Scheme. Over the past decade, there has been a significant increase in the number of non-surgical aesthetic procedures. Concerns have been raised that the MHRA is not fully capturing complications in terms of volume and impact on patients. Aim: This novel study explores the lived experiences of individuals who have experienced an adverse event following administration of Botulinum Toxin for aesthetic purposes. Using a combination of qualitative and quantitative methodologies, this analysis evaluates data relating to long-lasting physical, psychological, emotional, and financial sequelae of complications arising from cosmetic Botulinum Toxin injections in the UK. Methods: A mixed method, qualitative and quantitative approach was adopted to gain comprehensive insights into patients' experiences. A focus group which comprised patient representatives, psychologists, and researchers reached a consensus on a 17-question survey which was disseminated via social media channels. Deductive thematic analysis was used to analyse coded themes. Furthermore, for secondary analysis, sentiment analysis was used computationally as an innovative approach to identify and categorise free text responses associated with sentiments using natural language processing (NLP). Results: In the study, 655 responses were received, with 287 (44%) of respondents completing all questions. The mean age of respondents was 42.6 years old. 94.1% of respondents identified as female. In the sample, 79% of respondents reported an adverse event following their procedure, with the most common event being reported as ‘anxiety’. Findings revealed that 69% of respondents reported long-lasting adverse effects. From the responses, 68.4% reported not having recovered physically, 63.5% of respondents stated that they had not recovered emotionally from complications, and 61.7% said that they have not recovered psychologically. In addition, 84% of respondents stated that they do not know who regulates the aesthetics industry. Furthermore, 92% of participants reported that their clinic or practitioner did not inform them about the Yellow Card Reporting Scheme. The sentiment analysis using the AFINN Lexicon yielded adjusted scores ranging from −3 to +2, with a mean value of −1.58. Conclusion: This is the largest survey in the UK completed by patients who experienced an adverse outcome following the aesthetic administration of Botulinum Toxin. Our study highlights the extent of the challenges faced by patients who experience an adverse event from physical, emotional, psychological, and financial perspectives. The lack of awareness of MHRA reporting structures and the lack of regulation within the UK's cosmetic injectables sector represent a significant public health challenge.The work was supported by a research grant from QUAD A, a not-for-profit organisation in the United States that works to standardize and improve the provision of healthcare facilities and care quality