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BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. In this study, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. METHODS AND RESULTS: Skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Using mass spectrometry-based comparative secretome analysis, we demonstrated elevated secretion of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.
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OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders significantly impacting skeletal muscles; however, the precise correlation between muscle magnetic resonance imaging (MRI) findings, muscle pathology, disease subtypes, and clinical characteristics remains uncertain. Thus, we investigated the association of muscle MRI findings in IIMs with muscle pathology and clinical features. METHODS: New-onset IIM patients underwent proximal upper and/or lower limb muscle MRI. Patterns of muscle oedema on MRI were categorised into fascial, honeycomb, peripheral, foggy, dense, or coarse dot patterns and compared with inflammatory cell infiltration sites in corresponding muscle biopsies. The incidence of MRI patterns was examined in patient subgroups using myositis-specific antibodies (MSAs) and 2017 EULAR/ACR classification criteria. Univariate and multivariate analyses were conducted to determine the odds ratios (ORs) of MRI findings for clinical characteristics. RESULTS: Fifty-six of 85 patients underwent muscle biopsy. Foggy, honeycomb, and fascial patterns at biopsy sites correlated with inflammatory cell infiltration in the endomysium (OR 11.9, p= 0.005), perimysium (OR 6.0, p= 0.014), and fascia (OR 16.9, p< 0.001), respectively. Honeycomb and foggy patterns were characteristic of patients with anti-TIF1γ or anti-Mi2 antibodies and MSA-negative dermatomyositis, and those with anti-SRP or anti-HMGCR antibodies and MSA-negative polymyositis (PM), respectively. The honeycomb pattern positively correlated with malignancy (OR 6.87, p< 0.001) and Gottron sign (OR 8.05, p= 0.002); the foggy pattern correlated with muscle weakness (OR 11.24, p= 0.005). The dense dot pattern was associated with dysphagia (OR 6.27, p= 0.006) and malignancy (OR 8.49, p= 0.002). CONCLUSION: Muscle MRI holds promise in predicting muscle pathology, disease subtypes, and clinical manifestations of IIMs.
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Chronic lung allograft dysfunction is the major barrier to long-term survival in lung transplant recipients. Evidence supports type 1 alloimmunity as the predominant response in acute/chronic lung rejection, but the immunoregulatory mechanisms remain incompletely understood. We studied the combinatorial F-box E3 ligase system: F-box protein 3 (FBXO3; proinflammatory) and F-box and leucine-rich repeat protein 2 (FBXL2; anti-inflammatory and regulates TNFR-associated factor [TRAF] protein). Using the mouse orthotopic lung transplant model, we evaluated allografts from BALB/c â C57BL/6 (acute rejection; day 10) and found significant induction of FBXO3 and diminished FBXL2 protein along with elevated T-bet, IFN-γ, and TRAF proteins 1-5 compared with isografts. In the acute model, treatment with costimulation blockade (MR1/CTLA4-Ig) resulted in attenuated FBXO3, preserved FBXL2, and substantially reduced T-bet, IFN-γ, and TRAFs 1-5, consistent with a key role for type 1 alloimmunity. Immunohistochemistry revealed significant changes in the FBXO3/FBXL2 balance in airway epithelia and infiltrating mononuclear cells during rejection compared with isografts or costimulation blockade-treated allografts. In the chronic lung rejection model, DBA/2J/C57BL/6F1 > DBA/2J (day 28), we observed persistently elevated FBXO3/FBXL2 balance and T-bet/IFN-γ protein and similar findings from lung transplant recipient lungs with chronic lung allograft dysfunction versus controls. We hypothesized that FBXL2 regulated T-bet and found FBXL2 was sufficient to polyubiquitinate T-bet and coimmunoprecipitated with T-bet on pulldown experiments and vice versa in Jurkat cells. Transfection with FBXL2 diminished T-bet protein in a dose-dependent manner in mouse lung epithelial cells. In testing type 1 cytokines, TNF-α was found to negatively regulate FBXL2 protein and mRNA levels. Together, our findings show the combinatorial E3 ligase FBXO3/FBXL2 system plays a role in the regulation of T-bet through FBXL2, with negative cross-regulation of TNF-α on FBXL2 during lung allograft rejection.
