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Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.
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Inflamación/inmunología , Grasa Intraabdominal/inmunología , Linfocitos/inmunología , Tejido Linfoide/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/inmunología , Quimiocina CXCL13/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Inflamación/genética , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Linfocitos/metabolismo , Tejido Linfoide/citología , Tejido Linfoide/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células del Estroma/inmunología , Células del Estroma/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Cultural competence resides at the core of undergraduate and postgraduate medical and health professional education. The evolution of studies on cultural competence has resulted in the existence of multiple theoretical frameworks and models, each emphasising certain elements of culturally appropriate care, but generally lacking in providing a coherent and systematic approach to teaching this subject. METHODS: Following a meta-ethnographic approach, a systematic search of five databases was undertaken to identify relevant articles published between 1990 and 2022. After citation searching and abstract and full article screening, a consensus was reached on 59 articles for final inclusion. Key constructs and concepts of cultural competence were synthesised and presented as themes, using the lens of critical theory. RESULTS: Three key themes were identified: competences; roles and identities; structural competency. Actionable concepts and themes were incorporated into a new transformative ACT cultural model that consists of three key domains: activate consciousness, connect relations, and transform to true cultural care. CONCLUSION: This critical review provides an up-to-date synthesis of studies that conceptualise cultural competence frameworks and models in international medical and healthcare settings. The ACT cultural model provides a set of guiding principles for culturally appropriate care, to support high-quality educational interventions.
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Competencia Cultural , Educación Profesional , Humanos , Atención a la Salud , Competencia Clínica , Antropología CulturalRESUMEN
Neutrophils are the first and most numerous cells to arrive at the site of an inflammatory insult and are among the first to die. We previously reported that alpha defensins, released from apoptotic human neutrophils, augmented the antimicrobial capacity of macrophages while also inhibiting the biosynthesis of proinflammatory cytokines. In vivo, alpha defensin administration protected mice from inflammation, induced by thioglychollate-induced peritonitis or following infection withSalmonella entericaserovar Typhimurium. We have now dissected the antiinflammatory mechanism of action of the most abundant neutrophil alpha defensin, Human Neutrophil Peptide 1 (HNP1). Herein we show that HNP1 enters macrophages and inhibits protein translation without inducing the unfolded-protein response or affecting mRNA stability. In a cell-free in vitro translation system, HNP1 powerfully inhibited both cap-dependent and cap-independent mRNA translation while maintaining mRNA polysomal association. This is, to our knowledge, the first demonstration of a peptide released from one cell type (neutrophils) directly regulating mRNA translation in another (macrophages). By preventing protein translation, HNP1 functions as a "molecular brake" on macrophage-driven inflammation, ensuring both pathogen clearance and the resolution of inflammation with minimal bystander tissue damage.
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Macrófagos/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Infecciones por Salmonella/metabolismo , Salmonella typhimurium , alfa-Defensinas/metabolismo , Animales , Humanos , Macrófagos/patología , Ratones , Infecciones por Salmonella/patología , alfa-Defensinas/farmacologíaRESUMEN
Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn22-/- neutrophils. Tyrosine phosphorylation of Lyn and Syk was altered in Ptpn22-/- neutrophils. On stimulation with immobilized immune complexes, Ptpn22-/- neutrophils manifested reduced activation of key signaling intermediates. Ptpn22-/- mice were protected from immune complex-mediated arthritis, induced by the transfer of arthritogenic serum. In contrast, in vivo neutrophil recruitment following thioglycollate-induced peritonitis and in vitro chemotaxis were not affected by lack of PTPN22. Our data suggest an important role for PTPN22-dependent dephosphorylation events, which are required to enable full FcγR-induced activation, pointing to an important role for this molecule in neutrophil function.
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Artritis Experimental/inmunología , Artritis Reumatoide/genética , Neutrófilos/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/metabolismo , Animales , Complejo Antígeno-Anticuerpo , Artritis Experimental/genética , Adhesión Celular , Degranulación de la Célula , Predisposición Genética a la Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Activación Neutrófila , Fosforilación , Polimorfismo Genético , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores de IgG/metabolismo , Transducción de Señal , Quinasa Syk/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Long-lived plasma cells (LLPCs) that maintain humoral immunity to previously encountered Ags occupy a compartment in the bone marrow (BM). The rules and mechanisms by which cells enter (and leave) this compartment are poorly understood. We looked at what happens to the LLPC compartment and to plasma cell lifespan in general, in situations in which Ag stimulation and/or inflammation persist. We find that chronic Ag supply causes the generation of short-lived plasma cells in the local lymphoid organ, at the expense of any LLPC production. Furthermore, we find that inflammation caused by infection (mediated via TNF-α) causes a dramatic mobilization of LLPCs from the BM, with a concomitant reduction in circulating Ab levels against previously immunized Ags. These data are discussed in the context of the capacity of the BM LLPC compartment and competition for entry to it.
