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The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
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Caquexia/tratamiento farmacológico , Neoplasias/patología , Receptores del Factor de Necrosis Tumoral/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Atrofia/tratamiento farmacológico , Caquexia/patología , Muerte Celular , Neoplasias del Colon/tratamiento farmacológico , Citocina TWEAK , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Desarrollo de Músculos , Neoplasias/metabolismo , Receptores del Factor de Necrosis Tumoral/química , Receptores del Factor de Necrosis Tumoral/metabolismo , Alineación de Secuencia , Transducción de Señal , Receptor de TWEAK , Factores de Necrosis Tumoral/metabolismoRESUMEN
Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/patología , Macrófagos Alveolares/metabolismo , Células Epiteliales Alveolares/metabolismo , Animales , Apoptosis/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico/fisiología , Femenino , Homeostasis , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Pulmón/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Fagocitosis/fisiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfisema Pulmonar/metabolismo , Humo/efectos adversos , Fumar/efectos adversos , Nicotiana/efectos adversosRESUMEN
No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.
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Transfusión Sanguínea , Humanos , InglaterraRESUMEN
Chronic airway inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), and their associated exacerbations cause significant socioeconomic burden. There are still major obstacles to effective therapy for controlling severe asthma and COPD progression. Advances in understanding the pathogenesis of the two diseases at the cellular and molecular levels are essential for the development of novel therapies. In recent years, significant efforts have been made to identify natural products as potential drug leads for treatment of human diseases and to investigate their efficacy, safety, and underlying mechanisms of action. Many major active components from various natural products have been extracted, isolated, and evaluated for their pharmacological efficacy and safety. For the treatment of asthma and COPD, many promising natural products have been discovered and extensively investigated. In this chapter, we will review a range of natural compounds from different chemical classes, including terpenes, polyphenols, alkaloids, fatty acids, polyketides, and vitamin E, that have been demonstrated effective against asthma and/or COPD and their exacerbations in preclinical models and clinical trials. We will also elaborate in detail their underlying mechanisms of action unraveled by these studies and discuss new opportunities and potential challenges for these natural products in managing asthma and COPD.
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One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.g., liver, adipose tissues, and intestine) combined with changes in metabolism and microbiome. In contrast to this prevailing concept, we report that fatty liver could be triggered by a single mutated protein expressed only in the liver. We established a transgenic system that allows temporally controlled activation of the MAP kinase p38α in a tissue-specific manner by induced expression of intrinsically active p38α allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38α alone was sufficient to cause macrovesicular fatty liver. Animals did not become overweight, showing that fatty liver can be imposed solely by a genetic modification in liver per se and can be separated from obesity. Active p38α-induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38α mutant resulted in reversal of symptoms. The findings suggest that p38α plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38α activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene).
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Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Mutación con Ganancia de Función , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVE: This study is to evaluate if there is any difference in the balance between incidence of and remission from overweight/obesity in Hong Kong school-age children before and during the COVID-19 pandemic over three years. METHODS: This is a retrospective longitudinal study that involved children aged 6-16 years from a database of the School Physical Fitness Award Scheme. RESULTS: 2765 students were longitudinally followed up for two years. The prevalence of childhood overweight/obesity was increased between the 2019 and 2021 academic years (P < 0.001). During the COVID-19 pandemic, the rate of obesity remission significantly reduced by 7.9 % (P = 0.003), at a background of a plateau of obesity among children and adolescents. CONCLUSIONS: Our study provides evidence on the impact of school closure and home confinement as a standard infection control measure for the prevention of COVID-19, which are likely to break the balance between incidence of and remission from childhood obesity.
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COVID-19 , Obesidad Infantil , Adolescente , Humanos , Niño , Obesidad Infantil/epidemiología , COVID-19/epidemiología , COVID-19/prevención & control , Estudios Longitudinales , Estudios Retrospectivos , Hong Kong/epidemiología , Pandemias , Sobrepeso/epidemiologíaRESUMEN
Overactive bladder (OAB) is a common urological disease with a high prevalence in older adult populations. Antimuscarinic drugs have been the most common treatment for OAB for more than a decade, but their anticholinergic side-effects and potential impact on cognitive function among older patients are usually underestimated. This consensus aimed to provide practical recommendations concerning OAB management, with a particular emphasis on older patients. A joint consensus panel was formed by representatives of the Hong Kong Urological Association and the Hong Kong Geriatrics Society. Literature searches regarding OAB and its management were performed in PubMed and Ovid. Several working meetings were held to present and discuss available evidence, develop consensus statements, and vote for the statements. A modified Delphi method was used in this consensus process. To address questions regarding various aspects of OAB, 29 consensus statements were proposed covering the following areas: diagnosis, initial assessment, non-pharmacological treatments, considerations before administration of pharmacological treatments, various pharmacological treatments, combination therapy, and surgical treatment. Twenty-five consensus statements were accepted.
