RESUMEN
The depletion of CD8+ cells has been shown to prevent the initiation and progression of antiglomerular basement membrane (GBM) crescentic glomerulonephritis (GN) in Wistar-Kyoto (WKY) rats. In this study, we asked whether CD8+ cells produce their effects by perforin/granzyme-mediated or by Fas ligand (FasL)-mediated pathways. The glomerular mRNA expression of perforin and granzyme B corresponded with the number of CD8+ cells, whereas that of granzyme A, Fas, and FasL did not. The enhanced mRNA level of perforin and granzyme B was not evident in CD8+-depleted rats. The number of apoptotic cells in the glomeruli was significantly increased at day 3. Perforin mRNA was found in cells infiltrating the glomerulus by in situ hybridization and by using dual-staining immunohistochemistry perforin protein was found in glomerular CD8+ cells. We found that perforin was readily visualized at the inner surface of the glomerular capillaries by immunoelectron microscopy. Based on these results, we treated animals with a perforin antibody in vivo and found that it significantly reduced the amount of proteinuria, frequency of crescentic glomeruli, and the number of glomerular monocytes and macrophages, although the number of glomerular CD8+ cells was not changed. Our results suggest that CD8+ cells play a role in glomerular injury as effector cells in part through a perforin/granzyme-mediated pathway in the anti-GBM WKY rat model of crescentic GN.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Linfocitos T CD8-positivos/fisiología , Granzimas/metabolismo , Glomérulos Renales/metabolismo , Perforina/metabolismo , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/metabolismo , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Anticuerpos/uso terapéutico , Apoptosis/fisiología , Antígenos CD8/inmunología , Proteína Ligando Fas/metabolismo , Etiquetado Corte-Fin in Situ , Glomérulos Renales/patología , Masculino , Perforina/inmunología , Proteinuria/inmunología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas WKY , Receptor fas/metabolismoRESUMEN
BACKGROUND: We performed this prospective randomized study to determine the effect of a human urinary protease inhibitor (Ulinastatin) on respiratory function in pediatric patients undergoing cardiopulmonary bypass. METHODS: Twenty-two children were included in this study. They were randomly allocated to 1 of the following groups; a control group (n=11) or a Ulinastatin group (n=11) in which patients received 5000 U/kg of Ulinastatin. Arterial blood samples were obtained before cardiopulmonary bypass (CPB), immediately after CPB, and 30 min after protamine administration, as well as 3 hours after and 18 hours after CPB, and Interleukin-8 and neutrophil elastase concentration were evaluated. RESULTS: CPB time and aortic clamp time did not differ between the groups. Interleukin 8 and neutrophil elastase concentrations before CPB increased significantly immediately after CPB, these concentrations did not differ between the groups. However, neutrophil elastase concentrations of a Ulinastatin group were significantly lower than that of a control group at 30 min after protamine administration (a Ulinastatin group: 1011.3+/-539.1 mg/ml, a control group: 1619.7+/-595.7 mg/ml, p<0.05) and A-aDO2 of a Ulinastatin group was significantly lower than that of a control group at 2 hours after CPB (a Ulinastatin group: 67.1+/-70.6 mmHg, a control group: 169.2+/-116.3 g, p<0.05). CONCLUSIONS: These results suggest that Ulinastatin suppresses the increase in neutrophil elastase and protects the respiratory function in pediatric patients undergoing cardiopulmonary bypass.
