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The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium1, which is assumed to dominate the total extragalactic dispersion. Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs2, in at least one case there is evidence for an extreme magneto-ionic local environment3,4 and a compact persistent radio source5. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately [Formula: see text] parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies2,6, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
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Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.
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We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus [B. McKernan, K. E. S. Ford, I. Bartos et al., Astrophys. J. Lett. 884, L50 (2019)AJLEEY2041-821310.3847/2041-8213/ab4886] and is unlikely [
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The majority of ultraluminous X-ray sources are point sources that are spatially offset from the nuclei of nearby galaxies and whose X-ray luminosities exceed the theoretical maximum for spherical infall (the Eddington limit) onto stellar-mass black holes. Their X-ray luminosities in the 0.5-10 kiloelectronvolt energy band range from 10(39) to 10(41) ergs per second. Because higher masses imply less extreme ratios of the luminosity to the isotropic Eddington limit, theoretical models have focused on black hole rather than neutron star systems. The most challenging sources to explain are those at the luminous end of the range (more than 10(40) ergs per second), which require black hole masses of 50-100 times the solar value or significant departures from the standard thin disk accretion that powers bright Galactic X-ray binaries, or both. Here we report broadband X-ray observations of the nuclear region of the galaxy M82 that reveal pulsations with an average period of 1.37 seconds and a 2.5-day sinusoidal modulation. The pulsations result from the rotation of a magnetized neutron star, and the modulation arises from its binary orbit. The pulsed flux alone corresponds to an X-ray luminosity in the 3-30 kiloelectronvolt range of 4.9 × 10(39) ergs per second. The pulsating source is spatially coincident with a variable source that can reach an X-ray luminosity in the 0.3-10 kiloelectronvolt range of 1.8 × 10(40) ergs per second. This association implies a luminosity of about 100 times the Eddington limit for a 1.4-solar-mass object, or more than ten times brighter than any known accreting pulsar. This implies that neutron stars may not be rare in the ultraluminous X-ray population, and it challenges physical models for the accretion of matter onto magnetized compact objects.
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Asymmetry is required by most numerical simulations of stellar core-collapse explosions, but the form it takes differs significantly among models. The spatial distribution of radioactive (44)Ti, synthesized in an exploding star near the boundary between material falling back onto the collapsing core and that ejected into the surrounding medium, directly probes the explosion asymmetries. Cassiopeia A is a young, nearby, core-collapse remnant from which (44)Ti emission has previously been detected but not imaged. Asymmetries in the explosion have been indirectly inferred from a high ratio of observed (44)Ti emission to estimated (56)Ni emission, from optical light echoes, and from jet-like features seen in the X-ray and optical ejecta. Here we report spatial maps and spectral properties of the (44)Ti in Cassiopeia A. This may explain the unexpected lack of correlation between the (44)Ti and iron X-ray emission, the latter being visible only in shock-heated material. The observed spatial distribution rules out symmetric explosions even with a high level of convective mixing, as well as highly asymmetric bipolar explosions resulting from a fast-rotating progenitor. Instead, these observations provide strong evidence for the development of low-mode convective instabilities in core-collapse supernovae.
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Pulmonary hypertension (PH) is an important contributor to morbidity and mortality in patients with left-sided heart disease, including valvular heart disease. In this context, elevated left atrial pressure primarily leads to the development of post-capillary PH. Despite the fact that repair of left-sided valvular heart disease by surgical or interventional approaches will improve PH, recent studies have highlighted that PH (pre- or post-interventional) remains an important predictor of long-term outcome. Here, we review the current knowledge on PH in valvular heart disease taking into account new hemodynamic PH definitions, and the distinction between post- and pre-capillary components of PH. A specific focus is on the precise characterization of hemodynamics and cardiopulmonary interaction, and on potential strategies for the management of residual PH after mitral or aortic valve interventions. In addition, we highlight the clinical significance of tricuspid regurgitation, which may occur as a primary condition or as a consequence of PH and right heart dilatation (functional). In this context, proper patient selection for potential tricuspid valve interventions is crucial. Finally, the article highlights gaps in evidence, and points toward future perspectives.
