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BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.
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Asma , Conjuntivitis Alérgica , Conjuntivitis , Alérgenos , Animales , Asma/diagnóstico , Asma/etiología , Conjuntivitis Alérgica/diagnóstico , Eosinófilos , Humanos , PyroglyphidaeRESUMEN
BACKGROUND: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO. METHODS: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933. RESULTS: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). CONCLUSION: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.
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Hipertensión , Insuficiencia Renal Crónica , Desequilibrio Hidroelectrolítico , Anciano , Bumetanida/uso terapéutico , Clortalidona/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Terapia de Reemplazo Renal , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , AguaRESUMEN
BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.
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Alérgenos/toxicidad , Asma/inmunología , Eosinófilos/inmunología , Linfocitos/inmunología , Pyroglyphidae , Mucosa Respiratoria/inmunología , Adulto , Alérgenos/inmunología , Animales , Asma/patología , Eosinófilos/patología , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Linfocitos/patología , MasculinoRESUMEN
BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.
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COVID-19/inmunología , Infecciones por VIH/epidemiología , VIH-1/fisiología , Insuficiencia Respiratoria/epidemiología , SARS-CoV-2/fisiología , Factores Sexuales , Linfocitos T/inmunología , Adulto , Anciano , COVID-19/epidemiología , COVID-19/mortalidad , Estudios de Cohortes , Resistencia a la Enfermedad , Femenino , Humanos , Inmunocompetencia , Interleucina-6/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Transcriptoma/inmunología , Estados Unidos/epidemiología , Carga ViralRESUMEN
Prosthetic valve thrombosis (PVT) is considered an exceptionally rare condition, often associated with pro-thrombotic factors or suboptimal anticoagulant therapy. Guidelines recommend emergent surgery for patients with left heart valve prosthetic thrombosis who present in cardiogenic shock, and systemic thrombolysis is reserved in scenarios where surgery is not immediately available. However, several factors may affect surgical prognosis and are overlooked by current recommendations. We describe the case of a 34-year-old female who presented in the emergency department with cardiogenic shock and acute pulmonary edema due to acute valve thrombosis.
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Válvulas Cardíacas/anomalías , Terapia Trombolítica/métodos , Trombosis/tratamiento farmacológico , Adulto , Femenino , Fibrinolíticos/uso terapéutico , Prótesis Valvulares Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Válvulas Cardíacas/diagnóstico por imagen , Humanos , Trombosis/fisiopatologíaRESUMEN
T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.
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Epigénesis Genética , VIH-1/metabolismo , Activación de Linfocitos , Receptores CCR5/metabolismo , Receptores Virales/metabolismo , Linfocitos T/inmunología , Metilación de ADN , Humanos , Receptores CCR5/genéticaRESUMEN
BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.
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Alérgenos/inmunología , Antígenos Dermatofagoides/inmunología , Conjuntivitis Alérgica/inmunología , Pyroglyphidae/inmunología , Rinitis Alérgica/inmunología , Administración por Inhalación , Adulto , Animales , Conjuntivitis Alérgica/genética , Resistencia a la Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino , Proteínas Filagrina , Humanos , Recuento de Leucocitos , Masculino , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Rinitis Alérgica/genética , TranscriptomaRESUMEN
Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle.
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Dieta Alta en Grasa , Resistencia a la Insulina , Glicoproteínas de Membrana/fisiología , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , NADPH Oxidasas/fisiología , Animales , Apoptosis , Western Blotting , Células Cultivadas , Regulación hacia Abajo , Perfilación de la Expresión Génica , Glucosa/farmacología , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Ratones , Ratones Noqueados , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , NADPH Oxidasa 2 , Estrés Oxidativo/efectos de los fármacos , Palmitatos/farmacología , Fosforilación , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Edulcorantes/farmacologíaRESUMEN
BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR.