Asunto(s)
Puente Cardiopulmonar , Glicoproteínas/uso terapéutico , Respiración/efectos de los fármacos , Inhibidores de Tripsina/uso terapéutico , Preescolar , Femenino , Cardiopatías Congénitas/cirugía , Humanos , Interleucina-8/sangre , Elastasa de Leucocito/sangre , Masculino , Estudios ProspectivosRESUMEN
We previously showed that 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride (N2733) inhibits lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF)-alpha secretion and improves the survival of endotoxemic mice. Since overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in vascular smooth muscle cells (VSMCs) is largely responsible for the development of endotoxemic shock, and iNOS gene expression is mainly regulated by LPS and inflammatory cytokines, we studied whether or not N2733 affects interleukin (IL)-1beta-induced iNOS gene expression, NF-kappaB activation, and NF-kappaB inhibitor (IkappaB)-alpha degradation in cultured rat VSMCs. N2733 dose-dependently (10-100 microM) inhibited IL-1beta-stimulated NO production, and decreased IL-1beta-induced iNOS mRNA and protein expression, as found on Northern and Western blot analyses, respectively. Gel shift assay and an immunocytochemical study showed that N2733 inhibited IL-1beta-induced NF-kappaB activation and its nuclear translocation. Western blot analyses involving anti-IkappaB-alpha and anti-phospho IkappaB-alpha antibodies showed that IL-1beta induced transient degradation of IkappaB-alpha preceded by the rapid appearance of phosphorylated IkappaB-alpha, both of which were markedly blocked by N2733. N2733 blocked IL-1beta-induced phosphorylated IkappaB-alpha even in the presence of a proteasome inhibitor (MG115). Immunoblot analysis involving anti-IkappaB kinase (IKK)-alpha and anti-phosphoserine antibodies revealed that N2733 inhibited IL-1beta-induced IKK-alpha phosphorylation, whereas N2733 had no inhibitory effect on IL-1beta-stimulated p42/p44 MAP kinase or p38 MAP kinase activity. Our results suggest that the inhibitory action of N2733 toward IL-1beta-induced NF-kappaB activation and iNOS expression is due to its blockade of the upstream signal(s) leading to IKK-alpha activation, and subsequent phosphorylation and degradation of IkappaB-alpha in rat VSMCs.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas I-kappa B , Interleucina-1/antagonistas & inhibidores , FN-kappa B/metabolismo , Óxido Nítrico Sintasa/metabolismo , Pirrolidinonas/farmacología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Northern Blotting , Western Blotting , Células Cultivadas , ADN/genética , ADN/metabolismo , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Inducción Enzimática/efectos de los fármacos , Humanos , Interleucina-1/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/metabolismo , Inhibidor NF-kappaB alfa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirrolidinonas/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Recent evidence suggests the possible involvement of inducible nitric oxide synthase (iNOS) in the development and maintenance of hypertension in certain animal models. Inflammatory cytokines activate nuclear factor (NF)-kappaB, which plays a major role in transactivation of the inducible nitric oxide synthase (iNOS) gene. However, it remains unknown whether cytokine-mediated iNOS expression in vascular smooth muscle cells (VSMCs) requires signaling pathway(s) other than NF-kappaB activation. The purpose of this study was to determine whether the p42/p44 MAP kinase pathway is involved in cytokine-induced NF-kappaB activation and/or iNOS expression in cultured rat VSMCs. Nitrite/nitrate (NOx) production stimulated by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha in VSMCs was markedly suppressed by inhibiting MAP kinase by pretreatment with a p42/p44 MAP kinase kinase (MAPKK)-1 inhibitor (PD98059) or by transfecting the dominant-interfering form of the nonphosphorylated MAPKK-1 expressing construct (MAPKK S222A). Inhibition of p42/p44 MAP kinase also antagonized the upregulation of iNOS mRNA and protein, as demonstrated by the quantitative RT-PCR method and Western blot analysis, respectively. Furthermore, rat iNOS promoter activity using an iNOS-luciferase construct stimulated by cytokines was inhibited by MAPKK-1 inhibition. However, kappaB-dependent transcription analysis revealed that cytokine-stimulated NF-kappaB activity was unaffected by MAP kinase inhibition. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies showed that PD98059 had no effect on transient phosphorylation or degradation of IkappaB-alpha by cytokines. An electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that MAP kinase inhibition did not block cytokine-stimulated activation of NF-kappaB. These data suggest that the MAP kinase pathway is in part involved in cytokine-induced iNOS expression independent from NF-kappaB activation in rat VSMCs.
