RESUMEN
BACKGROUND AND PURPOSE: Fab fragments (Fabs) of antibodies have the ability to bind to specific allergens but lack the Fc portion that exerts effector functions via binding to receptors including FcεR1 on mast cells. In the present study, we investigated whether intranasal administration of the effector function-lacking Fabs of a monoclonal antibody IgG1 (mAb, P1-8) to the major allergen Cry j1 of Japanese cedar pollen (JCP) suppressed JCP-induced allergic rhinitis in mice. EXPERIMENTAL APPROACH: Balb/c mice sensitized with JCP on days 0 and 14 were challenged intranasally with the pollen on days 28, 29, 30 and 35. Fabs prepared by the digestion of P1-8 with papain were also administered intranasally 15 min before each JCP challenge. KEY RESULTS: Intranasal administration of P1-8 Fabs was followed by marked suppression of sneezing and nasal rubbing in mice with JCP-induced allergic rhinitis. The suppression of these allergic symptoms by P1-8 Fabs was associated with decreases in mast cells and eosinophils and decreased hyperplasia of goblet cells in the nasal mucosa. CONCLUSIONS AND IMPLICATIONS: These results demonstrated that intranasal exposure to P1-8 Fabs was effective in suppressing JCP-induced allergic rhinitis in mice, suggesting that allergen-specific mAb Fabs might be used as a tool to regulate allergic pollinosis.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Polen/inmunología , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/inmunología , Administración Intranasal , Animales , Anticuerpos Monoclonales/inmunología , Fragmentos Fab de Inmunoglobulinas/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Mucosa Nasal/inmunología , Estornudo/inmunologíaRESUMEN
Canine protein-losing enteropathy (PLE) is associated with severe gastrointestinal disorders and has a guarded to poor prognosis although little information is available regarding factors affecting prognosis. The purpose of this study was to identify the prognostic factors for survival of dogs with PLE. Ninety-two dogs diagnosed with PLE from 2006 to 2011 were included in a retrospective cohort study. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Variables recorded at the time of diagnosis were statistically analysed for possible prognostic factors in a univariate and multivariate Cox proportional hazard model. In the multivariate analysis, the predictors for mortality in dogs with PLE were more highly scored in terms of canine inflammatory bowel disease activity index (CIBDAI) (P = 0.0003), clonal rearrangement of lymphocyte antigen receptor genes (P = 0.003), and elevation of blood urea nitrogen (BUN) (P = 0.03). Using histopathological diagnosis, both small- and large-cell lymphomas were associated with significantly shorter survival times than chronic enteritis (CE) and intestinal lymphangiectasia (IL). Normalization of CIBDAI and plasma albumin concentration within 50 days of initial treatment was associated with a longer survival time. In conclusion, CIBDAI, clonal rearrangement of lymphocyte antigen receptor genes, histopathological diagnosis, and response to initial treatments would be valuable in separating the underlying causes and could be important in predicting prognosis in dogs with PLE.
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Enfermedades de los Perros/fisiopatología , Enteropatías Perdedoras de Proteínas/veterinaria , Animales , Perros , Femenino , Masculino , Pronóstico , Enteropatías Perdedoras de Proteínas/fisiopatología , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND AND PURPOSE: Mast cell hyperplasia has been observed in the lungs of mice with experimental asthma, but few reports have studied basophils. Here, we attempted to discriminate and quantify mast cells and basophils in the lungs in a murine asthma model, determine if both cells were increased by multiple antigen challenges and assess the roles of those cells in asthmatic responses. EXPERIMENTAL APPROACH: Sensitized Balb/c mice were intratracheally challenged with ovalbumin four times. Mast cells and basophils in enzymatically digested lung tissue were detected by flow cytometry. An anti-FcεRI monoclonal antibody, MAR-1, was i.p. administered during the multiple challenges. KEY RESULTS: The numbers of both mast cells (IgE(+) C-kit(+) ) and basophils (IgE(+) C-kit(-) CD49b(+) ) increased in the lungs after three challenges. Treatment with MAR-1 completely abolished the increases; however, a late-phase increase in specific airway resistance (sRaw), and airway eosinophilia and neutrophilia were not affected by the treatment, although the early-phase increase in sRaw was suppressed. MAR-1 reduced antigen-induced airway IL-4 production. Basophils infiltrating the lung clearly produced IL-4 after antigen stimulation in vitro; however, histamine and murine mast cell protease 1 were not increased in the serum after the challenge, indicating that mast cell activation was not evoked. CONCLUSION AND IMPLICATIONS: Both mast cells and basophils infiltrated the lungs by multiple intratracheal antigen challenges in sensitized mice. Neither mast cells nor basophils were involved in late-phase airway obstruction, although early-phase obstruction was mediated by basophils. Targeting basophils in asthma therapy may be useful for an early asthmatic response.