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Alérgenos/administración & dosificación , Cucarachas/inmunología , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica/métodos , Polen/inmunología , Rinitis Alérgica Estacional/terapia , Adulto , Alérgenos/química , Alérgenos/inmunología , Ambrosia/química , Ambrosia/inmunología , Animales , Cucarachas/química , Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/inmunología , Conjuntivitis Alérgica/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polen/química , Pyroglyphidae/química , Pyroglyphidae/inmunología , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/fisiopatología , Estaciones del Año , Índice de Severidad de la Enfermedad , Pruebas CutáneasRESUMEN
Adverse remodeling following myocardial infarction (MI) leading to heart failure is driven by an imbalanced resolution of inflammation. The macrophage cell is an important control of post-MI inflammation, as macrophage subtypes secrete mediators to either promote inflammation and extend injury (M1 phenotype) or suppress inflammation and promote scar formation (M2 phenotype). We have previously shown that the absence of caveolin-1 (Cav1), a membrane scaffolding protein, is associated with adverse cardiac remodeling in mice, but the mechanisms responsible remain to be elucidated. We explore here the role of Cav1 in the activation of macrophages using wild type C57BL6/J (WT) and Cav1(tm1Mls/J) (Cav1(-/-)) mice. By echocardiography, cardiac function was comparable between WT and Cav1(-/-) mice at 3days post-MI. In the absence of Cav1, there were a surprisingly higher percentage of M2 macrophages (arginase-1 positive) detected in the infarcted zone. Conversely, restoring Cav1 function after MI in WT mice by adding back the Cav1 scaffolding domain reduced the M2 activation profile. Further, adoptive transfer of Cav1 null macrophages into WT mice on d3 post-MI exacerbated adverse cardiac remodeling at d14 post-MI. In vitro studies revealed that Cav1 null macrophages had a more pronounced M2 profile activation in response to IL-4 stimulation. In conclusion, Cav1 deletion promotes an array of maladaptive repair processes after MI, including increased TGF-ß signaling, increased M2 macrophage infiltration and dysregulation of the M1/M2 balance. Our data also suggest that cardiac remodeling can be improved by therapeutic intervention regulating Cav1 function during the inflammatory response phase.
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Caveolina 1/genética , Activación de Macrófagos , Infarto del Miocardio/metabolismo , Miocardio/patología , Animales , Volumen Cardíaco , Caveolina 1/metabolismo , Femenino , Fibrosis , Técnicas de Inactivación de Genes , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Miocardio/inmunología , Miocardio/metabolismo , Función Ventricular IzquierdaRESUMEN
Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-ß (TGF-ß) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease.
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Diabetes Mellitus Tipo 2/metabolismo , Hiperglucemia/patología , Hiperinsulinismo/patología , Inflamación/patología , Riñón/patología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Glucemia , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Activación Enzimática , Fibronectinas/biosíntesis , Fibrosis , Hiperglucemia/metabolismo , Hiperinsulinismo/metabolismo , Inflamación/metabolismo , Riñón/metabolismo , Laminina/biosíntesis , Sistema de Señalización de MAP Quinasas/genética , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Proteína smad3/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan Leishmania donovani. We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of L. donovani. In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of L. donovani-infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of L. donovani is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.
