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The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (Kit(W-sh/W-sh)), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not Il2(-/-), mast cells into Kit(W-sh/W-sh) mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation.
Asunto(s)
Dermatitis Atópica/inmunología , Interleucina-2/biosíntesis , Mastocitos/inmunología , Animales , Enfermedad Crónica , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/patología , Inmunoglobulina E/inmunología , Interleucina-2/deficiencia , Interleucina-2/inmunología , Ratones , Ratones Noqueados , Oxazolona , Bazo/inmunologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a public health emergency and a pandemic of international concern. As of April 31st, the reported cases of COVID-19 are three million in 186 countries. Reported case fatality has crossed 200 thousand among which more than fifty thousand has been in the USA. Most patients present with symptoms of fever, cough, and shortness of breath following exposure to other COVID-19 patients. Respiratory manifestations predominate in patients with mild, moderate, severe illness. Imaging of patients with COVID-19 consistently reports various pulmonary parenchymal involvement. In this article we wanted to reinforce and review the various reported imaging patterns of cardiac and mediastinal involvement in COVID-19 patients. Among patients with COVID 19 who underwent various imaging of chest various cardiac findings including pericardial effusion, myocarditis, cardiomegaly has been reported. Most of these findings have been consistently reported in patients with significant acute myocardial injury, and fulminant myocarditis. Acute biventricular dysfunction has also been reported with subsequent improvement of the same following clinical improvement. Details of cardiac MRI is rather limited. In a patient with clinical presentation of acute myocarditis, biventricular myocardial interstitial edema, diffuse biventricular hypokinesia, increased ventricular wall thickness, and severe LV dysfunction has been reported. Among patients with significant clinical improvement in LV structure and function has also been documented. With increasing number of clinical cases, future imaging studies will be instrumental in identifying the various cardiac manifestations, and their relation to clinical outcome.
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Cardiomegalia/diagnóstico por imagen , Infecciones por Coronavirus/diagnóstico por imagen , Corazón/diagnóstico por imagen , Isquemia Miocárdica/diagnóstico por imagen , Miocarditis/diagnóstico por imagen , Derrame Pericárdico/diagnóstico por imagen , Neumonía Viral/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico por imagen , Betacoronavirus , COVID-19 , Cardiomegalia/fisiopatología , Angiografía Coronaria , Infecciones por Coronavirus/fisiopatología , Ecocardiografía , Edema/diagnóstico por imagen , Edema/fisiopatología , Corazón/fisiopatología , Humanos , Imagen por Resonancia Magnética , Isquemia Miocárdica/fisiopatología , Miocarditis/fisiopatología , Pandemias , Derrame Pericárdico/fisiopatología , Neumonía Viral/fisiopatología , Radiografía Torácica , Recuperación de la Función , SARS-CoV-2 , Tomografía Computarizada por Rayos X , Disfunción Ventricular/diagnóstico por imagen , Disfunción Ventricular/fisiopatología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Neurological manifestations in patients with COVID-19 are more frequently being reported. Cerebrovascular events have been reported in around 3% of patients. In this review we summarize the published literature on cerebrovascular events in patients with COVID-19 as available on the PubMed database. So far, 3 studies have reported cerebrovascular events. Cerebrovascular events were identified on screening patients with decreased consciousness or in the presence of focal neurological deficits. These events were common in elderly, critically ill patients and in patients with prior cardio-cerebrovascular comorbidities. The diagnosis of cerebrovascular events was confirmed with computed tomography of the brain in most studies reporting neurological events. Multiple pathological mechanisms have been postulated regarding the process of neurological and vascular injury among which cytokine storm is shown to correlate with mortality. Patients with severe illness are found to have a higher cardio- cerebrovascular comorbidity. With an increasing number of cases and future prospective studies, the exact mechanism by which these cerebrovascular events occur and attribute to the poor outcome will be better understood.
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Betacoronavirus , Trastornos Cerebrovasculares/etiología , Infecciones por Coronavirus/complicaciones , Enfermedad Crítica , Neumonía Viral/complicaciones , COVID-19 , Trastornos Cerebrovasculares/epidemiología , Salud Global , Humanos , Incidencia , Pandemias , SARS-CoV-2Asunto(s)
Trastorno Depresivo , Trastornos Relacionados con Sustancias , Depresión , Salud Global , HumanosRESUMEN
FcεRI engagement in mast cells (MCs) induces the activation of two distinct sphingosine kinase isoforms (SphK1 and SphK2) to produce sphingosine-1-phosphate, a mediator essential for MC responses. Whereas embryonic-derived SphK2-null MCs showed impaired responses to Ag, RNA silencing studies on other MC types indicated a dominant role for SphK1. Given the known functional heterogeneity of MCs, we explored whether the reported differences in SphK1 or SphK2 usage could be reflective of phenotypic differences between MC populations. Using lentiviral-based short hairpin RNA to silence SphK1 or SphK2, we found that SphK2 is required for murine MC degranulation, calcium mobilization, and cytokine and leukotriene production, irrespective of the tissue from which the MC progenitors were derived, the stage of MC granule maturity, or the conditions used for differentiation. This finding was consistent with the lack of a full allergic response in SphK2-null mice challenged to undergo passive cutaneous anaphylaxis. A redundant role for both SphKs was uncovered, however, in chemotaxis toward Ag in all MC types tested and in TNF-α production in certain MC types. In contrast, human MC responses were dependent only on SphK1, associating with a more robust expression of this isoform and a more varied representation of SphK variants relative to murine MCs. The findings show that the function of SphK1 and SphK2 can be interchangeable in MCs; however, an important determinant of SphK isoform usage is the species of origin and an influencing factor, the tissue from which MCs may be derived and/or their differentiation state.
