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INTRODUCTION AND OBJECTIVES: To compare gonad doses with and without a gonad protector and to optimize the use of gonadal protectors in infants thorax radiography. MATERIALS AND METHODS: Two pediatric anthropomorphic phantoms are used: an X-ray system for KXO-50SS/DRX-3724HD, and a digital radiography system for CALNEO Smart C12, with and without a gonad protector during infants thorax radiography. A real time skin dosimeter is placed on the X-ray system, and a real time skin dosimeter is inserted on the front side of the mammary gland, the front and back sides of the true pelvis level, and on the ovaries and testes. The X-ray system is irradiated 15 times using phantoms with and without a gonad protector. The measured entrance patient doses values of for the real time skin dosimeter are compared for each phantom, with and without the gonad protector. RESULTS: The medium of measured entrance patient doses values for front side dose of the true pelvis level with and without the protector are 10.00 and 5.00 µGy at newborn, and 10.00 and 0.00µGy at one year, respectively. The medium of measured entrance patient doses values for the back side dose of the true pelvis level with and without the protector are 0.00 and 0.00 µGy at both newborn one year, respectively. The measured entrance patient doses cannot be detected in the ovaries and testes with or without the protector. No significant differences are observed in the measured entrance patient doses values for the front and back side doses of the pelvis, ovaries, and testes at newborn and one year, with and without the protector (p>0.05). CONCLUSIONS: No significant difference was observed in gonad dose measurements with and without the gonad protector during infants chest radiography. We believe that gonadal protector wearing is not necessary.
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Gónadas , Lactante , Recién Nacido , Humanos , Niño , RadiografíaRESUMEN
The Hayabusa2 spacecraft investigated the small asteroid Ryugu, which has a rubble-pile structure. We describe an impact experiment on Ryugu using Hayabusa2's Small Carry-on Impactor. The impact produced an artificial crater with a diameter >10 meters, which has a semicircular shape, an elevated rim, and a central pit. Images of the impact and resulting ejecta were recorded by the Deployable CAMera 3 for >8 minutes, showing the growth of an ejecta curtain (the outer edge of the ejecta) and deposition of ejecta onto the surface. The ejecta curtain was asymmetric and heterogeneous and it never fully detached from the surface. The crater formed in the gravity-dominated regime; in other words, crater growth was limited by gravity not surface strength. We discuss implications for Ryugu's surface age.
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Bezoares/complicaciones , Bezoares/diagnóstico por imagen , Enteroscopía de Doble Balón , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Intestino Delgado/diagnóstico por imagen , Anciano de 80 o más Años , Bezoares/patología , Femenino , Migración de Cuerpo Extraño/complicaciones , Humanos , Obstrucción Intestinal/patología , Intestino Delgado/patología , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: Breast cancer incidence increases from the age of 30 years. As this age range coincides with that in which women usually pursue pregnancy, undergoing medical examinations for conditions such as breast cancer is a concern, especially when pregnancy is uncertain during the first eight weeks. Moreover, in this age range, breast often exhibits a high density, thus compromising diagnosis. For such density, digital breast tomosynthesis (DBT) provides a more accurate diagnosis than 2D mammography given its higher sensitivity and specificity. However, radiation exposure increases during DBT, and it should be determined. METHODS: We determined the entrance surface dose, scattered radiation dose, and average glandular dose (AGD), which can be mutually compared following an international protocol. Using our proposed method, the distribution of scattered radiation can be easily and quickly obtained with a minor load to the equipment. Then, we can determine the indoor scattered radiation and surface dose on patients during DBT. RESULTS: We obtained a maximum AGD of 2.32 mGy. The scattered radiation was distributed over both sides with maximum of approximately 40 µGy, whereas the maximum dose around the eye was approximately 10 µGy. CONCLUSION: By measuring doses using the proposed method, a correct dose information can be provided for patients to mitigate their concerns about radiation exposure. Although the obtained doses were low, their proper management is still required. Overall, the results from this study can help to enhance dose management for patients and safety management regarding indoor radiation.