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Proteínas F-Box , Animales , Ratones , Abatacept , Aloinjertos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Rechazo de Injerto , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , ARN Mensajero , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Despite recent technological advances such as ex vivo lung perfusion (EVLP), the outcome of lung transplantation remains unsatisfactory with ischemic injury being a common cause for primary graft dysfunction. New therapeutic developments are hampered by limited understanding of pathogenic mediators of ischemic injury to donor lung grafts. Here, to identify novel proteomic effectors underlying the development of lung graft dysfunction, using bioorthogonal protein engineering, we selectively captured and identified newly synthesized glycoproteins (NewS-glycoproteins) produced during EVLP with unprecedented temporal resolution of 4 h. Comparing the NewS-glycoproteomes in lungs with and without warm ischemic injury, we discovered highly specific proteomic signatures with altered synthesis in ischemic lungs, which exhibited close association to hypoxia response pathways. Inspired by the discovered protein signatures, pharmacological modulation of the calcineurin pathway during EVLP of ischemic lungs offered graft protection and improved posttransplantation outcome. In summary, the described EVLP-NewS-glycoproteomics strategy delivers an effective new means to reveal molecular mediators of donor lung pathophysiology and offers the potential to guide future therapeutic development.NEW & NOTEWORTHY This study developed and implemented a bioorthogonal strategy to chemoselectively label, enrich, and characterize newly synthesized (NewS-)glycoproteins during 4-h ex vivo lung perfusion (EVLP). Through this approach, the investigators uncovered specific proteomic signatures associated with warm ischemic injury in donor lung grafts. These signatures exhibit high biological relevance to ischemia-reperfusion injury, validating the robustness of the presented approach.
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Trasplante de Pulmón , Daño por Reperfusión , Humanos , Perfusión , Proteómica , Isquemia Tibia , Pulmón/metabolismo , Daño por Reperfusión/metabolismo , Glicoproteínas/metabolismoRESUMEN
OBJECTIVES: In patients with RA, baricitinib not only improves arthritis symptom severity, but also patients' neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema, which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the area postrema. Therefore, we sought to assess the effect of baricitinib on microglia in the area postrema using the CIA mouse model. METHODS: Microglia number and morphology in the area postrema were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the area postrema was also immunohistochemically examined. Behavioural outcomes were assessed by examining feeding behaviours and sucrose preference tests. RESULTS: In the early phase, activated microglial levels in the area postrema were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. CONCLUSION: Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviours during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.
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Antirreumáticos , Artritis Reumatoide , Azetidinas , Animales , Ratones , Barrera Hematoencefálica , Microglía , Artritis Reumatoide/tratamiento farmacológico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Antirreumáticos/uso terapéuticoRESUMEN
BACKGROUND: The number of lung transplants from donors after circulatory death has increased over the last decade. This study aimed to describe the evolution and outcomes following lung transplantation donation after circulatory death (DCD) and report the practices and outcomes of ex vivo lung perfusion (EVLP) in this donor population. METHODS: This was a retrospective study using a prospectively collected national registry. The United Network for Organ Sharing (UNOS) database was queried to identify adult patients who underwent lung transplantation between May 1, 2005, and December 31, 2021. Kaplan-Meier analysis and Weibull regression were used to compare survival in four cohorts (donation after brain death [DBD] with or without EVLP, and DCD with or without EVLP). The primary outcome of interest was patient survival. RESULTS: Of the 21 356 recipients who underwent lung transplantation, 20 380 (95.4%) were from brain death donors and 976 (4.6%) from donors after circulatory death. Kaplan-Meier analysis showed no difference in the survival time between the two groups. In a multivariable analysis that controlled for baseline differences in donor and recipient characteristics, recipients who received lungs from cardiac death donors after EVLP had 28% shorter survival time relative to donor lungs after brain death without EVLP (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.10-2.15, p = .01). CONCLUSIONS: The early survival differences observed after lung transplants from donors after circulatory death in lungs evaluated with EVLP deserves further investigation.