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Doenças das Valvas Cardíacas , Hipertensão Pulmonar , Insuficiência da Valva Tricúspide , Doenças das Valvas Cardíacas/complicações , Hemodinâmica , Humanos , Hipertensão Pulmonar/complicações , Valva Tricúspide , Insuficiência da Valva Tricúspide/complicaçõesRESUMO
Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.
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Predisposição Genética para Doença , Deficiência Intelectual/genética , Convulsões/genética , Proteínas de Transporte Vesicular/genética , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Convulsões/fisiopatologia , Sequenciamento do ExomaRESUMO
AIM: To compare lesion detectability and positron-emission tomography (PET) metric measurements between early-PET/magnetic resonance imaging (MRI) acquisition and same-day PET/computed tomography (CT). MATERIALS AND METHODS: The study was approved by the institutional review board and written informed consent was obtained from all patients. Twenty-one patients underwent non-time-of-flight (TOF) PET/MRI immediately following 68GA-prostate-specific membrane antigen (PSMA) tracer injection in two steps: firstly, early prostate PET/MRI (pPET/MRI) and early whole-body (WB) PET/MRI (wbPET/MR) followed by WB TOF PET/CT (wbPET/CT). Lesion detectability was compared between wbPET/MRI and wbPET/CT while PET metric measurements were compared between pPET/MR, wbPET/MRI, and wbPET/CT. RESULTS: Sixty-one and 63 lesions were found on wbPET/MRI and wbPET/CT, respectively (K=0.95, 95% confidence interval (CI)=0.89-1.0) with very good correlation between PET metric measurements (r=0.91; p=0.001). Bland-Altman plots demonstrated a mean percentage difference between wbPET/CT with wbPET/MRI of 34.4% with 95% limits of agreement (LOA) between -39% to 107.9% for metabolic tumour volume (MTV) and a mean difference of 30% with LOA between -13.4% to 73.4% for peak standardised uptake value (SUVpeak). CONCLUSION: Early PET/MRI demonstrates very good lesion detectability agreement and correlation with PET metrics compared to same-day PET/CT. Nevertheless, LOA are far beyond the clinically acceptable range, and therefore, PET/CT and early PET/MRI metrics cannot be used interchangeably.
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Antígenos de Superfície , Detecção Precoce de Câncer/métodos , Glutamato Carboxipeptidase II , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Compostos Organometálicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Wheezing in infancy has been associated with subsequent asthma, but whether cough similarly influences asthma risk has been little studied. We sought to determine whether prolonged cough and cough without cold in the first year of life are associated with childhood asthma. METHODS: Participants in the Infant Immune Study, a non-selected birth cohort, were surveyed 7 times in the first 9 months of life regarding the presence of wheeze and cough. Cough for more than 28 days was defined as prolonged. Parents were asked at 1 year if the child ever coughed without a cold. Asthma was defined as parental report of physician diagnosis of asthma, with symptoms or medication use between 2 and 9 years. Logistic regression was used to assess adjusted odds for asthma associated with cough characteristics. RESULTS: A total of 24% (97) of children experienced prolonged cough and 23% (95) cough without cold in the first 9 months, respectively. Prolonged cough was associated with increased risk of asthma relative to brief cough (OR 3.57, CI: 1.88, 6.76), with the risk being particularly high among children of asthmatic mothers. Cough without cold (OR 3.13, 95% CI: 1.76, 5.57) was also independently associated with risk of childhood asthma. Both relations persisted after adjustment for wheeze and total IgE at age 1. CONCLUSIONS AND CLINICAL RELEVANCE: Prolonged cough in infancy and cough without cold are associated with childhood asthma, independent of infant wheeze. These findings suggest that characteristics of cough in infancy are early markers of asthma susceptibility, particularly among children with maternal asthma.