Asunto(s)
Citocinas/fisiología , Expresión Génica/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/metabolismo , FN-kappa B/fisiología , Óxido Nítrico Sintasa/genética , Animales , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Genes Dominantes , Masculino , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/fisiología , Nitratos/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Nitritos/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
In this study, we tried a DNA vaccination regime in rhesus macaques using a full genome HIV-1 plasmid. The HIV-1 genome is under the control of its original LTR promoter, but has a mutated zinc finger motif gene in the nucleocapsid region. Due to the lack of genomic RNA packaging, the plasmid produces only noninfectious viral particles. We repeatedly injected four macaque monkeys intramuscularly with the naked DNA over a period of 40 weeks. To evaluate the humoral and cell-mediated immunity provided by this DNA vaccination, no other booster or other recombinant viral vectors were used. Immunological responses against HIV-1 were elicited in all of the vaccinated monkeys: stable anti-HIV-1 Env antibodies were raised in two monkeys and CTL activities were induced in the other monkeys. The macaques were intravenously challenged at 54 weeks with 100 TCID(50) of SHIV-NM-3rN, which possesses an envelope gene homologous to the one in the vaccinated plasmid. In all of the vaccinated macaques, the peak plasma viral loads induced by the challenge virus were two to three orders of magnitude lower than those of the naive controls. These results suggest that a DNA vaccination regime with a full genome plasmid alone is potentially efficacious and provides a new possibility for the development of an AIDS vaccine.
Asunto(s)
Vacunas contra el SIDA/inmunología , Genoma Viral , VIH-1/inmunología , Macaca mulatta/inmunología , Macaca mulatta/virología , Plásmidos/genética , Vacunas de ADN/inmunología , Vacunas contra el SIDA/química , Vacunas contra el SIDA/genética , Secuencia de Aminoácidos , Animales , Células Cultivadas , ADN Viral/análisis , ADN Viral/genética , Productos del Gen env/genética , Productos del Gen env/inmunología , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Anticuerpos Anti-VIH/inmunología , Antígenos VIH/genética , Antígenos VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/química , VIH-1/genética , VIH-1/fisiología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Macaca mulatta/sangre , Masculino , Datos de Secuencia Molecular , Pruebas de Neutralización , Plásmidos/inmunología , Provirus/genética , Provirus/fisiología , ARN Viral/sangre , ARN Viral/genética , Alineación de Secuencia , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/virología , Vacunación , Vacunas de ADN/química , Vacunas de ADN/genética , Carga Viral , Dedos de ZincRESUMEN
Docarpamine is a dopamine prodrug which has been selected from a large number of dopamine derivatives in order to develop an orally effective dopamine. The pharmacokinetics after oral administration of docarpamine have not yet been studied in children undergoing open heart surgery. This study examined the effects of docarpamine on hemodynamics and evaluated its safety in 11 children undergoing open heart surgery for congenital heart disease. This study began when the patientOs postoperative condition was stabilized by continuous dopamine infusion into the vein at a rate of 5 micro g/kg/min. The patients were administered 40 mg/kg of docarpamine every 8 hours, and hemodynamics were measured every 4 hours for 16 hours after the initial docarpamine administration. Immediately after the initial docarpamine administration, the dose of dopamine was reduced to 3 micro g/kg/min. Infusion of dopamine was stopped 8 hours after the initial docarpamine administration. Systemic systolic and diastolic blood pressure and heart rate showed no significant changes. Mean right atrial pressure decreased 4 hours after docarpamine administration. Mixed venous oxygen saturation and mean velocity of circumferential fiber shortening increased significantly after docarpamine administration. No significant changes were observed in urine volume. All patients could be weaned from dopamine within 8 hours. No changes were observed in ECG, and no arrhythmia-inducing action was noted. Our study indicates that 40 mg/kg oral doses of docarpamine produce plasma dopamine concentration equivalent to those of a 3 to 5 micro g/kg/min dopamine infusion. Our data suggest that docarpamine is a safe and effective drug for children who have undergone open heart surgery.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Agonistas de Dopamina/administración & dosificación , Dopamina/análogos & derivados , Cardiopatías Congénitas/cirugía , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Profármacos/administración & dosificación , Puente Cardiopulmonar , Niño , Preescolar , Dopamina/administración & dosificación , Dopamina/sangre , Electrocardiografía , Femenino , Corazón/fisiopatología , Cardiopatías Congénitas/sangre , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Infusiones Intravenosas , Unidades de Cuidado Intensivo Pediátrico , Tiempo de Internación , Masculino , Estudios Retrospectivos , Seguridad , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine whether or not the breast milk feeding has a role in the prevalence of atopic dermatitis among children. METHODS: The target population of the study was all children participating in health check-up program for 3-year-old children in 60 municipalities locating 10 selected prefectures during designated 2 months between October and December 1997. Using a questionnaire, information on nutrition in infants (breast milk only, bottled milk only, or mixed), parity, mothers' age at birth, and a history of atopic dermatitis was obtained. Besides, data on potential confounding factors were obtained. RESULTS: Questionnaires from 3856 children (81.6% of those who were to participate in the programs, and 96.4% of children who participated them) were analyzed. After the adjustment for all potential confounding factors using unconditional logistic models, the risk of atopic dermatitis was slightly higher among children with breast milk (odds ratio [OR] = 1.16 with 95% confidence interval [CI] 0.96-1.40). Mothers' age at birth (OR for those who were more than 30 years or older in comparison with those who were younger than 30 years = 1.15; 95% CI, 0.96-1.37) and those with second or later parity orders (OR = 1.14, 95% CI; 0.95-1.35) showed odds ratios that were higher than unity without statistical significance. CONCLUSION: Breast milk elevates the risk of atopic dermatitis slightly without statistical significance; the risk may be, however, higher in children in second or later parity orders.