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Trasplante de Pulmón , Obtención de Tejidos y Órganos , Adulto , Humanos , Estados Unidos , Muerte Encefálica , Estudios Retrospectivos , Pulmón , Donantes de Tejidos , Muerte , Supervivencia de InjertoRESUMEN
BACKGROUND: The safety of lung transplantation using ex vivo lung perfusion (EVLP) has been confirmed in multiple clinical studies; however, limited evidence is currently available regarding the potential effects of EVLP on posttransplant graft complications and survival with mid- to long-term follow-up. In this study, we reviewed our institutional data to better understand the impact of EVLP. METHODS: Lungs placed on EVLP from 2014 through 2020 and transplant outcomes were retrospectively analyzed. Data were compared between lungs transplanted and declined after EVLP, between patients with severe primary graft dysfunction (PGD3) and no PGD3 after EVLP, and between matched patients with lungs transplanted with and without EVLP. RESULTS: In total, 98 EVLP cases were performed. Changes in metabolic indicators during EVLP were correlated with graft quality and transplantability, but not changes in physiological parameters. Among 58 transplanted lungs after EVLP, PGD3 at 72 h occurred in 36.9% and was associated with preservation time, mechanical support prior to transplant, and intraoperative transfusion volume. Compared with patients without EVLP, patients who received lungs screened with EVLP had a higher incidence of PGD3 and longer ICU and hospital stays. Lung grafts placed on EVLP exhibited a significantly higher chance of developing airway anastomotic ischemic injury by 30 days posttransplant. Acute and chronic graft rejection, pulmonary function, and posttransplant survival were not different between patients with lungs screened on EVLP versus lungs with no EVLP. CONCLUSION: EVLP use is associated with an increase of early posttransplant adverse events, but graft functional outcomes and patient survival are preserved.
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Trasplante de Pulmón , Pulmón , Humanos , Circulación Extracorporea , Pulmón/fisiología , Trasplante de Pulmón/efectos adversos , Perfusión , Estudios RetrospectivosRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) can be comorbid with psychiatric symptoms. Brain abnormalities in RA patients and in arthritis models have been reported. However, it remains unclear when these abnormalities occur and where they are distributed. In this study, we analyzed spatiotemporal changes in gene expression in the brains of mice with collagen-induced arthritis (CIA). METHODS: Mice were divided into three groups: (i) CIA (all mice developed arthritis on day 35): complete Freund's adjuvant (CFA) and type II collagen at initial immunization, and incomplete Freund's adjuvant (IFA) and type II collagen at booster immunization; (ii) C(+/-) (50% mice developed arthritis on day 35): only IFA at booster immunization; and (iii) C(-/-) (no arthritis): only CFA at initial immunization and only IFA at booster immunization. Whole brains were collected at ten stages of arthritis and divided into six sections. Real-time polymerase chain reaction was performed using RNA extracted from the brain, and the expression of proinflammatory cytokines and glial markers was semi-quantified. Arthritis score, body weight, and food and water intakes were recorded and analyzed for correlations with brain gene expression. We also investigated the effect of interleukin-6 (IL-6) injection in the olfactory bulbs (OBs) on the food intake. RESULTS: After booster immunization, a transient increase in Integrin subunit α-M and IL-1ß was observed in multiple areas in CIA. IL-6 is persistently expressed in the OB before the onset of arthritis, which is correlated with body weight loss and decreased food intake. This change in the OB was observed in the C(+/-) but not in the C(-/-) groups. In the C(+/-) group, non-arthritic mice showed the same changes in the OB as the arthritic mice. This elevation in IL-6 levels persisted throughout the chronic phase until day 84. In addition, IL-6 injection into the OB reduced food intake. CONCLUSION: Persistent elevation of IL-6 in the OB from the early stage of arthritis may be an important finding that might explain the neuropsychiatric pathophysiology of RA, including appetite loss, which is present in the early stages of the disease and manifests as a variety of symptoms over time.