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Asma/epidemiologia , Asma/etiologia , Tosse/complicações , Tosse/epidemiologia , Suscetibilidade a Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Although body mass index (BMI) and waist circumference (WC) are correlated, the relationship between WC and BMI may have changed over time. OBJECTIVES: To describe temporal trends in BMI and WC distributions and quantify the increase in WC at a given BMI over time. SUBJECTS/METHODS: Data on adults aged 20-59 years from two waves (1993 and 2009) of the China Health and Nutrition Survey were used in a pooled cross-sectional analysis. Quantile regression examined age-adjusted temporal trends in the distributions of BMI and WC. Linear regression examined changes in mean WC over time, adjusting for BMI, age at survey and survey year. All models were stratified by gender. RESULTS: There was a significant increase in BMI and WC over time, particularly at the 95th quantile: on average, men had 2.8 kg m(-2) (95% confidence interval (CI): 2.4, 3.3) and women 1.5 kg m(-)(2) (95% CI: 1.1, 2.0) higher BMI in 2009 compared with their counterparts in 1993. WC increased by 9.0 cm (95% CI: 7.5, 10.1) and 5.0 cm (95% CI: 3.4, 6.6) for men and women, respectively. On average, men and women had a 3.2 cm (95% CI: 2.8, 3.7) and 2.1 cm (95% CI: 1.7, 2.5) higher WC in 2009 compared with their counterparts in 1993, holding BMI and age constant. WC adjusted for BMI increased to a larger extent among obese versus lean individuals and among younger versus older women. CONCLUSIONS: For both genders, BMI and WC increased significantly over time, with particularly greatest increase in magnitude in the upper tail of the BMI and WC distributions. Furthermore, WC at equivalent BMIs was higher in 2009, compared with their counterparts in 1993. Our findings suggest that even if BMI remained constant from 1993 to 2009, adults in 2009 might be at increased cardiometabolic risk as a result of their higher WC.
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Povo Asiático/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade Abdominal/epidemiologia , Circunferência da Cintura , Adulto , Distribuição da Gordura Corporal , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Humanos , Estilo de Vida , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/prevenção & controle , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade Abdominal/sangue , Obesidade Abdominal/prevenção & controle , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores de TempoRESUMO
UNLABELLED: Quantitative vertebral morphometry (QVM) was performed by parametric modeling of vertebral bodies in three dimensions (3D). INTRODUCTION: Identification of vertebral fractures in two dimensions is a challenging task due to the projective nature of radiographic images and variability in the vertebral shape. By generating detailed 3D anatomical images, computed tomography (CT) enables accurate measurement of vertebral deformations and fractures. METHODS: A detailed 3D representation of the vertebral body shape is obtained by automatically aligning a parametric 3D model to vertebral bodies in CT images. The parameters of the 3D model describe clinically meaningful morphometric vertebral body features, and QVM in 3D is performed by comparing the parameters to their statistical values. Thresholds and parameters that best discriminate between normal and fractured vertebral bodies are determined by applying statistical classification analysis. RESULTS: The proposed QVM in 3D was applied to 454 normal and 228 fractured vertebral bodies, yielding classification sensitivity of 92.5% at 7.5% specificity, with corresponding accuracy of 92.5% and precision of 86.1%. The 3D shape parameters that provided the best separation between normal and fractured vertebral bodies were the vertebral body height and the inclination and concavity of both vertebral endplates. CONCLUSION: The described QVM in 3D is able to efficiently and objectively discriminate between normal and fractured vertebral bodies and identify morphological cases (wedge, (bi)concavity, or crush) and grades (1, 2, or 3) of vertebral body fractures. It may be therefore valuable for diagnosing and predicting vertebral fractures in patients who are at risk of osteoporosis.
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Vértebras Lombares/diagnóstico por imagem , Modelos Anatômicos , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento Tridimensional/métodos , Vértebras Lombares/lesões , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/patologia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Sensibilidade e Especificidade , Fraturas da Coluna Vertebral/patologia , Vértebras Torácicas/lesões , Vértebras Torácicas/patologia , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.