Asunto(s)
Lactancia Materna/estadística & datos numéricos , Dermatitis Atópica/epidemiología , Adulto , Orden de Nacimiento , Alimentación con Biberón/estadística & datos numéricos , Preescolar , Intervalos de Confianza , Factores de Confusión Epidemiológicos , Femenino , Humanos , Lactante , Fenómenos Fisiológicos Nutricionales del Lactante , Japón/epidemiología , Modelos Logísticos , Masculino , Edad Materna , Oportunidad Relativa , Paridad , Prevalencia , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
We report a 44-year-old woman with atypical aortic coarctation accompanied by cerebral artery disease. She was hospitalized for vertigo. An extra-anatomic bypass between the ascending aorta and abdominal aorta was performed using partial cardiopulmonary bypass under moderate hypothermia to reduce the after load of the left ventricle and maintain cerebral blood flow and cerebral perfusion pressure. The postoperative course was uneventful and there was no postoperative neurological deficiency.
Asunto(s)
Coartación Aórtica/cirugía , Puente Cardiopulmonar , Adulto , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/cirugía , Coartación Aórtica/complicaciones , Coartación Aórtica/diagnóstico por imagen , Aortitis/etiología , Enfermedades Arteriales Cerebrales/etiología , Femenino , Humanos , Radiografía , Vértigo/etiologíaRESUMEN
Glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory and immune diseases. Nitric oxide (NO) has a diversity of physiological functions, but its excess production has been implicated in the inflammatory process. The present study was designed to elucidate the mechanisms by which glucocorticoids and NSAIDs affect inducible nitric oxide synthase (iNOS) expression in cultured rat vascular smooth muscle cells (VSMCs). Both interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha potently stimulated nitrite/nitrate (NOx) production with a concomitant expression of iNOS mRNA and protein as demonstrated by Northern and Western blot analysis, respectively. Both IL-1beta and TNF-alpha activated nuclear factor (NF)-kappaB as demonstrated by electrophoretic mobility shift assay. Dexamethasone, salicylate and aspirin, but not indomethacin, dose dependently inhibited cytokine-stimulated NOx production and iNOS protein expression. Dexamethasone decreased cytokine-induced NF-kappaB activation and iNOS mRNA expression, but neither salicylate nor aspirin affected NF-kappaB activation or iNOS mRNA expression. IL-1beta caused a rapid increase in phosphorylated IkappaB-alpha levels and subsequent transient decrease in IkappaB-alpha levels, an inhibitor of NF-kappaB, as revealed by Western blot analysis using specific antibodies for phosphorylated and nonphosphorylated IkappaB-alpha. These effects were blocked by pretreatment with dexamethasone. Aspirin dose dependently inhibited iNOS enzymatic activity, whereas salicylate and dexamethasone had limited effect. The present study demonstrates that 1) inhibitory effect of dexamethasone on cytokine-induced iNOS expression and NO production in rat VSMCs, although potentially acting at multiple levels, is partly mediated by inhibition of NF-kappaB activation resulting from decreased phosphorylation and degradation of IkappaB-alpha, 2) both salicylate and aspirin inhibit cytokine-stimulated NO production at translational and/or posttranslational levels without affecting NF-kappaB- mediated iNOS gene expression, and 3) aspirin directly inhibits iNOS enzyme activity. These data suggest the differential inhibitory mechanisms of iNOS-mediated NO synthesis by glucocorticoids and NSAIDs in the vasculature.