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Artritis Experimental , Artritis Reumatoide , Interleucina-6 , Bulbo Olfatorio , Animales , Ratones , Colágeno Tipo II/metabolismo , Ingestión de Alimentos , Interleucina-6/metabolismo , Bulbo Olfatorio/metabolismoRESUMEN
It is expected that human iPS cell-derived cardiomyocytes (hiPSC-CMs) can be used to treat serious heart diseases. However, the properties and functions of human adult cardiomyocytes and hiPSC-CMs, including cell maturation, differ. In this study, we focused on the temperature dependence of hiPSC-CMs by integrating the temperature regulation system into our sensor platform, which can directly and quantitatively measure their mechanical motion. We measured the beating frequency of hiPSC-CMs at different environmental temperatures and found that the beating frequency increased as the temperature increased. Although the rate at which the beating frequency increased with temperature varied, the temperature at which the beating stopped was relatively stable at approximately 20 °C. The stopping of beating at this temperature was stable, even in immature hiPSC-CMs, and was considered to be a primitive property of cardiomyocytes.
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Células Madre Pluripotentes Inducidas , Sistemas Microelectromecánicos , Adulto , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Temperatura , Diferenciación Celular , Miocitos Cardíacos/fisiología , Células CultivadasRESUMEN
BACKGROUND: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. METHODS: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC ß1 subunit (sGCß1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. RESULTS: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCß1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCß1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCß1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. CONCLUSIONS: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCß1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCß1-cGMP signaling and ameliorate EIPH.
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Factor de Unión a CCAAT/metabolismo , Insuficiencia Cardíaca/etiología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/etiología , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , MicroARNs/genética , Especies Reactivas de Oxígeno/metabolismo , Guanilil Ciclasa Soluble/genética , Animales , Animales Modificados Genéticamente , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Ejercicio Físico , Regulación de la Expresión Génica , Insuficiencia Cardíaca/diagnóstico , Humanos , Síndrome Metabólico/complicaciones , Mitocondrias Cardíacas , Miocitos del Músculo Liso/metabolismo , Fenotipo , Ratas , Transducción de Señal , Estrés Fisiológico , Volumen Sistólico , Disfunción Ventricular DerechaRESUMEN
OBJECTIVES: Several studies have indicated that arthralgia may be driven by central sensitisation. Central sensitivity syndrome (CSS) is a concept that unifies various symptoms due to central sensitisation. Recently, the central sensitisation inventory (CSI) was developed as a screening questionnaire to detect CSS. Using the CSI, we examined the prevalence, the clinical characteristics of CSS, and the association between CSS and neuropathic pain (NP)-like symptoms among rheumatoid arthritis (RA) patients. METHODS: The CSI was administered to 240 RA outpatients. We evaluated their disease activity and several potentially relevant patient-reported outcomes. We compared the clinical parameters depending on the severity of CSS and examined the effect of the CSI score on NP-like symptoms among the relevant clinical parameters using multivariate analyses. RESULTS: The mean disease duration was 9.58 ± 7.76 years. Eighteen (7.5 %) patients had CSS, which was associated with evaluator global assessment (EGA) (odds ratio (OR) 0.860); fibromyalgia symptom scale (OR 1.46); painDETECT questionnaire score (OR 1.24); hospital anxiety and depression scale-anxiety (OR 1.35); and physical (OR 0.898), mental (OR 0.828), and role-social (OR 0.946) component summary scores on the Short-Form 36-Item Health Survey. CSI score was the factor that contributed most to NP-like symptoms (p=0.000, ß=0.266). CONCLUSIONS: NP-like symptoms might be one of the symptoms of CSS in longstanding RA patients. In longstanding RA patients who have disproportionately greater NP-like symptoms and/or widespread pain compared with degree of inflammation, detecting CSS using CSI might help to understand the pathogenesis of patients.