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INTRODUCTION: Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. METHODS: This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. RESULTS: Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. CONCLUSION: Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.
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INTRODUCTION: Febrile seizures in children can be associated with various underlying conditions, including COVID-19. Differentiating COVID-19 and non-COVID-19 related febrile seizures is crucial for tailored patient management and for implementing appropriate infection control measures to prevent nosocomial transmission. This study aimed to describe the clinical features of children hospitalised for COVID-19 and non-COVID-19 febrile seizures and to identify factors that differentiate between the two groups. MATERIALS AND METHODS: This retrospective cross-sectional study involved children aged 6 months to 6 years who were hospitalised for febrile seizures in Hospital Tuanku Ja'afar Seremban (HTJS) from January 2021 to June 2022. Descriptive statistics were used to summarise the differences in demographics and clinical presentations. Logistic regression analyses were performed to identify factors associated with COVID-19 and non-COVID-19 febrile seizures. RESULTS: Of the 345 patients (median age 22 months, IQR 15- 32; 59.7% were males) included in the study, 130 (37.7%) tested positive for COVID-19, while 215 (62.3%) tested negative. There were no significant differences between both groups based on age, comorbidities, history of febrile seizures, seizure types, temperature on arrival, cough and rhinorrhoea. Multivariate analysis revealed that a family history of febrile seizures and leucocytosis were associated with increased odds of non-COVID-19 febrile seizures. In contrast, lymphopenia was associated with decreased odds. CONCLUSION: The clinical presentation of COVID-19 and non- COVID-19 febrile seizures are remarkably similar, highlighting the importance of including COVID-19 screening in febrile seizures workup. Full blood count readings may be potentially useful for differentiating between these conditions.
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COVID-19 , Convulsiones Febriles , Humanos , COVID-19/complicaciones , COVID-19/diagnóstico , Masculino , Convulsiones Febriles/diagnóstico , Femenino , Estudios Retrospectivos , Lactante , Preescolar , Estudios Transversales , Niño , SARS-CoV-2 , Hospitalización , Diagnóstico DiferencialRESUMEN
BACKGROUND: Allergic asthma is a common respiratory disease that significantly impacts human health. Through in silico analysis of human lung RNASeq, we found that asthmatic lungs display lower levels of Isthmin-1 (ISM1) expression than healthy lungs. ISM1 is an endogenous anti-inflammatory protein that is highly expressed in mouse lungs and bronchial epithelial cells, playing a crucial role in maintaining lung homeostasis. However, how ISM1 influences asthma remains unclear. This study aims to investigate the potential involvement of ISM1 in allergic airway inflammation and uncover the underlying mechanisms. METHODS: We investigated the pivotal role of ISM1 in airway inflammation using an ISM1 knockout mouse line (ISM1-/-) and challenged them with house dust mite (HDM) extract to induce allergic-like airway/lung inflammation. To examine the impact of ISM1 deficiency, we analyzed the infiltration of immune cells into the lungs and cytokine levels in bronchoalveolar lavage fluid (BALF) using flow cytometry and multiplex ELISA, respectively. Furthermore, we examined the therapeutic potential of ISM1 by administering recombinant ISM1 (rISM1) via the intratracheal route to rescue the effects of ISM1 reduction in HDM-challenged mice. RNA-Seq, western blot, and fluorescence microscopy techniques were subsequently used to elucidate the underlying mechanisms. RESULTS: ISM1-/- mice showed a pronounced worsening of allergic airway inflammation and hyperresponsiveness upon HDM challenge. The heightened inflammation in ISM1-/- mice correlated with enhanced lung cell necroptosis, as indicated by higher pMLKL expression. Intratracheal delivery of rISM1 significantly reduced the number of eosinophils in BALF and goblet cell hyperplasia. Mechanistically, ISM1 stimulates adiponectin secretion by type 2 alveolar epithelial cells partially through the GRP78 receptor and enhances adiponectin-facilitated apoptotic cell clearance via alveolar macrophage efferocytosis. Reduced adiponectin expression under ISM1 deficiency also contributed to intensified necroptosis, prolonged inflammation, and heightened severity of airway hyperresponsiveness. CONCLUSIONS: This study revealed for the first time that ISM1 functions to restrain airway hyperresponsiveness to HDM-triggered allergic-like airway/lung inflammation in mice, consistent with its persistent downregulation in human asthma. Direct administration of rISM1 into the airway alleviates airway inflammation and promotes immune cell clearance, likely by stimulating airway adiponectin production. These findings suggest that ISM1 has therapeutic potential for allergic asthma.