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Citocinas/farmacología , Glucocorticoides/farmacología , Proteínas I-kappa B , Músculo Liso Vascular/metabolismo , Óxido Nítrico/biosíntesis , Animales , Aorta Torácica , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Dexametasona/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The mechanism underlying the fatal complications in jaundiced states after shock has not been fully clarified. The present study was designed to examine the effect of hemorrhagic shock on myocardial high-energy phosphate stores and the arterial ketone body ratio (AKBR:acetoacetate/beta-hydroxybutyrate), which reflects the redox state of the liver mitochondria, in normal and jaundiced rats. MATERIALS AND METHODS: At 1 week after ligation of the common bile duct, hemorrhagic shock was induced by exsanguination (mean arterial blood pressure = 40 mmHg) and maintained for 2 h. Serial changes in AKBR were measured. The myocardial adenine nucleotides phosphocreatine (PCr) and inorganic phosphate (Pi) were determined before and after hemorrhagic shock. RESULTS: Before shock, myocardial ATP in the jaundiced group was lower than that in the sham group. However, the myocardial PCr levels in the two groups did not differ. After reinfusion of the shed blood, ATP and PCr recovered to the preshock levels in the sham group. However, ATP and PCr were further increased in the jaundiced group. At 60 min after reinfusion, AKBR recovered to the normal level in the sham group, but decreased below 0.7 in the jaundiced group. Metabolic acidosis was more severe in the jaundiced group than in the sham group. CONCLUSIONS: The decrease in AKBR indicated irreversible metabolic acidosis. As a result, fatal circulatory failure occurred, although the phosphoenergetic level in the myocardium was sufficiently maintained.
Asunto(s)
Adenosina Trifosfato/metabolismo , Ictericia/metabolismo , Hígado/metabolismo , Miocardio/metabolismo , Fosfocreatina/metabolismo , Acidosis/complicaciones , Acidosis/metabolismo , Animales , Presión Sanguínea , Frecuencia Cardíaca , Ictericia/sangre , Ictericia/complicaciones , Cuerpos Cetónicos/sangre , Masculino , Oxidación-Reducción , Ratas , Ratas Wistar , Choque Hemorrágico/complicaciones , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatología , Factores de TiempoRESUMEN
Performing direct surgery for postoperative hemorrhage caused by intraperitoneal arterial injury is very difficult. We report herein the case of a 52-year-old woman who developed sudden right lower abdominal pain after numerous laparotomies and radiotherapy for advanced uterine cancer. A diagnosis of pseudoaneurysm of the right external iliac artery was made, and an emergency catheter embolization and femorofemoral bypass was successfully performed under local anesthesia. The patient was able to walk the next day. To the best of our knowledge, this is the first report of such a combined procedure in the literature.
Asunto(s)
Aneurisma Falso/cirugía , Embolización Terapéutica , Arteria Femoral/cirugía , Arteria Ilíaca/lesiones , Hemorragia Posoperatoria/cirugía , Adenocarcinoma/cirugía , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/etiología , Angiografía de Substracción Digital , Neoplasias del Colon/cirugía , Femenino , Humanos , Persona de Mediana Edad , Hemorragia Posoperatoria/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Neoplasias del Cuello Uterino/cirugíaRESUMEN
BACKGROUND: Endotoxemia after major vascular surgery has been suggested to be caused by the passage of bacterial endotoxins through the gut. Early enteral feeding has been reported to prevent bacterial translocation. Therefore, we investigated the incidence of endotoxemia in 12 patients with normal liver function after elective surgery for abdominal aortic aneurysm. METHODS: Blood samples were taken from the brachial vein of each patient before surgery, 1 day after surgery, and 3 days after surgery. The endotoxin concentration was measured using a chromogenic endotoxin-specific assay. RESULTS: The endotoxin concentration was significantly higher one day after surgery (2.15+/-1.36 pg/ml) than that before surgery (1.27+/-1.00 pg/mL), (p<0.05). The mean endotoxin concentration in the patients after early oral feeding (0.74+/-0.74 pg/ml) was significantly lower than that in the patients who could not eat (1.58+/-0.48 pg/ml). CONCLUSIONS: A low concentration of systemic endotoxins can be observed after surgery for abdominal aortic aneurysm, and early oral feeding prevented this elevation.