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Proteínas de Ligação a DNA/metabolismo , Pulmão/patologia , Traumatismo por Reperfusão/etiologia , Fatores de Transcrição/metabolismo , Animais , Fatores de Coagulação Sanguínea/biossíntese , Quimiocinas/biossíntese , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Fatores de Crescimento Endotelial/biossíntese , Genes de Troca , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Lipopolissacarídeos/toxicidade , Pulmão/irrigação sanguínea , Linfocinas/biossíntese , Camundongos , Camundongos Mutantes , Fatores de Transcrição/genética , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Dedos de Zinco/genéticaRESUMO
Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.
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Arteriosclerose/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Angiopatias Diabéticas/tratamento farmacológico , Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/uso terapêutico , Animais , Arteriosclerose/etiologia , Linhagem Celular , Diabetes Mellitus Experimental/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Solubilidade , Spodoptera , EstreptozocinaRESUMO
Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) under hypoxia signaling. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways.
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Morte Celular/fisiologia , Hipóxia Celular , Neurônios/patologia , Proteínas/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Choque Térmico HSP70 , Humanos , Camundongos , Neurônios/metabolismo , Proteínas/antagonistas & inibidoresRESUMO
Accumulation of fibrils composed of amyloid A in tissues resulting in displacement of normal structures and cellular dysfunction is the characteristic feature of systemic amyloidoses. Here we show that RAGE, a multiligand immunoglobulin superfamily cell surface molecule, is a receptor for the amyloidogenic form of serum amyloid A. Interactions between RAGE and amyloid A induced cellular perturbation. In a mouse model, amyloid A accumulation, evidence of cell stress and expression of RAGE were closely linked. Antagonizing RAGE suppressed cell stress and amyloid deposition in mouse spleens. These data indicate that RAGE is a potential target for inhibiting accumulation of amyloid A and for limiting cellular dysfunction induced by amyloid A.
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Amiloidose/metabolismo , Receptores Imunológicos/metabolismo , Proteína Amiloide A Sérica/metabolismo , Amiloide/metabolismo , Amiloidose/patologia , Animais , Linhagem Celular , Glicoproteínas/metabolismo , Glicoproteínas/farmacologia , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1 , Humanos , Interleucina-6/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Fator Estimulador de Colônias de Macrófagos/genética , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Coelhos , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Nitrato de Prata/metabolismo , Nitrato de Prata/farmacologia , Baço/metabolismo , Baço/patologiaRESUMO
Tumor necrosis factor/cachectin (TNF) is a mediator of the septic state, which involves diffuse abnormalities of coagulation throughout the vasculature. Since previous studies have shown that endothelial cells can play an active role in coagulation, we wished to determine whether TNF could modulate endothelial cell hemostatic properties. Incubation of purified recombinant TNF with cultured endothelial cells resulted in a time- and dose-dependent acquisition of tissue factor procoagulant activity. Concomitant with enhanced procoagulant activity, TNF also suppressed endothelial cell cofactor activity for the anticoagulant protein C pathway; both thrombin-mediated protein C activation and formation of functional activated protein C-protein S complex on the cell surface were considerably attenuated. Comparable concentrations of TNF (half-maximal affect at approximately 50 pM) and incubation times (half-maximal affect by 4 h after addition to cultures) were required for each of these changes in endothelial cell coagulant properties. This unidirectional shift in cell surface hemostatic properties favoring promotion of clot formation indicates that, in addition to leukocyte procoagulants, endothelium can potentially be instrumental in the pathogenesis of the thrombotic state associated with inflammatory and malignant disorders.