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Mamografía/métodos , Fantasmas de Imagen , Dosis de Radiación , Exposición a la Radiación/estadística & datos numéricos , Sensibilidad y EspecificidadAsunto(s)
Pólipos/diagnóstico por imagen , Pólipos/cirugía , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/cirugía , Anciano de 80 o más Años , Endoscopía Gastrointestinal/métodos , Endosonografía , Fibrosis , Estudios de Seguimiento , Humanos , Masculino , Pólipos/patología , Neoplasias Gástricas/patología , Factores de TiempoRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-ß1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis.
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Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/fisiología , Fibrosis Pulmonar/terapia , Administración Intranasal/métodos , Animales , Bleomicina/farmacología , Colágeno/análisis , Femenino , Fibroblastos/metabolismo , Fibrosis , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/terapia , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Oligonucleótidos , Oligonucleótidos Antisentido/metabolismo , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/farmacología , Factor de Crecimiento Transformador beta/análisisAsunto(s)
Laparoscopía/métodos , Recto/cirugía , Engrapadoras Quirúrgicas , Grapado Quirúrgico/instrumentación , Cirugía Endoscópica Transanal/métodos , Humanos , Laparoscopía/instrumentación , Posicionamiento del Paciente , Instrumentos Quirúrgicos , Grapado Quirúrgico/métodos , Cirugía Endoscópica Transanal/instrumentaciónRESUMEN
Arachidonic acid increased intracellular calcium, in cells expressing green fluorescent protein-tagged human FFA4 receptors, with an EC50 of ~40µM. This action was not blocked by cyclooxygenase or lipoxigenase inhibitors but it was inhibited by AH7614, a FFA4 antagonist. Arachidonic acid induced ERK activation accompanied by EGF receptor transactivation. However, EGF transactivation was not the major mechanism through which the fatty acid induced ERK phosphorylation, as evidenced by the inability of AG1478 to block it. Arachidonic acid increased FFA4 receptor phosphorylation that reached its maximum within 15min with an EC50 of ~30µM; inhibitors of protein kinase C partially diminish this effect and AH7614 blocked it. Arachidonic acid induced rapid and sustained Akt/PKB phosphorylation and FFA4 - ß-arrestin interaction. Confocal microscopy evidenced that FFA4 receptor activation and phosphorylation were associated to internalization. In conclusion, arachidonic acid is a bona fide FFA4 receptor agonist.
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Ácido Araquidónico/farmacología , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Calcio/metabolismo , Línea Celular , Células HEK293 , Humanos , Fosforilación , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Tirfostinos/farmacología , beta-Arrestinas/metabolismoRESUMEN
The Hitomi Soft X-ray Spectrometer (SXS) was a pioneering non-dispersive imaging x-ray spectrometer with 5 eV FWHM energy resolution, consisting of an array of 36 silicon-thermistor microcalorimeters at the focus of a high-throughput soft x-ray telescope. The instrument enabled astrophysical plasma diagnostics in the 0.3-12 keV band. We introduce the SXS calibration strategy and corresponding ground calibration measurements that took place from 2012-2015, including both the characterization of the microcalorimeter array and measurements of the x-ray transmission of optical blocking filters.
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In an experiment with the BigRIPS separator at the RIKEN Nishina Center, we observed two-proton (2p) emission from ^{67}Kr. At the same time, no evidence for 2p emission of ^{59}Ge and ^{63}Se, two other potential candidates for this exotic radioactivity, could be observed. This observation is in line with Q value predictions which pointed to ^{67}Kr as being the best new candidate among the three for two-proton radioactivity. ^{67}Kr is only the fourth 2p ground-state emitter to be observed with a half-life of the order of a few milliseconds. The decay energy was determined to be 1690(17) keV, the 2p emission branching ratio is 37(14)%, and the half-life of ^{67}Kr is 7.4(30) ms.