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Homeostasis/inmunología , Inmunidad Humoral/inmunología , Inflamación/inmunología , Células Plasmáticas/inmunología , Animales , Antígenos/inmunología , Médula Ósea/inmunología , Quimiotaxis de Leucocito/inmunología , Citometría de Flujo , Tejido Linfoide/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Intracellular protein complexes containing nucleic acids are common targets of autoantibodies in many autoimmune diseases. Central tolerance to these antigens is incomplete, yet nucleosomal DNA is expressed on the surface of cells dying by apoptosis. It is commonly believed that autoimmunity is prevented by the rapid uptake of apoptotic cells (ACs) by neighbors or professional phagocytes to which they deliver anti-inflammatory signals. Self-reactive, innate-like B cells contact and are selected by intracellular antigens expressed on ACs; however, how self-tolerance is maintained is not well understood. Here we report that IL-10 production by B cells, stimulated by contact with ACs, results from the engagement of Toll-like receptor 9 (TLR9) within the B cell after recognition of DNA-containing complexes on the surface of ACs. Until now, TLR9 ligation has been considered an inflammatory signal, but we have confirmed a hitherto unexpected immunoregulatory role by demonstrating the absence of the protective effect of ACs during experimental autoimmune encephalitis (EAE) in TLR9-deficient mice. Human circulating CD27(+) B cells also respond to DNA-bearing ACs, but not to DNase-treated cells, by secreting IL-10. Chronic autoimmune disease may arise if this tolerance mechanism is not reimposed after episodes of inflammation, or if the regulatory B-cell response is subverted.
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Apoptosis/inmunología , Linfocitos B/citología , Linfocitos B/inmunología , Comunicación Celular/inmunología , ADN/inmunología , Tolerancia Inmunológica/inmunología , Receptor Toll-Like 9/inmunología , Animales , Desoxirribonucleasas/metabolismo , Humanos , Terapia de Inmunosupresión , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Ratones , Muramidasa/inmunología , Transducción de Señal/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
OBJECTIVES: Feedback frameworks/models focus on certain aspects of the feedback process, but a coherent and systematic model is lacking. A meta-ethnography was conducted to identify and synthesise guidance for optimising feedback interactions in undergraduate clinical communication simulations. METHODS: A systematic search of 4 electronic databases and grey literature was conducted. Following Noblit and Hare's seven phases for conducting meta-ethnography, key themes and concepts were synthesised to provide new interpretations of components in effective feedback interactions. RESULTS: 373 publications were identified and 14 included for the final synthesis, which informed the development of a new Feedback Kidney Model. The Model illustrates the interconnections of various components that allow for effective feedback interactions. The main processes include preparation, proactivity, analysis and feedback information, reception and response, and influencing factors. CONCLUSIONS: This meta-ethnography moves beyond providing an up-to-date synthesis of feedback guidance to proposing the brand-new Feedback Kidney Model, which can guide medical education and future research into how feedback is co-constructed and utilised to promote learning. PRACTICE IMPLICATIONS: Clinical communication should incorporate meta-cognitive training and using this Model will help students better utilise on-site face-to-face feedback to enhance their learning and improve future communication with patients.
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Antropología Cultural , Estudiantes , Humanos , Comunicación , Retroalimentación , Riñón , Investigación CualitativaRESUMEN
Objective: To report the use of progressive, high-frequency movement-based dilator therapy (MBDT) to create a neovagina in a patient with congenital vaginal agenesis. Design: Case report. Setting: Tertiary care military hospital. Patients: A 22-year-old woman with congenital vaginal agenesis. Interventions: Self-directed MBDT. Main Outcome Measures: Vaginal elongation by self-directed MBDT. Results: The patient achieved a 6.5-cm vaginal length after 6 pelvic health physical therapy sessions over a span of 4 months of progressive, high-frequency MBDT. Conclusions: Progressive, high-frequency MBDT should be considered as part of a first-line dilator therapy regimen for patients with congenital vaginal agenesis interested in creating a neovagina.