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Expresión Génica , Mastocitos/enzimología , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Animales , Calcio/metabolismo , Degranulación de la Célula/genética , Degranulación de la Célula/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/biosíntesis , Citocinas/inmunología , Activación Enzimática , Silenciador del Gen , Vectores Genéticos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Lentivirus , Leucotrienos/genética , Leucotrienos/inmunología , Lisofosfolípidos/metabolismo , Mastocitos/citología , Mastocitos/metabolismo , Ratones , Especificidad de Órganos , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , ARN Interferente Pequeño/genética , Receptores de IgE/genética , Receptores de IgE/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Transducción GenéticaAsunto(s)
Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Accidente Cerebrovascular/etiología , Administración Oral , COVID-19 , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/prevención & control , Humanos , Pandemias/prevención & control , Neumonía Viral/mortalidad , Neumonía Viral/prevención & control , SARS-CoV-2 , Accidente Cerebrovascular/prevención & controlAsunto(s)
Hepatopatías/mortalidad , Hígado/diagnóstico por imagen , Calidad de la Atención de Salud/normas , Consumo de Bebidas Alcohólicas/efectos adversos , Costo de Enfermedad , Femenino , Humanos , Industrias/legislación & jurisprudencia , Hígado/patología , Hígado/fisiopatología , Hepatopatías/epidemiología , Masculino , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Infective endocarditis (IE) is a life-threatening infection with an annual mortality of 40%. Embolic events reported in up to 80% of patients. Vegetations of > 10 mm size are associated with increased embolic events and poor prognosis. There is a paucity of literature on the association of multiple vegetations with outcome. AIM: To study the echocardiographic (ECHO) features and outcomes associated with the presence of multiple vegetations. METHODS: In this retrospective, single-center, cohort study patients diagnosed with IE were recruited from June 2017 to June 2019. A total of 84 patients were diagnosed to have IE, of whom 67 with vegetation were identified. Baseline demographic, clinical, laboratory, and ECHO parameters were reviewed. Outcomes that were studied included recurrent admission, embolic phenomenon, and mortality. RESULTS: Twenty-three (34%) patients were noted to have multiple vegetations, 13 (56.5%) were male and 10 (43.5%) were female. The mean age of these patients was 50. Eight (35%) had a prior episode of IE. ECHO features of moderate to severe valvular regurgitation [odds ratio (OR) = 4], presence of pacemaker lead (OR = 4.8), impaired left ventricle (LV) relaxation (OR = 4), and elevated pulmonary artery systolic pressure (PASP) (OR = 2.2) are associated with higher odds of multiple vegetations. Of these moderate to severe valvular regurgitation (P = 0.028), pacemaker lead (P = 0.039) and impaired relaxation (P = 0.028) were statistically significant. These patients were noted to have an increased association of recurrent admissions (OR = 3.6), recurrent bacteremia (OR = 2.4), embolic phenomenon (OR = 2.5), intensive care unit stay (OR = 2.8), hypotension (OR = 2.1), surgical intervention (OR = 2.8) and device removal (OR = 4.8). Of this device removal (P = 0.039) and recurrent admissions (P = 0.017) were statistically significant. CONCLUSION: This study highlights the associations of ECHO predictors and outcomes in patients with IE having multiple vegetations. ECHO features of moderate to severe regurgitation, presence of pacemaker lead, impaired LV relaxation, and elevated PASP and outcomes including recurrent admissions and device removal were found to be associated with multiple vegetations.
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Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancer in vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell line in vivo to reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a "difficult to xenograft" PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.
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Precision medicine should aspire to reduce error and improve accuracy in medical and health recommendations by comparison with contemporary practice, while maintaining safety and cost-effectiveness. The etiology, clinical manifestation and prognosis of diseases such as obesity, diabetes, cardiovascular disease, kidney disease and fatty liver disease are heterogeneous. Without standardized reporting, this heterogeneity, combined with the diversity of research tools used in precision medicine studies, makes comparisons across studies and implementation of the findings challenging. Specific recommendations for reporting precision medicine research do not currently exist. The BePRECISE (Better Precision-data Reporting of Evidence from Clinical Intervention Studies & Epidemiology) consortium, comprising 23 experts in precision medicine, cardiometabolic diseases, statistics, editorial and lived experience, conducted a scoping review and participated in a modified Delphi and nominal group technique process to develop guidelines for reporting precision medicine research. The BePRECISE checklist comprises 23 items organized into 5 sections that align with typical sections of a scientific publication. A specific section about health equity serves to encourage precision medicine research to be inclusive of individuals and communities that are traditionally under-represented in clinical research and/or underserved by health systems. Adoption of BePRECISE by investigators, reviewers and editors will facilitate and accelerate equitable clinical implementation of precision medicine.