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Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN, the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls (p=0.0067), and A allele at rs4251981 in 5' upstream of IL1RN with borderline significance (p=0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40-10.8, p=0.0057). For SCN1A, no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A, the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance (p=0.011). We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.
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Encefalopatías/genética , Citocinas/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo Genético/genética , Canales de Sodio/genética , Encefalopatías/complicaciones , Niño , Preescolar , Epilepsias Parciales/complicaciones , Femenino , Genotipo , Humanos , Lactante , Japón , Masculino , Estudios Retrospectivos , Convulsiones Febriles/complicacionesRESUMEN
INTRODUCTION: For the patients undergoing liver transplantation for hepatitis B virus (HBV)-related diseases, hepatitis B immunoglobulin (HBIG) should be administered to prevent reinfection. Because HBIG is highly expensive and a blood product, an alternative strategy using HBV vaccination has been made in an attempt to discontinue use of HBIG. The aim of this study was to evaluate the impact of long-term HBV vaccination for discontinuation of HBIG, paying attention to the status of active immunization using T-cell proliferation assay. PATIENTS AND METHODS: Among the 144 recipients who underwent liver transplantation in our hospital, 16 had HBV-related liver diseases; the 14 patients who had received vaccination were subjects in our study. To evaluate the status of active immunization, T-cell proliferation was examined by counting the number of T cells after adding HBV vaccine to the culture supernatant of T cells, and tumor necrosis factor α and interferon γ were measured in the culture supernatant. RESULTS: The ratio of male/female was 13/1 (median age: 55 years; range: 37 years to 67 years). The median follow-up time was 102 months (range: approximately 14 months to 148 months). All 14 patients were free of HBV recurrence. HBIG-free status could be achieved in 9 patients (64.3%) during the treatment period for more than 50 months after beginning of HBV vaccination, of whom 5 (35.7%) became HBV vaccine-free. T-cell proliferation was confirmed by fact that the stimulation index ranged from 2.34 to 5.2 in the patients who were HBIG-free. CONCLUSION: Long-term HBV vaccination after LT is a useful and effective treatment in preventing HBV recurrence, allowing the discontinuation of HBIG treatment.
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Carcinoma Hepatocelular/cirugía , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis B/prevención & control , Inmunoglobulinas/uso terapéutico , Cirrosis Hepática/cirugía , Fallo Hepático Agudo/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Complicaciones Posoperatorias/prevención & control , Prevención Secundaria , Adulto , Anciano , Carcinoma Hepatocelular/etiología , Femenino , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Humanos , Cirrosis Hepática/etiología , Fallo Hepático Agudo/etiología , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Linfocitos T , Células TH1 , Resultado del Tratamiento , VacunaciónRESUMEN
We have developed a focusing system for extreme ultraviolet light produced by high-order harmonic generation. An ellipsoidal mirror with a precise surface shape was fabricated and installed into the focusing system. A rigid mirror manipulator and a beam profiler were employed to perform precise and stable mirror alignment. As a demonstration of the focusing performance, high-order harmonics in the wavelength range of 13.5-19.5 nm were successfully focused into a 2.4 × 2.3 µm(2) spot.
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ADP-Ribosil Ciclasa 1/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Interferón-alfa/farmacología , Leucemia-Linfoma de Células T del Adulto/inmunología , Glicoproteínas de Membrana/metabolismo , Linfocitos T/efectos de los fármacos , Tretinoina/farmacología , ADP-Ribosil Ciclasa 1/inmunología , Adulto , Sinergismo Farmacológico , Humanos , Interferón-alfa/administración & dosificación , Leucemia-Linfoma de Células T del Adulto/patología , Glicoproteínas de Membrana/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tretinoina/administración & dosificación , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
UNLABELLED: Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. SUMMARY: Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis.