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B cells are key pathogenic drivers of chronic inflammation in rheumatoid arthritis (RA). There is limited understanding of the relationship between synovial B cell subsets and pathogenic antibody secreting cells (ASCs). This knowledge is crucial for the development of more targeted B-cell depleting therapies. While CD11c+ double-negative 2 (DN2) B cells have been suggested as an ASC precursor in lupus, to date there is no proven link between the two subsets in RA. We have used both single-cell gene expression and BCR sequencing to study synovial B cells from patients with established RA, in addition to flow cytometry of circulating B cells. To better understand the differentiation patterns within the diseased tissue, a combination of RNA-based trajectory inference and clonal lineage analysis of BCR relationships were used. Both forms of analysis indicated that DN2 B cells serve as a major precursors to synovial ASCs. This study advances our understanding of B cells in RA and reveals the origin of pathogenic ASCs in the RA synovium. Given the significant role of DN2 B cells as a progenitor to pathogenic B cells in RA, it is important to conduct additional research to investigate the origins of DN2 B cells in RA and explore their potential as therapeutic targets in place of the less specific pan-B cells depletion therapies currently in use.
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Artritis Reumatoide , Subgrupos de Linfocitos B , Humanos , Células Plasmáticas , Linfocitos B , Células Productoras de AnticuerposRESUMEN
Neutrophils are recruited to sites of injury but their timely removal is thought to be vital to prevent exacerbating inflammation. In addition, the recognition of apoptotic cells by cells of the innate immune system provides potent anti-inflammatory and anti-immunogenic signals. In this article, we describe how human neutrophils dying by apoptosis or necrosis release anti-inflammatory peptides, the alpha-defensins. This family of small cationic peptides effectively inhibits the secretion of multiple proinflammatory cytokines and NO from macrophages, the main innate immune cell found at sites of chronic inflammation. In addition, the systemic administration of necrotic neutrophil supernatants and alpha-defensins protects mice from a murine model of peritonitis. Hence. their effects may be far-reaching and serve to kill microbes while regulating a potentially tissue-destructive inflammatory response.
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Apoptosis , Neutrófilos/inmunología , alfa-Defensinas/metabolismo , Animales , Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Necrosis , Neutrófilos/citología , Óxido Nítrico/antagonistas & inhibidores , Peritonitis/tratamiento farmacológico , alfa-Defensinas/farmacología , alfa-Defensinas/uso terapéuticoRESUMEN
INTRODUCTION: While two-thirds of women will experience dyspareunia and vaginal dilators are often used to treat dyspareunia, outside of a single case report, no study has investigated the potential of low-dose, high frequency movement-based dilator therapy for dyspareunia in premenopausal female patients. AIM: To determine the utility of low-dose, high frequency movement-based dilator use for dyspareunia in premenopausal female patients. METHODS: Retrospective study of women presenting to outpatient hospital-based pelvic floor physical therapy office in a tertiary care center. All adult premenopausal female patients who were referred to pelvic floor physical therapy for dyspareunia and completed movement-based dilator therapy (MBDT) and met study criteria (n = 26) were included for analysis. MAIN OUTCOME MEASURE: Patient change in pain level status using Numeric Pain Rating Scale with intercourse was compared between initial evaluation and time of discharge from pelvic floor physical therapy. RESULTS: Among the 26 women who met criteria for this study, the average pain score decreased from 8.3 (SD 2.2) before treatment to 1.3 (SD 2.0) after treatment and was statistically significant (P< .001). Complete resolution of dyspareunia was reported in 58% of patients. Patients completed between 2 and 6 total pelvic floor physical therapy visits (average 3.7, SD1.5), over 0-44 weeks (mean 9.6 weeks, SD 8.3). CONCLUSION: Low-dose, high frequency, movement-based dilator therapy significantly reduced or resolved the experience of pain with penetrative vaginal intercourse with dyspareunia. Future prospective studies with larger samples and the inclusion of sexual functional status should be considered to explore the full potential of this modality in treatment of premenopausal patients with dyspareunia. Miles K, Miles S. Low Dose, High Frequency Movement Based Dilator Treatment for Dyspareunia: Retrospective Analysis of 26 Cases. Sex Med 2021;9:100344.
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INTRODUCTION: The Dundee Ready Educational Environment Measure (DREEM) is a valid instrument to evaluate the educational environment of institutions. This quantitative study aimed to discover if applying interactive educational approaches to a component of a traditionally taught medical curriculum improved the educational environment, as measured by the DREEM. METHODS: The bilingual Arabic-English DREEM questionnaire was distributed twice to all third-year medical students (273 students) at the Hashemite University in Jordan. The first data collection occurred at the completion of a traditionally taught component of the Neurology module and the second data collection at the end of an interactively taught component of the same module. A paired t-test was used to compare the results. RESULTS: The total DREEM score for the innovative interactive course was 120.04/200 (from 183 questionnaires) and for the traditionally taught course was 114.69/200 (from 198 questionnaires). Of the five DREEM sub-scales, the interactive course scored statistically significantly higher than the traditionally taught course for "perceptions of learning" and "perceptions of atmosphere" (p-value 0.013 and 0.011, respectively). The interactively taught course was particularly valued by students for being participative, student-centered, and developing their professional competence. The lowest scoring item for both courses was "there is a good support system for students who get stressed." DISCUSSION: This study demonstrated that students value interactive learning environments and that there is benefit in introducing these components to a traditionally taught medical curriculum, when it may not be feasible to bring innovation to the entire medical curriculum due to resource constraints. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01359-y.