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Lista de Verificación , Medicina de Precisión , Humanos , Investigación Biomédica/normas , Proyectos de Investigación/normas , Guías como Asunto , Relevancia ClínicaRESUMEN
Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both sclGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4Rα, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13-treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets.
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Quimiocina CCL2/genética , Enfermedad Injerto contra Huésped/genética , Interleucina-13/genética , Esclerodermia Sistémica/genética , Animales , Quimiocina CCL2/antagonistas & inhibidores , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Regulación hacia ArribaRESUMEN
Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3,4,5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, such as Bcl-XL, were observed in PTEN-deficient mast cells, and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.
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Permeabilidad Capilar/inmunología , Hipersensibilidad/patología , Mastocitos/patología , Mastocitos/fisiología , Mastocitosis/patología , Fosfohidrolasa PTEN/genética , Traslado Adoptivo , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Degranulación de la Célula/inmunología , División Celular/inmunología , Supervivencia Celular/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Mastocitosis/inmunología , Mastocitosis/fisiopatología , Ratones , Ratones Mutantes , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: Fibrosis in human diseases and animal models is associated with aberrant Wnt/ß-catenin pathway activation. The aim of this study was to characterize the regulation, activity, mechanism of action, and significance of Wnt/ß-catenin signaling in the context of systemic sclerosis (SSc). METHODS: The expression of Wnt signaling pathway components in SSc skin biopsy specimens was analyzed. The regulation of profibrotic responses by canonical Wnt/ß-catenin was examined in explanted human mesenchymal cells. Fibrotic responses were studied using proliferation, migration, and gel contraction assays. The cell fate specification of subcutaneous preadipocytes by canonical Wnt signaling was evaluated. RESULTS: Analysis of published genome-wide expression data revealed elevated expression of the Wnt receptor FZD2 and the Wnt target LEF1 and decreased expression of Wnt antagonists DKK2 and WIF1 in skin biopsy specimens from subsets of patients with diffuse cutaneous SSc compared to the other distinct subsets. Immunohistochemical analysis showed increased nuclear ß-catenin expression in these biopsy specimens. In vitro, Wnt-3a induced ß-catenin activation, stimulated fibroblast proliferation and migration, collagen gel contraction, and myofibroblast differentiation, and enhanced profibrotic gene expression. Genetic and pharmacologic approaches were used to demonstrate that these profibrotic responses involved autocrine transforming growth factor ß signaling via Smads. In contrast, in explanted subcutaneous preadipocytes, Wnt-3a repressed adipogenesis and promoted myofibroblast differentiation. CONCLUSION: Canonical Wnt signaling was hyperactivated in SSc skin biopsy specimens. In explanted mesenchymal cells, Wnt-3a stimulated fibrogenic responses while suppressing adipogenesis. Taken together, these results indicate that Wnts have potent profibrotic effects, and that canonical Wnt signaling plays an important role in the pathogenesis of fibrosis and lipoatrophy in SSc.
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Mesodermo/metabolismo , Mesodermo/patología , Esclerodermia Sistémica/metabolismo , Transducción de Señal/fisiología , Proteínas Smad/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Biopsia , Estudios de Casos y Controles , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Receptores Frizzled/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Mesodermo/efectos de los fármacos , Proteínas Represoras/metabolismo , Esclerodermia Sistémica/patología , Piel/metabolismo , Piel/patología , Proteína Wnt3A/farmacologíaRESUMEN
Laboratory mice are typically housed at temperatures below the thermoneutral zone for the species, resulting in cold stress and premature cancellous bone loss. Furthermore, mice are more dependent upon non-shivering thermogenesis to maintain body temperature during spaceflight, suggesting that microgravity-induced bone loss may be due, in part, to altered thermogenesis. Consequently, we assessed whether housing mice at room temperature modifies the skeletal response to simulated microgravity. This possibility was tested using the hindlimb unloading (HLU) model to mechanically unload femora. Humeri were also assessed as they remain weight bearing during HLU. Six-week-old female C57BL6 (B6) mice were housed at room temperature (22 °C) or near thermoneutral (32 °C) and HLU for 2 weeks. Compared to baseline, HLU resulted in cortical bone loss in femur, but the magnitude of reduction was greater in mice housed at 22 °C. Cancellous osteopenia in distal femur (metaphysis and epiphysis) was noted in HLU mice housed at both temperatures. However, bone loss occurred at 22 °C, whereas the bone deficit at 32 °C was due to failure to accrue bone. HLU resulted in cortical and cancellous bone deficits (compared to baseline) in humeri of mice housed at 22 °C. In contrast, fewer osteopenic changes were detected in mice housed at 32 °C. These findings support the hypothesis that environmental temperature alters the skeletal response to HLU in growing female mice in a bone compartment-specific manner. Taken together, species differences in thermoregulation should be taken into consideration when interpreting the skeletal response to simulated microgravity.