Asunto(s)
Aneurisma de la Aorta Abdominal/cirugía , Endotoxemia/terapia , Nutrición Enteral , Infecciones por Escherichia coli/terapia , Infección de la Herida Quirúrgica/terapia , Procedimientos Quirúrgicos Vasculares/efectos adversos , Anciano , Endotoxemia/etiología , Endotoxinas/sangre , Escherichia coli , Infecciones por Escherichia coli/sangre , Infecciones por Escherichia coli/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infección de la Herida Quirúrgica/sangre , Infección de la Herida Quirúrgica/etiología , Resultado del TratamientoRESUMEN
Nitric oxide (NO) is known to have antiatherogenic and anti-inflammatory properties, but its effects on the cytokine-induced nuclear factor-kappa B (NF-kappaB) activation pathway in relation to the regulation of inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs) remain elusive. To elucidate the roles of NO in the regulation of cytokine-induced NF-kappaB activation and consequent iNOS gene expression, we studied the effects of NO donors [(+/-)-(E)-ethyl-2-[(E)-hydroxyamino]-5-nitro-3-hexeneamide (NOR3) and sodium nitroprusside] on interleukin (IL)-1beta-induced NF-kappaB activation and IkappaB-alpha degradation and subsequent iNOS expression in rat VSMCs. Northern blot and Western blot analyses demonstrated that NO donors decreased IL-1beta-induced iNOS mRNA and protein expression. Electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that NOR3 inhibited IL-1beta-induced NF-kappaB activation and its nuclear translocation, as demonstrated with immunocytochemical study. These effects were independent of guanylate cyclase activation; an inhibitor of soluble guanylate cyclase (1H-oxadiazolo-1,2,4-[4,3-alpha]quinoxaline-1-one) had no effect on NOR3-induced inhibition of NF-kappaB activation or iNOS mRNA expression by IL-1beta, and a cGMP derivative (8-bromo-cGMP) failed to mimic the effects of NO donors. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies revealed that IL-1beta induced a transient degradation of IkappaB-alpha preceded by a rapid appearance of phosphorylated IkappaB-alpha, both of which were completely blocked by NOR3. A proteasome inhibitor (MG115) blocked IL-1beta-induced transient degradation of IkappaB-alpha and stabilized the appearance of phosphorylated IkappaB-alpha stimulated by IL-1beta. NOR3 inhibited the appearance of IL-1beta-induced phosphorylated IkappaB-alpha even in the presence of MG115. Our results indicate that an inhibitory action by NO on cytokine-induced NF-kappaB activation and iNOS gene expression is due to its direct blockade on phosphorylation and subsequent degradation of IkappaB-alpha via the cGMP-independent pathway in rat VSMCs.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteínas I-kappa B , Interleucina-1/farmacología , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico Sintasa/genética , Óxido Nítrico/fisiología , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Cisteína Endopeptidasas/efectos de los fármacos , Interleucina-1/antagonistas & inhibidores , Masculino , Complejos Multienzimáticos/efectos de los fármacos , Inhibidor NF-kappaB alfa , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II , Fosforilación , Complejo de la Endopetidasa Proteasomal , Ratas , Ratas WistarRESUMEN
Inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha), are known to activate sphingomyelinase (SMase) and nuclear factor-kappaB (NF-kappaB) in certain cell types, which also stimulate inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains unknown whether the SMase pathway is involved in iNOS gene expression in VSMCs. Therefore, the present study was designed to examine whether SMase induces iNOS gene expression via the NF-kappaB activation pathway similar to that of IL-1beta and TNF alpha in cultured rat VSMCs. Neutral SMase, although less potently than IL-1beta and TNF alpha, stimulated nitrite/nitrate (NOx) production, and iNOS messenger RNA and protein expression, as assessed by Northern and Western blot analyses, respectively. Neutral SMase, IL-1beta, and TNF alpha activated NF-kappaB, as revealed by electrophoretic mobility shift assay, and its nuclear translocation, as demonstrated by immunocytochemical study. Neutral