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B cells are critical for promoting autoimmunity and the success of B cell depletion therapy in rheumatoid arthritis (RA) confirms their importance in driving chronic inflammation. Whilst disease specific autoantibodies are useful diagnostically, our understanding of the pathogenic B cell repertoire remains unclear. Defining it would lead to novel insights and curative treatments. To address this, we have undertaken the largest study to date of over 150 RA patients, utilizing next generation sequencing (NGS) to analyze up to 200,000 BCR sequences per patient. The full-length antigen-binding variable region of the heavy chain (IgGHV) of the IgG B cell receptor (BCR) were sequenced. Surprisingly, RA patients do not express particular clonal expansions of B cells at diagnosis. Rather they express a polyclonal IgG repertoire with a significant increase in BCRs that have barely mutated away from the germline sequence. This pattern remains even after commencing disease modifying therapy. These hypomutated BCRs are expressed by TNF-alpha secreting IgG+veCD27-ve B cells, that are expanded in RA peripheral blood and enriched in the rheumatoid synovium. A similar B cell repertoire is expressed by patients with Sjögren's syndrome. A rate limiting step in the initiation of autoimmunity is the activation of B cells and this data reveals that a sizeable component of the human autoimmune B cell repertoire consists of polyclonal, hypomutated IgG+ve B cells, that may play a critical role in driving chronic inflammation.
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Artritis Reumatoide/inmunología , Autoinmunidad , Linfocitos B/inmunología , Genes de Inmunoglobulinas , Inmunoglobulina G/genética , Subgrupos Linfocitarios/inmunología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Autoanticuerpos/inmunología , Linaje de la Célula , Células Clonales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunoglobulina G/análisis , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Activación de Linfocitos , Receptores de Antígenos de Linfocitos B/genética , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The chronic autoimmune inflammatory diseases, systemic lupus erythematosus and Sjogren's syndrome, develop when tolerance to apoptotic cells (ACs) is lost. We have previously reported that this tolerance is maintained by innate-like, IL-10 secreting regulatory B cells. Two questions remained. First, do these regulatory B cells belong predominantly to a single subset of steady-state B cells and second, what is their specificity? We report here that innate-like B cells with markers characteristic for B1a cells (CD43+veCD19hiCD5+veIgMhiIgDlo) constitute 80% of splenic and 96% of peritoneal B cells that respond to ACs by secreting IL-10. AC responsive B1a cells secrete self-reactive natural antibodies (NAbs) and IL-10, which is augmented by toll-like receptor (TLR) 7 or TLR9 stimulation. In so doing, they both accelerate the clearance of dying cells by macrophages and inhibit their potential to mount proinflammatory immune responses. While B1a cells make prolonged contact with ACs, they do not require TIM1 or complement to mediate their regulatory function. In an animal model of neural inflammation (experimental autoimmune encephalomyelitis), just 105 activated B1a B cells was sufficient to restrain inflammation. Activated B1a B cells also induced antigen-specific T cells to secrete IL-10. Hence, regulatory B1a cells specifically recognize and augment tolerance to apoptotic self via IL-10 and NAbs; but once activated, can also prevent autoimmune mediated inflammation.
RESUMEN
Plasmacytoid dendritic cells (pDCs) play a pivotal role in driving the autoimmune disease systemic lupus erythematosus, via the secretion of IFN-α in response to nuclear self-antigens complexed with autoantibodies. Apoptotic cells, generated at sites of inflammation or secondary lymphoid organs, are exposed to activated pDCs and also express the same nuclear antigens on their cell surface. Here, we show that in the absence of autoantibodies, activated pDCs directly respond to apoptotic cell-expressed chromatin complexes by secreting IL-10 and IL-6, which also induces T cells to secrete IL-10. Conversely, when activated by the viral mimetic CpG-A, apoptotic cells enhance their secretion of IFN-α. This study demonstrates that activated pDCs respond directly to apoptotic cells and may maintain tolerance via IL-10, or promote inflammation through secretion of IFN-α, depending on the inflammatory context.