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Proteínas Sanguíneas/metabolismo , Células Epiteliales/patología , Fibrosis Pulmonar Idiopática/sangre , Pulmón/efectos de los fármacos , Proteína S/metabolismo , Células A549 , Anciano , Animales , Apoptosis , Bleomicina , Líquido del Lavado Bronquioalveolar , Caspasa 3/metabolismo , Femenino , Fibrosis/patología , Perfilación de la Expresión Génica , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Técnicas para Inmunoenzimas , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , FosforilaciónAsunto(s)
Placenta Accreta/epidemiología , Placenta , Estudios de Cohortes , Femenino , Humanos , Embarazo , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: Bronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting ß2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. METHODS: There were 20 patients with asthma and seven healthy controls. The number of CD45(+)Collagen I(+) circulating fibrocytes was assessed in the peripheral blood by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting ß2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. CONCLUSION: The results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.
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Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Asma/sangre , Biomarcadores/sangre , Inflamación/sangre , Células Madre Mesenquimatosas/inmunología , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Adulto , Anciano , Asma/tratamiento farmacológico , Colágeno Tipo I/metabolismo , Femenino , Citometría de Flujo , Humanos , Japón , Antígenos Comunes de Leucocito/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Persona de Mediana Edad , Pruebas de Función Respiratoria , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.
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Receptores de Células Precursoras de Linfocitos B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Agammaglobulinemia Tirosina Quinasa , Animales , Línea Celular , Proliferación Celular/genética , Ciclina D3/genética , Ciclina D3/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Immunoblotting , Inmunohistoquímica , Ratones Endogámicos C57BL , Ratones Endogámicos , Receptores de Células Precursoras de Linfocitos B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Factores de Transcripción/genéticaRESUMEN
We examined cytotoxicity of replication-competent type 5 adenoviruses (Ad5) in human pancreatic carcinoma cells with a p53-defective genotype. The replication-competent Ad5 of which E1A gene was activated by exogenous transcriptional regulatory sequences, derived from the midkine and survivin genes, achieved cytotoxicity to the pancreatic carcinoma. These cells were susceptible to replication-incompetent Ad5 expressing the wild-type p53 gene. We also produced the replication-competent Ad5 bearing the same exogenous regulatory sequences and the type 35 Ad-derived fiber-knob region, and showed that the cytotoxicity was comparable to that of the replication-competent Ad5 prototype. We then investigated possible combinatory effects of the fiber-modified replication-competent Ad and Ad5 expressing the wild-type p53 gene, both of which did not interfere respective infections. The combination produced synergistic cytotoxic effects with enhanced cleavages of caspase-3 and PARP molecules, and with increased sub-G1 fractions and annexin V-positive populations although the viral production of the replication-competent Ad was rather suppressed by expressed p53. Pancreatic cells infected with both Ad showed increase of p53 and decrease of MDM2 and p21 levels, compared with those infected with Ad expressing the p53 gene. These data collectively indicated that replication-competent Ad augmented susceptibility of pancreatic cells to apoptosis through upregulated p53 expression.
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Adenocarcinoma/patología , Adenovirus Humanos/fisiología , Proteínas Inhibidoras de la Apoptosis/fisiología , Factores de Crecimiento Nervioso/fisiología , Neoplasias Pancreáticas/patología , Proteína p53 Supresora de Tumor/biosíntesis , Proteínas E1A de Adenovirus/deficiencia , Adenovirus Humanos/genética , Apoptosis , Proteínas de la Cápside/genética , Caspasa 3/metabolismo , Ciclo Celular , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Efecto Citopatogénico Viral , Virus Defectuosos/fisiología , Genes p53 , Células HEK293 , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Midkina , Factores de Crecimiento Nervioso/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , Proteínas Proto-Oncogénicas c-mdm2/genética , Survivin , Replicación Viral/genéticaRESUMEN
BACKGROUND: Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown. OBJECTIVES: This study investigated the role of PS in acute alcoholic hepatitis. METHODS: A mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol. RESULTS: The levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared with WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls. CONCLUSIONS: The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.