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Artritis Reumatoide , Fibromialgia , Neuralgia , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Sensibilización del Sistema Nervioso Central , Estudios Transversales , Fibromialgia/diagnóstico , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiología , Neuralgia/etiología , Encuestas y Cuestionarios , SíndromeRESUMEN
OBJECTIVES: Central sensitivity syndrome (CSS) comprises various symptoms caused by central sensitisation (CS). Using the central sensitisation inventory (CSI), a screening questionnaire developed for detecting CSS, this syndrome was recently identified in patients with long-standing rheumatoid arthritis (RA). However, the descriptors of CS-related pain and the effects of CSS on symptoms in patients with rheumatoid arthritis (RA) remain unknown. We examined the characteristics of pain and influence of CSS on patient and evaluator global assessment among multiple clinical variables. METHODS: We used the central sensitisation inventory (CSI) and short-form McGill pain questionnaire to evaluate CSS and characteristics of pain in 240 outpatients with RA. Disease activity, fibromyalgia, neuropathic pain, anxiety, depression, pain catastrophising, and health-related quality of life were evaluated. We used multivariate analysis to analyse the characteristics of CS-related pain according to CSI and the effect of CSS on patient global assessment (PGA), evaluator global assessment (EGA), and PGA minus EGA among relevant clinical variables. RESULTS: In patients with RA, the main descriptors of pain according to severity of CSI scores were "sharp" and "stabbing", whereas those of pain according to disease activity were "tender" and "throbbing". CSS was associated with EGA (p=0.000, ß=- 0.199) and PGA minus EGA (p=0.021, ß=0.147), but not with PGA. CONCLUSIONS: In patients with RA, descriptors for CS-related pain differ from those for disease activity-related pain. CSS may have an important impact on EGA and PGA minus EGA. Additionally, CSI may be helpful in identifying why there is discordance between PGA and EGA.
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Artritis Reumatoide , Sensibilización del Sistema Nervioso Central , Humanos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Dolor , Calidad de Vida , Índice de Severidad de la Enfermedad , SíndromeRESUMEN
Rationale: Tissue-resident memory T cells (TRM) play a critical role in the defense against inhaled pathogens. The isolation and study of human lung tissue-resident memory T cells and lung-resident macrophages (MLR) are limited by experimental constraints. Objectives: To characterize the spatial and functional relationship between MLR and human lung tissue-resident memory T cells using ex vivo lung perfusion (EVLP). Methods: TRM and MLR were isolated using EVLP and intraperfusate-labeled CD45 antibody. Cells isolated after 6 hours of EVLP were analyzed using spectral flow cytometry. Spatial relationships between CD3+ and CD68+ cells were explored with multiplexed immunohistochemistry. Functional relationships were determined by using coculture and T-cell-receptor complex signal transduction. Measurements and Main Results: Lungs from 8 research-consenting organ donors underwent EVLP for 6 hours. We show that human lung TRM and MLR colocalize within the human lung, preferentially around the airways. Furthermore, we found that human lung CD8+ TRM are composed of two functionally distinct populations on the basis of PD1 (programed cell death receptor 1) and ZNF683 (HOBIT) protein expression. We show that MLR provide costimulatory signaling to PD1hi CD4+ and CD8+ lung TRM,, augmenting the effector cytokine production and degranulation of TRM. Conclusions: EVLP provides an innovative technique to study resident immune populations in humans. Human MLR colocalize with and provide costimulation signaling to TRM, augmenting their effector function.