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Coagulação Sanguínea/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Glicoproteínas/farmacologia , Hemostasia/efeitos dos fármacos , Animais , Bovinos , Células Cultivadas , Fator X/fisiologia , Glicoproteínas/metabolismo , Humanos , Proteína C , Tromboplastina/biossíntese , Fator de Necrose Tumoral alfaRESUMO
Advanced glycosylation end products (AGE) of proteins accumulate in the vasculature with diabetes and aging, and are thought to be associated with vascular complications. This led us to examine the interaction of AGE-BSA as a prototype of this class of nonenzymatically glycosylated proteins subjected to further processing, with endothelium. Incubation of 125I-AGE-BSA with cultured bovine endothelium resulted in time-dependent, saturable binding that was half-maximal at a concentration of approximately 100 nM. Although unlabeled normal BSA was not a competitor, unlabeled AGE-BSA was an effective competitor of 125I-AGE-BSA-endothelial cell interaction. In addition, AGE modification of two alternative proteins, hemoglobin and ribonuclease, rendered them inhibitors of 125I-AGE-BSA binding to endothelium, although the native, unmodified forms of these proteins were not. At 37 degrees C, binding of 125I-AGE-BSA or gold-labeled AGE-BSA was followed by internalization and subsequent segregation either to a lysosomal compartment or to the endothelial-derived matrix after transcytosis. Exposure of endothelium to AGE-BSA led to perturbation of two important endothelial cell homeostatic properties, coagulant and barrier function. AGE-BSA downregulated the anticoagulant endothelial cofactor thrombomodulin, and induced synthesis and cell surface expression of the procoagulant cofactor tissue factor over the same range of concentrations that resulted in occupancy of cell surface AGE-BSA binding sites. In addition, AGE-BSA increased endothelial permeability, resulting in accelerated passage of an inert macromolecular tracer, [3H]inulin, across the monolayer. These results indicate that AGE derivatives of proteins, potentially important constituents of pathologic vascular tissue, bind to specific sites on the endothelial cell surface and modulate central endothelial cell functions. The interaction of AGE-modified proteins with endothelium may play an important role in the early stages of increased vascular permeability, as well as vessel wall-related abnormalities of the coagulation system, characteristic of diabetes and aging.
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Endotélio Vascular/metabolismo , Glicoproteínas/metabolismo , Albumina Sérica/metabolismo , Citoesqueleto de Actina/ultraestrutura , Animais , Coagulação Sanguínea , Bovinos , Células Cultivadas , Endotélio Vascular/citologia , Produtos Finais de Glicação Avançada , Glicosilação , Imuno-Histoquímica , Técnicas In Vitro , Permeabilidade , Ligação Proteica , Receptores de Superfície Celular/metabolismo , Receptores de Trombina , Soroalbumina Bovina , Tromboplastina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Albumina Sérica GlicadaRESUMO
Recent studies have indicated that TNF can promote activation of the coagulation mechanism by modulating coagulant properties of endothelial cells. In this report, we demonstrate that infusion of low concentrations of TNF (3 micrograms/animal) into mice bearing meth A fibrosarcomas leads to localized fibrin deposition with formation of occlusive intravascular thrombi in close association with the endothelial cell surface. Studies with 125I-fibrinogen showed tenfold enhanced accumulation of radioactivity in tumor within 2 h after TNF infusion. Western blots of tumor extracts subjected to SDS-PAGE and visualized with a fibrin-specific mAb indicated that fibrin forms in the tumor after the TNF infusion. Electron microscopic studies demonstrated fibrin strands, based on the characteristic 21-nm periodicity, which appeared to be adherent to the endothelial cell surface. Further ultrastructural studies indicated that fibrin formation, first evident within 30 min of the TNF infusion, led to occlusive thrombi limited to the tumor vascular bed (i.e., not in the normal mouse vasculature) within 2 h and was associated with an 80% reduction in tumor perfusion based on studies with Evans blue. In view of previous work concerning TNF induction of endothelial cell procoagulant activity, the hypothesis that tumor cell products prime the response of endothelium to this cytokine was tested. Supernatants of cultured meth A fibrosarcomas obtained serum-free conditions, which had no intrinsic procoagulant activity, considerably enhanced tissue factor induction in endothelium in response to submaximal concentrations of TNF. The factor(s) in the tumor-conditioned medium appeared to be distinct from IL-1, fibroblast growth factor, IFN-gamma, TNF, endotoxin, TGF-alpha, and TGF-beta. These studies delineate a novel model of localized clot formation in which thrombosis is initiated by a pathophysiologic mediator, TNF, and provides an opportunity to examine mechanisms in the microenvironment directing clot formation to the tumor vascular bed.