SMase potentiated NOx production, iNOS expression, and NF-kappaB activation stimulated by TNF alpha, but not by IL-1beta. Aldehyde peptide proteasome inhibitors completely blocked NOx production, iNOS expression, NF-kappaB activation, and its nuclear translocation induced by cytokines and neutral SMase. IL-1beta and TNF alpha, but not neutral SMase, caused a transient decrease in IkappaB-alpha protein levels, whereas IkappaB-beta protein expression was not affected by either agent. Proteasome inhibitors prevented cytokine-mediated IkappaB-alpha degradation. Several cell-permeable ceramide analogs (C2, C6, and C8), hydrolysis products of sphingomyelin, activated NF-kappaB less potently than neutral SMase, but had no effect on NOx production. These results demonstrate an essential role of NF-kappaB activation in mediation of neutral SMase-induced iNOS expression, but distinct from the proteasome-mediated IkappaB-alpha degradation by cytokines, suggesting the possible involvement of an additional signaling pathway(s).
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Citocinas/farmacología , Músculo Liso Vascular/metabolismo , FN-kappa B/fisiología , Óxido Nítrico Sintasa/biosíntesis , Esfingomielina Fosfodiesterasa/farmacología , Animales , Northern Blotting , Western Blotting , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Inducción Enzimática/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Ratas , Ratas Wistar , Esfingomielina Fosfodiesterasa/biosíntesis , Translocación Genética/efectos de los fármacosRESUMEN
Article 32 of the Mental Health Act was enacted in 1965 and entitles psychiatric outpatients to financial aid towards payment of psychiatric care costs. Psychiatric outpatients can make applications under Article 32 voluntarily at local public health centers. These centers are operated by the prefectural governments. Therefore, records of the applications are kept by the local public health centers. In order to study the effects of Article 32 on psychiatric care, we analyzed the records of those who applied for such benefits in I. County of Shiga Prefecture, at the K. local Public Health Center, and performed a comparative analysis of applicants vs. non-applicants. We also tried to find out which psychiatric illnesses were more significantly represented among those who applied than among those who did not. Our study showed that about 43.5 percent of all psychiatric outpatients in I. County had made applications for Article 32 benefits. This was significantly higher than any former percentages that had been anticipated. We also discovered that a significantly higher number of people with schizophrenia, atypical psychosis and epilepsy could be identified among those who had applied for benefits than those who had not applied. On the other hand, the number of people with neurosis and emotional disorders seemed higher among those who did not apply for the benefits. In addition, the study indicated that a large proportion of those who applied belonged to the 40 s and 50 s age group and to the group with chronic psychiatric problems. All of the above make it clear that Article 32 has been effective in making psychiatric care accessible to those people who suffer from chronic mental diseases over quite a long period time.
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Financiación Gubernamental/legislación & jurisprudencia , Servicios de Salud Mental/economía , Adulto , Epilepsia/terapia , Humanos , Japón , Persona de Mediana Edad , Trastornos Psicóticos/terapia , Esquizofrenia/terapiaRESUMEN
Extensive en-bloc resection of the aortic arch and anterior wall of the main pulmonary artery was performed in a 46-year-old man with invasive thymoma. The aortic arch was replaced with a Hemashield vascular graft under hypothermic circulatory arrest with retrograde cerebral perfusion. Patch plasty with Xenomedica was performed for the anterior wall of the main pulmonary artery under cardiopulmonary bypass. The patient was treated with postoperative radiotherapy and has remained asymptomatic for 15 months after the operation. An extensive operation is considered necessary to improve the prognosis of invasive thymoma.