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Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica/fisiología , Pulmón/inmunología , Pulmón/patología , Macrófagos Alveolares/fisiología , Adulto , Técnicas de Cocultivo , Citocinas/metabolismo , Femenino , Humanos , Trasplante de Pulmón , Masculino , Persona de Mediana Edad , Perfusión , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Despite advances in critical care for acute respiratory distress syndrome (ARDS), some survivors in the acute phase are unable to wean from extracorporeal membrane oxygenation (ECMO) or mechanical ventilation. To date, little is known regarding whether lung transplantation confers a survival benefit for irreversible ARDS. METHODS: This retrospective study was conducted using the United Network for Organ Sharing database (May 2005-December 2018). Patients with restrictive lung disease were divided into two groups: patients with and without ARDS. Propensity score matching identified recipients without ARDS for the control group. RESULTS: A total of 63 patients with ARDS were waitlisted for lung transplantation, while 39 received a lung transplant after a median waitlist duration of 8 days. Seventy-eight patients were matched as controls. In the ARDS group, the median age was 30 years, and the median lung allocation score was 88.4. Among the 39 recipients, 30 (76.9%) received ECMO support prior to transplantation. Lung transplantation for ARDS and restrictive lung disease showed similar 90-day (87.2% vs. 88.5%, p = .80), 1-year (82.1% vs. 85.9%, p = .52), and 3-year (69.2% vs. 65.4%, p = .94) survival rates. CONCLUSIONS: Lung transplantation provides acceptable outcomes in selected patients with irreversible ARDS.
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Oxigenación por Membrana Extracorpórea , Trasplante de Pulmón , Síndrome de Dificultad Respiratoria , Adulto , Humanos , Respiración Artificial , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Patients with ulcerative colitis (UC) often develop arthropathy. The purpose of this study was to determine the frequency of and risk factors for arthropathy in patients with UC who underwent total colectomy which is the final radical treatment lead to remission. METHODS: Patients who underwent total colectomy from January 2007 to April 2016 were analyzed for the development of arthropathy. The type of arthropathy and risk factors for developing arthropathy were analyzed by clinical and endoscopic severity classification, extraintestinal manifestations (EIMs) and medical treatment. RESULTS: Total of 219 patients who underwent total colectomy with sufficient medical records were analyzed. Forty-eight cases (21.9%) had EIMs, and 40 cases (18.2%) developed arthropathy (57.0% polyarthropathy; 42.5% peripheral arthropathy). Multivariate analysis showed that severity of Matts classification grade 3 or 4 versus grade 1 or 2 (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.22-4.36, p < .05) and EIMs other than arthropathy (HR 3.29, 95% CI 1.43-7.58, p < .05) were risk factors for the development of arthropathy. CONCLUSION: This study showed that approximately one fifth of patients with UC who underwent total colectomy developed arthropathy. The risk factors for the development of arthropathy were preoperative endoscopic disease activity and EIMs.
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Colectomía/efectos adversos , Colitis Ulcerosa/cirugía , Artropatías/epidemiología , Complicaciones Posoperatorias/epidemiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Primary graft dysfunction (PGD) is directly related to ischemia-reperfusion (I/R) injury and a major obstacle in lung transplantation (LTx). Nitrite (NO2-), which is reduced in vivo to form nitric oxide (NO), has recently emerged as an intrinsic signaling molecule with a prominent role in cytoprotection against I/R injury. Using a murine model, we provide the evidence that nitrite mitigated I/R-induced injury by diminishing infiltration of immune cells in the alveolar space, reducing pulmonary edema, and improving pulmonary function. Ultrastructural studies support severe mitochondrial impairment in the lung undergoing I/R injury, which was significantly protected by nitrite treatment. Nitrite also abrogated the increased pulmonary vascular permeability caused by I/R. In vitro, hypoxia-reoxygenation (H/R) exacerbated cell death in lung epithelial and microvascular endothelial cells. This contributed to mitochondrial dysfunction as characterized by diminished complex I activity and mitochondrial membrane potential but increased mitochondrial reactive oxygen species (mtROS). Pretreatment of cells with nitrite robustly attenuated mtROS production through modulation of complex I activity. These findings illustrate a potential novel mechanism in which nitrite protects the lung against I/R injury by regulating mitochondrial bioenergetics and vascular permeability.