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Asma , Hipersensibilidad , Péptidos y Proteínas de Señalización Intercelular , Macrófagos Alveolares , Animales , Humanos , Ratones , Adiponectina , Asma/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Pulmón/metabolismo , Macrófagos Alveolares/metabolismo , Pyroglyphidae , Péptidos y Proteínas de Señalización Intercelular/metabolismoRESUMEN
Severe asthma is a difficult-to-treat chronic airway inflammatory disease requiring systemic corticosteroids to achieve asthma control. It has recently been shown that drugs targeting immunometabolism have elicited anti-inflammatory effects. The purpose of this study was to investigate potential immunometabolic modulatory actions of systemic dexamethasone (Dex) in an Aspergillus fumigatus (Af)-induced severe asthma model. Mice were repeatedly exposed to the Af aeroallergen before systemic treatment with Dex. Simultaneous measurements of airway inflammation, real-time glycolytic and oxidative phosphorylation (OXPHOS) activities, expression levels of key metabolic enzymes, and amounts of metabolites were studied in lung tissues, and in primary alveolar macrophages (AMs) and eosinophils. Dex markedly reduced Af-induced eosinophilic airway inflammation, which was coupled with an overall reduction in lung glycolysis, glutaminolysis, and fatty acid synthesis. The anti-inflammatory effects of Dex may stem from its immunometabolic actions by downregulating key metabolic enzymes including pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase. Substantial suppression of eosinophilic airway inflammation by Dex coincided with a specific escalation of mitochondrial proton leak in primary lung eosinophils. Besides, while our findings confirmed that inflammation corresponds with an upregulation of glycolysis, it was accompanied with an unexpectedly stable or elevated OXPHOS in the lungs and activated immune cells, respectively. Our findings reveal that the anti-inflammatory effects of Dex in severe asthma are associated with downregulation of pyruvate dehydrogenase kinase, glutaminase, and fatty acid synthase, and the augmentation of mitochondrial proton leak in lung eosinophils. These enzymes and biological processes may be valuable targets for therapeutic interventions against severe asthma.
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The p38MAPK-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38MAPK-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38MAPK-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38MAPK-MK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and time-dependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-α, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38MAPK-MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG.
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Diterpenos , Proteínas Serina-Treonina Quinasas , Ratones , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Diterpenos/farmacología , Diterpenos/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. However, loss of appropriate control mechanisms can result in constitutive pathogenic ISG upregulation. Here, we used genome-scale loss-of-function screening to establish genes critical for IFN-induced transcription, identifying all expected members of the JAK-STAT signaling pathway and a previously unappreciated epigenetic reader, bromodomain-containing protein 9 (BRD9), the defining subunit of non-canonical BAF (ncBAF) chromatin-remodeling complexes. Genetic knockout or small-molecule-mediated degradation of BRD9 limits IFN-induced expression of a subset of ISGs in multiple cell types and prevents IFN from exerting full antiviral activity against several RNA and DNA viruses, including influenza virus, human immunodeficiency virus (HIV1), and herpes simplex virus (HSV1). Mechanistically, BRD9 acts at the level of transcription, and its IFN-triggered proximal association with the ISG transcriptional activator, STAT2, suggests a functional localization at selected ISG promoters. Furthermore, BRD9 relies on its intact acetyl-binding bromodomain and unique ncBAF scaffolding interaction with GLTSCR1/1L to promote IFN action. Given its druggability, BRD9 is an attractive target for dampening ISG expression under certain autoinflammatory conditions.