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Quimiocinas/metabolismo , Células Dendríticas/inmunología , Leishmania donovani/inmunología , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/inmunología , Ganglios Linfáticos/citología , Desnutrición/inmunología , Animales , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos BALB C , Receptores de Quimiocina/biosíntesisRESUMEN
BACKGROUND: Cardiac resynchronization therapy (CRT) has been established as an effective therapy for heart failure with reduced ejection fraction. Randomized clinical trials have shown its impact on mortality and HF hospitalizations, as well as improvement of symptoms and quality of life. OBJECTIVES: Finding clinical, electrocardiographic, and echocardiographic variables that may predict the response to cardiac resynchronization therapy (CRT). METHODS: We performed a single-center, observational, analytic, and retrospective study that included 102 patients with heart failure (HF) diagnosis who underwent CRT according to guideline-directed therapy from January 2010 to April 2020 in a third-level center. CRT response was defined as an improvement of New York Heart Association functional class in at least 1 category associated with a recovery of ≥ 5% in the left ventricular ejection fraction (LVEF). RESULTS: Our study population was 102 patients of which 61 (59.8%) were men. The mean age at HF diagnosis was 54 ± 18.7 years. Ischemic heart disease was the etiology in 37 (36.3%) cases. Fifty-one (50%) patients were classified as responders. Responders had wider QRS, and lower LVEF and right ventricular fractional area change at baseline. After CRT, responders had a greater reduction of QRS duration, and improvement in LVEF, global longitudinal strain, and echocardiographic dyssynchrony parameters. Multivariate regression analysis showed that left bundle branch block (LBBB), left ventricular end-diastolic volume (LVEDV), tricuspid annular plane systolic excursion (TAPSE), and baseline difference of pre-ejection periods were predictors of a positive response to CRT in this population. CONCLUSIONS: LBBB, TAPSE, LVEDV, and pre-ejection time difference are independent variables that can predict adequate response to CRT.
ANTECEDENTES: La terapia de resincronización cardíaca (TRC) se ha establecido como una terapia efectiva para la insuficiencia cardíaca con fracción de eyección reducida. Ensayos clínicos aleatorizados han demostrado su impacto en la mortalidad y hospitalizaciones por insuficiencia cardíaca, así como la mejora de los síntomas y la calidad de vida. OBJETIVOS: Determinar las variables clínicas, electrocardiográficas y ecocardiográficas que puedan predecir la respuesta a la terapia de resincronización cardíaca (TRC). MÉTODO: Estudio unicéntrico, observacional, analítico, retrospectivo, que incluyó 102 pacientes con diagnóstico de IC sometidos a TRC y terapia dirigida por guías, de enero de 2010 a abril de 2020, en un centro de tercer nivel. La respuesta a TRC fue definida como mejoría de la clase funcional de la New York Heart Association en al menos 1 categoría, asociado con una recuperación ≥ 5% en la fracción de expulsión del ventrículo izquierdo (FEVI). RESULTADOS: Incluimos a 102 pacientes, 61 (59.8%) fueron hombres. El promedio de edad al diagnóstico de IC fue 54 ± 18.7 años. La cardiopatía isquémica fue la etiología en 37 (36.3%) pacientes. 51 (50%) pacientes, fueron clasificados como respondedores. Los respondedores presentaron QRS amplio, menor FEVI y menor fracción de acortamiento del ventrículo derecho al inicio del estudio. Después de la TRC, los respondedores tuvieron una mayor reducción en la duración del QRS, mejoría en la FEVI, strain longitudinal global y parámetros de disincronía ecocardiográfica. El análisis de regresión multivariado mostró que el bloqueo de rama izquierdo (BRI), el volumen telediastólico del ventrículo izquierdo (VTDVI) la excursión sistólica del plano anular tricuspídeo (TAPSE) y la diferencia basal del período expulsivo fueron predictores de respuesta positiva a TRC. CONCLUSIONES: BRI, TAPSE, VTDVI y la diferencia basal de períodos preexpulsivos son variables independientes que predicen respuesta adecuada a TRC.