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Permeabilidad Capilar/efectos de los fármacos , Pulmón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Nitritos/farmacología , Daño por Reperfusión/tratamiento farmacológico , Células A549 , Animales , Línea Celular Tumoral , Citoprotección/efectos de los fármacos , Complejo I de Transporte de Electrón/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Pulmón/metabolismo , Trasplante de Pulmón/métodos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Disfunción Primaria del Injerto/tratamiento farmacológico , Disfunción Primaria del Injerto/metabolismo , Edema Pulmonar/tratamiento farmacológico , Edema Pulmonar/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Objectives: Rheumatoid arthritis (RA) pain is thought to be nociceptive. However, recent studies indicate that RA also involves the neuropathic pain (NP) mechanism. We examined pain features and the effect of NP-like symptoms on health-related quality of life (HRQOL) among patients with RA.Methods: The painDETECT questionnaire (PDQ) was used to evaluate NP-like symptoms among 145 outpatients with RA. Disease activity, pain quality, and HRQOL were evaluated. We compared clinical parameters between patients with and without NP-like symptoms and analyzed pain features and the effect of NP-like symptoms on HRQOL, along with multiple other pain-related parameters.Results: Thirty (20.7%) patients had NP-like symptoms (PDQ ≥13). Patient global assessment and evaluator global assessment diverged for patients with RA who had NP-like symptoms. Of the examined pain-related parameters, PDQ score (p = .038, ß = -.173) was associated with the Short-Form 36-Item Health Survey role-social component summary score, but not with the physical or mental component summary scores.Conclusion: NP-like symptoms affected HRQOL among patients with RA. There was discordance between global assessments by patients and by evaluators for patients with RA who had NP-like symptoms. Therefore, NP-like symptoms should be given somewhat more attention when treating patients with RA.
Asunto(s)
Artritis Reumatoide/complicaciones , Neuralgia/patología , Dimensión del Dolor/métodos , Calidad de Vida , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/etiología , Dimensión del Dolor/normas , Encuestas y CuestionariosRESUMEN
A current detection surface plasmon resonance (SPR) sensor with an Au grating on an n-Si wafer was proposed. SPR excitation light is illuminated from the backside of the device and diffracted by the grating. Since the diffraction provides matching conditions, SPR can be coupled to the Au/analyte interface. Since the coupled SPR excites free electrons on the Au surface, the SPR can be detected as a current signal by a Schottky barrier diode formed on the Au/n-Si interface. The obtained angular current spectrum showed clear agreement with SPR coupling theory, thereby confirming that the sample on the Au surface can be electrically detected using the proposed sensor.
RESUMEN
Ethanol concentration was quantified by the use of a compact surface plasmon resonance (SPR) system, which electrically detects hot electrons via a Schottky barrier. Although it is well known that SPR can be used as bio/chemical sensors, implementation is not necessarily practical, due to the size and cost impediments associated with a system with variable wavelength or angle of incidence. However, scanning capability is not a prerequisite if the objective is to use SPR in a sensor. It is possible to build a small, inexpensive SPR sensor if the optics have no moving parts and a Schottky barrier is used for electrical current detection in place of a photodetector. This article reports on the design and performance of such a novel SPR sensor, and its application for quantifying ethanol concentration. As the concentration of ethanol is increased, the change in the angle dependence of the SPR current is observed. This change can be understood as a superposition of contributions of SPR coupled with the +3rd- and -3rd-order diffraction. Moreover, real-time monitoring of ethanol concentration was demonstrated using the proposed SPR system.
RESUMEN
A 59-year-old female with diffuse large B-cell lymphoma was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen. In addition, we administered pegfilgrastim for treating chemotherapy-induced febrile neutropenia. She complained of fever and neck and chest pain a few days after pegfilgrastim administration during the third and fourth courses of R-CHOP. Radiological imaging revealed an inflammation of large vessels, which led to the diagnosis of drug-associated vasculitis. We confirmed that vasculitis observed in this case was caused by pegfilgrastim administration because similar symptoms appeared with both injections of pegfilgrastim.