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Antivirales , Interferones , Antivirales/farmacología , Expresión Génica , Humanos , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/metabolismo , Factores de Transcripción/genéticaRESUMEN
Fat necrosis of the breast is a commonly encountered condition in daily practice. It is a benign pathology, but it can have variable manifestations and patterns that may sometimes mimic malignancy, depending on its stage of evolution and its underlying cause. This review demonstrates the wide spectrum of appearances of fat necrosis on mammography, digital breast tomosynthesis (DBT), ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), and positron-emission tomography (PET). Sequential follow-up images are included in some cases to illustrate the temporal change of the findings. The typical location and distribution of fat necrosis from a comprehensive list of aetiologies are discussed. Improved knowledge of the multimodality imaging features of fat necrosis could enhance diagnostic accuracy and clinical management, thus avoiding unnecessary invasive investigations.
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Neoplasias de la Mama , Necrosis Grasa , Humanos , Femenino , Necrosis Grasa/diagnóstico por imagen , Necrosis Grasa/patología , Mama/diagnóstico por imagen , Mama/patología , Mamografía/métodos , Tomografía Computarizada por Rayos X , Imagen por Resonancia Magnética/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patologíaRESUMEN
INTRODUCTION: This study evaluated the arched bridge and vacuole signs, which constitute morphological patterns of lung sparing in coronavirus disease 2019 (COVID-19), then examined whether these signs could be used to differentiate COVID-19 pneumonia from influenza pneumonia or bacterial pneumonia. METHODS: In total, 187 patients were included: 66 patients with COVID-19 pneumonia, 50 patients with influenza pneumonia and positive computed tomography findings, and 71 patients with bacterial pneumonia and positive computed tomography findings. Images were independently reviewed by two radiologists. The incidences of the arched bridge sign and/or vacuole sign were compared among the COVID-19 pneumonia, influenza pneumonia, and bacterial pneumonia groups. RESULTS: The arched bridge sign was much more common among patients with COVID-19 pneumonia (42/66, 63.6%) than among patients with influenza pneumonia (4/50, 8.0%; P<0.001) or bacterial pneumonia (4/71, 5.6%; P<0.001). The vacuole sign was also much more common among patients with COVID-19 pneumonia (14/66, 21.2%) than among patients with influenza pneumonia (1/50, 2.0%; P=0.005) or bacterial pneumonia (1/71, 1.4%; P<0.001). The signs occurred together in 11 (16.7%) patients with COVID-19 pneumonia, but they did not occur together in patients with influenza pneumonia or bacterial pneumonia. The arched bridge and vacuole signs predicted COVID-19 pneumonia with respective specificities of 93.4% and 98.4%. CONCLUSION: The arched bridge and vacuole signs are much more common in patients with COVID-19 pneumonia and can help differentiate COVID-19 pneumonia from influenza and bacterial pneumonia.
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COVID-19 , Gripe Humana , Neumonía Bacteriana , Humanos , Vacuolas , SARS-CoV-2 , Estudios Retrospectivos , Pulmón , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear. METHODS: Using Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining. RESULTS: We reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1-/- mice, Ism1-/- lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-ß upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages. CONCLUSION: Together with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.
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Lesión Pulmonar Aguda , Neumonía , Fibrosis Pulmonar , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Aguda/metabolismo , Animales , Antiinflamatorios , Citocinas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lipopolisacáridos/farmacología , Pulmón/patología , Ratones , FN-kappa B/metabolismo , Neumonía/metabolismo , Fibrosis Pulmonar/metabolismoRESUMEN
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin-angiotensin system (RAS) in the pathogenesis of COPD. Alveolar macrophages (AMs) are the first line immune defense in the respiratory system and play a critical role in the lung homeostasis. This study aimed to investigate the role of AMs in contributing to the protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD. The AM polarization, phagocytosis and metabolism, and the underlying biochemical mechanisms of compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, were evaluated in a two-week CS-induced COPD mouse model. C21 restored AM phagocytosis ability, reversing CS-induced AM phagocytosis impairment. CS exposure polarized AMs towards M1 phenotype, whereas, C21 skewed the CS-exposed AMs towards M2 phenotype. C21 reprogrammed CS-exposed AM metabolism from a high glycolysis-driven process to support inflammation energy demand to a high mitochondrial respiration process to limit inflammation. Besides, C21 upregulated AT2R and Mas receptor levels in CS-exposed AMs, favoring the anti-inflammatory Ang II/AT2R axis and Ang 1-7/Mas axis in the RAS. C21 restored the normal levels of sirtuin 1 (SIRT1) and MAPK phosphatase 1 (MKP1) in CS-exposed AMs, leading to the reduction of phospho-p38, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed AMs. We report here for the first time that AT2R agonist C21 acts by boosting the protective functions of AMs against CS-induced COPD, and our results support the development of AT2R agonist for the treatment of COPD.