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Aorta Torácica/cirugía , Circulación Cerebrovascular , Paro Cardíaco Inducido , Hipotermia Inducida , Timoma/cirugía , Neoplasias del Timo/cirugía , Aorta Torácica/patología , Implantación de Prótesis Vascular , Puente Cardiopulmonar , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Implantación de Prótesis , Arteria Pulmonar/patología , Arteria Pulmonar/cirugía , Radioterapia Adyuvante , Timoma/patología , Neoplasias del Timo/patologíaRESUMEN
BACKGROUND: Following major surgery, detection of endotoxaemia using the Toxicolor (Limulus) test has been reported. In addition to endotoxins, this test detects a reactant from human tissue, factor G pathway reactive activity (GPRA). We measured endotoxin and GPRA in 10 patients during and after elective surgery for abdominal aortic aneurysm. Additionally, we measured phosphokinase (CPK) and GPRA levels in the muscle of 10 patients during abdominal aortic aneurysm surgery and 6 during open laparotomy for other causes. METHODS: Samples were taken from the arterial lines prior to surgery, before cross-clamping of the aorta, immediately after and 1, 3, 6, and 18 hours after declamping. Muscle specimens were taken from the rectus abdominus and homogenized in many levels. Endotoxin concentrations were measured with the Endotoxin-Specific test. GPRA concentrations were determined by subtracting the values from the Endotoxin-Specific test from those given by the Toxicolor test (Limulus assay with achromogenic substrate). CPK was also measured. RESULTS: Endotoxin did not significantly increase during or after surgery, but GPRA was elevated. GPRA in muscle correlated significantly with CPK in muscle. CONCLUSIONS: We conclude that GPRA was elevated after surgery, while endotoxin did not increase significantly. The GPRA probably originated from human muscle tissue.
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Aneurisma de la Aorta Abdominal/cirugía , Endotoxemia/diagnóstico , Prueba de Limulus , Anciano , Aneurisma de la Aorta Abdominal/sangre , Pruebas Enzimáticas Clínicas , Creatina Quinasa/sangre , Humanos , Músculo Esquelético/metabolismoRESUMEN
Congenital aneurysms of the sinus of Valsalva are rare lesions. Because the aortic root is central, the aneurysm can rupture into any cardiac chamber, and virtually all combinations of sinus and chamber fistulas have been described. Rupture into the pulmonary artery, however, is very rare. We encountered a 14-year-old boy with conal ventricular septal defect and right coronary cusp prolapse with an unruptured aneurysm of the sinus of Valsalva into the pulmonary artery.
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Aneurisma de la Aorta/patología , Fístula Arterio-Arterial/patología , Arteria Pulmonar/patología , Seno Aórtico/patología , Adolescente , Aneurisma de la Aorta/congénito , Insuficiencia de la Válvula Aórtica/patología , Prolapso de la Válvula Aórtica/patología , Defectos del Tabique Interventricular/patología , Humanos , MasculinoRESUMEN
A nine-month-old boy, weighing 4840 g, with VSD associated with absent right superior vena cava and persistent left superior vena cava, successfully underwent surgical repair of VSD. This anomaly is rare and causes some surgical and electrophysiological problems. We discussed these problems and described the details of surgery in our case.
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Defectos del Tabique Interventricular/cirugía , Vena Cava Superior/anomalías , Humanos , Lactante , Masculino , Vena Cava Superior/cirugíaRESUMEN
N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examined for its effect on TNF-alpha production by human myeloid THP-1 cells stimulated with lipopolysaccharide (LPS). N2733 inhibited LPS-induced release of TNF-alpha from THP-1 cells with an IC50 of 11 microM. N2733 did not affect the cell viability at the concentration of 50 microM or 100 microM. This indicates that N2733 is a potent inhibitor for TNF-alpha production without severe cytotoxicity. N2733 was also studied in two murine endotoxin shock models induced with LPS. One model was DBA/2 mice injected with LPS (5.6 mg/kg, i.v.), which increased the serum level of TNF-alpha within 1 hr. Treatment of these mice with N2733 (100 mg/kg x 2, i.p.) decreased the serum level of TNF-alpha significantly. Another model was DBA/2 mice induced with LPS (30 mg/kg, i.v.), which reduced the survival rate to 30% during 7 days. Administrations of 30 mg/kg and 100 mg/kg N2733 (i.v.) restored the survival rates to 60% and 90% respectively. Our data demonstrate that N2733 inhibits LPS-induced TNF-alpha production, and this response is associated with an improvement in the survival rate of endotoxemic mice.