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Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca , Masculino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Femenino , Volumen Sistólico/fisiología , Estudios Retrospectivos , Calidad de Vida , Resultado del Tratamiento , Función Ventricular Izquierda , Bloqueo de Rama/terapiaRESUMEN
Introduction: In developing countries, there is a notable scarcity of real-world data on adherence to optimal medical therapy (OMT) and its correlation with major cardiovascular adverse events (MACEs) after ST-elevation myocardial infarction (STEMI). Our study focuses on addressing this gap by evaluating adherence to OMT, examining its influence on the risk of MACEs after STEMI, and assessing subsequent cardiovascular risk factor control in Mexico. Methods: We conducted a prospective observational study of post-STEMI patients after hospital discharge. Adherence to treatment was assessed over a median of 683 days (interquartile range: 478-833) using the Simplified Medication Adherence Questionnaire (SMAQ). Patients were followed up for 4.5 years to monitor MACEs (cardiovascular death, cardiogenic shock, recurrent myocardial infarction, and heart failure). Results: We included 349 patients with a mean age of 58.08 years (±10.9), predominantly male (89.9%). Hypertension (42.4%), smoking (34.3%), type 2 diabetes mellitus (31.2%), obesity (22.92%), and dyslipidemia (21.4%) were highly prevalent. Adherence to OMT per SMAQ was 44.7%. The baseline clinical characteristics of adherent and non-adherent patients did not significantly differ. OMT prescription rates were as follows: acetylsalicylic acid, 91.1%; P2Y12 inhibitors, 76.5%; and high-intensity statins, 86.6%. While non-adherent patients had a numerically higher rate of MACEs (73 vs. 49 first events), there was no statistically significant difference (hazard ratio 1.30, 95% confidence interval 0.90-1.88). Discussion: In this real-world study of patients after STEMI, we observed low adherence to OMT, a low proportion of global cardiovascular risk factor control, and a numerically higher incidence of recurrent major adverse cardiovascular events in non-adherent patients. Strategies to improve adherence to OMT and risk factor control are needed.
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Nephrogenic systemic fibrosis (NSF) is associated with gadolinium-based magnetic resonance imaging (MRI) contrast exposure in the setting of acute or chronic renal compromise. It has been proposed that circulating fibrocytes mediate the disease. A study was conducted to determine whether bone marrow-derived fibroblast precursors are involved in contributing to organ fibrosis in MRI contrast-treated rodents with renal insufficiency. Rats status post 5/6 nephrectomy underwent bone marrow transplant from human placental alkaline phosphatase (hPAP)-expressing donors. After engraftment, animals were treated with gadolinium-based MRI contrast (2.5 mmol/kg IP), during weekdays for 4 weeks, or an equivalent volume of normal saline. Dermal cellularity in the contrast-treated group was fourfold that of control. Skin cells from the contrast-treated group demonstrated greater hPAP expression with co-expression of pro-collagen I and α-smooth muscle actin-positive stress fibers. Donor and host cells expressed CD34. Dihydroethidium staining of skin was greater in the contrast-treated animals, indicating oxidative stress. This was abrogated when the animals were co-administered the superoxide dismutase mimetic tempol. In conclusion, a bone marrow-derived cell population is increased in the dermis of MRI contrast-treated rodents. The cell markers are consistent with fibrocytes mediating the disease. These changes correlate with oxidative stress and expression of Nox4, suggestive of a novel therapeutic target. Elucidation of the mechanisms of MRI contrast-induced fibrosis may aid in discovering therapies to this devastating disease.
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Médula Ósea/patología , Fibroblastos/patología , Hígado/patología , Miocardio/patología , Dermopatía Fibrosante Nefrogénica/patología , Estrés Oxidativo , Piel/patología , Animales , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Colágeno Tipo I/metabolismo , Medios de Contraste/efectos adversos , Dermis/patología , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Factor XIIIa/metabolismo , Femenino , Fibroblastos/metabolismo , Fibrosis , Humanos , Hígado/metabolismo , Imagen por Resonancia Magnética , Nefrectomía , Dermopatía Fibrosante Nefrogénica/metabolismo , Tamaño de los Órganos , Ratas , Ratas Endogámicas F344 , Especies Reactivas de Oxígeno/metabolismo , Piel/metabolismo , Grosor de los Pliegues CutáneosRESUMEN
Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.