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Fumar Cigarrillos , Enfermedad Pulmonar Obstructiva Crónica , Angiotensina II/metabolismo , Animales , Fumar Cigarrillos/efectos adversos , Imidazoles , Inflamación/metabolismo , Macrófagos Alveolares/metabolismo , Ratones , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , FN-kappa B/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Receptor de Angiotensina Tipo 2/metabolismo , Sirtuina 1/metabolismo , Sulfonamidas , Tiofenos , NicotianaRESUMEN
Anomalies in number and location may occur during splenic development. This review aims to offer a brief overview of splenic function and embryology and a detailed account of the imaging appearances using different imaging techniques of the normal spleen and various congenital splenic anomalies including (1) abnormal viscero-atrial situs, (2) splenogonadal fusion, (3) intrapancreatic accessory spleen, (4) wandering spleen, and (5) splenosis. Emphasis is placed on the salient features that help radiologists recognise important associations (e.g., asplenia/polysplenia in situs abnormalities), avoid diagnostic pitfalls (e.g., mistaking intrapancreatic accessory spleen as pancreatic neoplasms), and potential complications (e.g., acute torsion in wandering spleen). The correct identification of the said anomalies from more sinister causes, such as malignancies, are essential, where early intervention is necessary.
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Síndrome de Heterotaxia , Enfermedades del Bazo , Ectopía del Bazo , Síndrome de Heterotaxia/diagnóstico por imagen , Humanos , Imagen Multimodal , Enfermedades del Bazo/diagnóstico por imagenRESUMEN
Climate change will lead to higher temperatures, increased precipitation and runoff, as well as more intense and frequent extreme weather events in Norway. More extreme rainfall and increased runoff are historically associated with higher concentrations of indicator bacteria, colour and turbidity in raw water of Norwegian waterworks. Regional information about the risk for drinking water deterioration by the end of the century is essential for evaluating potential treatment capacity upgrades at the waterworks. We combined locally downscaled future climate scenarios with historical associations between weather/runoff and water quality from a wide spread of waterworks in Norway. With continued climate change, we estimate higher concentrations of water quality indicators of raw water by the end of the century. The water quality is estimated to deteriorate mainly due to the projected increase in rainfall, and mainly in the Western and Northern parts of Norway. While large waterworks seem to be able to adapt to future conditions, the degradation of raw water quality may cause future challenges for the treatment processes at smaller waterworks. Combining these results with further studies of treatment effects and microbial risk assessments is needed to ensure sufficient treatment capacities of the raw water in the future.
Asunto(s)
Agua Potable , Calidad del Agua , Cambio Climático , Noruega , Tiempo (Meteorología)RESUMEN
There are an estimated 1 billion cases of superficial fungal infection globally. Fungal pathogens form biofilms within wounds and delay the wound healing process. Miconazole and terbinafine are commonly used to treat fungal infections. They induce the accumulation of reactive oxygen species (ROS) in fungi, resulting in the death of fungal cells. ROS are highly reactive molecules, such as oxygen (O2), superoxide anion (O2â¢-), hydrogen peroxide (H2O2) and hydroxyl radicals (â¢OH). Although ROS generation is useful for killing pathogenic fungi, it is cytotoxic to human keratinocytes. To the best of our knowledge, the effect of miconazole and terbinafine on HaCaT cells has not been studied with respect to intracellular ROS stimulation. We hypothesized that miconazole and terbinafine have anti-wound healing effects on skin cells when used in antifungal treatment because they generate ROS in fungal cells. We used sulforhodamine B protein staining to investigate cytotoxicity and 2',7'-dichlorofluorescein diacetate to determine ROS accumulation at the 50% inhibitory concentrations of miconazole and terbinafine in HaCaT cells. Our preliminary results showed that topical treatment with miconazole and terbinafine induced cytotoxic responses, with miconazole showing higher cytotoxicity than terbinafine. Both the treatments stimulated ROS in keratinocytes, which may induce oxidative stress and cell death. This suggests a negative correlation between intracellular ROS accumulation in keratinocytes treated with miconazole or terbinafine and the healing of fungi-infected skin wounds.