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COVID-19 , Longevidad , Femenino , Humanos , Envejecimiento , Inflamación , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD). RESULTS: Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2(+/+) mice, processes that were ameliorated following the genetic inactivation of CCR2. CONCLUSION: Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.
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Vasos Coronarios/patología , Receptores CCR2/metabolismo , Vasculitis/inmunología , Animales , Aorta/patología , Linfocitos B/inmunología , Células de la Médula Ósea/patología , Candida albicans/citología , Candida albicans/fisiología , Movimiento Celular , Proliferación Celular , Pared Celular/metabolismo , Vasos Coronarios/inmunología , Modelos Animales de Enfermedad , Inmunidad/inmunología , Inflamación/complicaciones , Inflamación/patología , Interleucina-6/metabolismo , Depleción Linfocítica , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Monocitos/patología , Peroxidasa/sangre , Receptores CCR2/deficiencia , Receptores CCR5/deficiencia , Receptores CCR5/metabolismo , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/citología , Células Th17/inmunología , Vasculitis/sangre , Vasculitis/microbiología , Vasculitis/prevención & controlRESUMEN
We postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.
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Diferenciación Celular/inmunología , Quimiocina CCL2/fisiología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , FN-kappa B/fisiología , Receptores CCR2/fisiología , Animales , Diferenciación Celular/genética , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Células Dendríticas/patología , Interleucina-12/biosíntesis , Interleucina-12/genética , Células de Langerhans/inmunología , Células de Langerhans/metabolismo , Células de Langerhans/patología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/metabolismo , Leishmaniasis Cutánea/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Modelos Inmunológicos , FN-kappa B/metabolismo , Receptores CCR2/biosíntesis , Receptores CCR2/deficiencia , Activación Transcripcional/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
Background: Lung ultrasound (LUS) shows a higher sensitivity when compared with physical examination for the detection of pulmonary congestion. The objective of our study was to evaluate the association of pulmonary congestion assessed by LUS after reperfusion therapy with cardiovascular outcomes in patients with ST-segment Elevation acute Myocardial Infarction (STEMI) who received reperfusion therapy. Methods: A prospective observational study including patients with STEMI from the PHASE-Mx study. LUS was performed in four thoracic sites (two sites in each hemithorax). We categorized participants according to the presence of pulmonary congestion. The primary endpoint of the study was the composite of death for any cause, new episode or worsening of heart failure, recurrent myocardial infarction and cardiogenic shock at 30 days of follow-up. Results: A total of 226 patients were included, of whom 49 (21.6%) patients were classified within the "LUS-congestion" group and 177 (78.3%) within the "non-LUS-congestion" group. Compared with patients in the "non-LUS-congestion" group, patients in the "LUS-congestion" group were older and had higher levels of blood urea nitrogen and NT-proBNP. Pulmonary congestion assessed by LUS was significantly associated with a higher risk of the primary composite endpoint (HR: 3.8, 95% CI 1.91-7.53, p = 0.001). Differences in the primary endpoint were mainly driven by an increased risk of heart failure (HR 3.91; 95%CI 1.62-9.41, p = 0.002) and cardiogenic shock (HR 3.37; 95%CI 1.30-8.74, p = 0.012). Conclusion: The presence of pulmonary congestion assessed by LUS is associated with increased adverse cardiovascular events, particularly heart failure and cardiogenic shock. The application of LUS should be integrated as part of the initial risk stratification in patients with STEMI as it conveys important prognostic information.
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This report describes a rare case of a global myocardial infarction caused by severe vasospasm of the coronary arteries secondary to the administration of pyridostigmine in a patient with polyarteritis nodosa (PAN). Details about the clinical presentation, the typical electrocardiographic pattern of multivessel disease, the differential diagnoses suspected in the multi-imaging approach, and the treatment of cardiogenic shock are described. The definitive diagnosis of infarction and the histopathological findings compatible with polyarteritis nodosa were made by autopsy.