Asunto(s)
Asma/inmunología , Basófilos/inmunología , Pulmón/inmunología , Mastocitos/inmunología , Obstrucción de las Vías Aéreas/inmunología , Resistencia de las Vías Respiratorias/inmunología , Animales , Antígenos/administración & dosificación , Antígenos/inmunología , Asma/metabolismo , Basófilos/metabolismo , Modelos Animales de Enfermedad , Femenino , Interleucina-4/inmunología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Factores de TiempoRESUMEN
Sphingosine kinase 1 (SPHK1) overexpression in malignant cells has been reported. Mouse Friend cells showed higher SPHK1 but not SPHK2 expression compared with other mouse cell lines. A Sphk1 promoter analysis demonstrated the region between -53bp and the first exon as the minimal promoter. Further promoter truncation revealed the importance of a MYB-binding site. EMSA using this region as the probe demonstrated one band containing c-MYB protein, and its intensity decreased during erythroid differentiation with hexamethylane bisacetamide (HMBA), a potent inducer of erythroid differentiation of Friend cells. ChIP assay also revealed in vivo binding of c-MYB. c-MYB overexpression and siRNA for c-Myb affected SPHK1 expression, confirming the important regulatory role of c-MYB in SPHK1 expression. HMBA reduced c-MYB expression rapidly. Induced differentiation by HMBA caused a marked and rapid reduction of SPHK1 mRNA, protein and enzyme activity leading to the rapid decrease of cellular sphingosine 1-phosphate level. Moreover, terminally differentiated cells did not resume SPHK1 expression. Compared with original Friend cells, stable overexpression of wild-type SPHK1 showed higher cell proliferation, resistance to cell death by serum depletion. Interestingly, HMBA-induced differentiation of these cells was delayed but not completely suppressed. In contrast, SPHK inhibitor and its siRNA inhibited cell growth and enhanced HMBA-induced differentiation significantly, suggesting that SPHK1 delayed HMBA-induced differentiation by its cell proliferation-promoting activity. Effects of pertussis toxin, a G-protein-coupled receptor inhibitor, and S1P receptor antagonist on Friend cell growth and differentiation were negligible, suggesting the importance of the intracellular SPHK1/S1P signaling in Friend cells.
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Diferenciación Celular/genética , Fosfotransferasas (Aceptor de Grupo Alcohol) , Proteínas Proto-Oncogénicas c-myb , Receptores de Lisoesfingolípidos , Animales , Línea Celular , Regulación hacia Abajo , Humanos , Ratones , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas c-myb/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Angiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved. METHODS: Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks. RESULTS: The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells. CONCLUSION: These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.
Asunto(s)
Angiopoyetinas/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Insulina/metabolismo , Células 3T3-L1 , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/metabolismo , Animales , Línea Celular Tumoral , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/etiología , Dieta Alta en Grasa , Regulación hacia Abajo/efectos de los fármacos , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Estreptozocina , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND AND PURPOSE: Fab fragments (Fabs) of antibodies maintain the ability to bind specific antigens, but lack the binding site for complement as well as the site for binding to receptors on effector cells, such as macrophages that play an important role in inflammation. In the present study, we investigated whether Fabs specific for ovalbumin (OVA) were specifically able to suppress anti-OVA antibody-mediated arthritis (AOA-MA) in mice. EXPERIMENTAL APPROACH: AOA-MA was induced by i.v. injection of purified anti-OVA antibodies into naïve mice followed by intra-articular (left ankle) challenge with the antigen. Anti-OVA Fabs prepared by digestion of anti-OVA antibodies with papain were injected i.v. immediately after administration of the intact antibodies. Normal Fabs were used as a control. Arthritis was assessed by thickness of the joints (caliper) and by histology of paw sections, stained with haematoxylin and eosin. KEY RESULTS: AOA-MA was markedly suppressed by anti-OVA Fabs, but not by control Fabs. Histologically, mice treated with control Fabs showed marked oedema of synovial tissues with a large number of inflammatory cells including neutrophils, whereas animals given anti-OVA Fabs had mild oedema of the synovium and sparse infiltration of such cells. The antigen-specific suppression of joint inflammation by anti-OVA Fabs was associated with reduced consumption of complement. In vitro studies showed that anti-OVA Fabs significantly blocked the binding of intact anti-OVA antibodies to OVA. CONCLUSIONS AND IMPLICATIONS: Antibody-mediated arthritis appears to be specifically down-regulated by Fabs that competitively inhibit the binding of antibodies to antigens.
Asunto(s)
Anticuerpos/toxicidad , Artritis Experimental/inmunología , Artritis Experimental/prevención & control , Fragmentos Fab de Inmunoglobulinas/toxicidad , Ovalbúmina/inmunología , Animales , Anticuerpos/metabolismo , Reacciones Antígeno-Anticuerpo/inmunología , Artritis Experimental/patología , Fragmentos Fab de Inmunoglobulinas/biosíntesis , Masculino , Ratones , Ratones Endogámicos DBA , Ovalbúmina/metabolismoRESUMEN
BACKGROUND: Hedgehog (Hh) signaling plays an important role in pancreas development. However, its role in the developed endocrine pancreas remains to be elucidated. To clarify whether Hh signaling participates in beta-cell survival, we investigated the role of Hh signaling in cytokine-induced apoptosis in pancreatic beta-cells. METHODS: Insulin-producing INS-1E cells were transfected with Sonic Hh (Shh) expression vector or siRNA against Indian Hh (siIhh). The Hh signal inhibitor cyclopamine were pretreated in INS-1E cells and rat islets. The cells were exposed to 200 U/ml IL-1ß and 200 U/ml IFN-γ for 48 h. Apoptosis was estimated by flow cytometory and immunofluorescence staining for cleaved caspase-3. Nitric oxide generation was measured by Griess reaction. RESULTS: We found that exposure to proinflammatory cytokines increased Ihh expression in rat islets and INS-1E cells. Overexpression of Shh reduced cytokine-induced apoptosis. By contrast, treatment with cyclopamine increased cytokine-induced apoptosis in INS-1E cells and rat islets. Treatment with the siIhh showed same results in INS-1E cells. Forced expression of Shh suppressed cytokine-induced nuclear factor-κB promoter activity, leading to attenuation of nitric oxide synthase 2 expression and nitric oxide production, while Ihh knockdown enhanced this pathway in INS-1E cells. CONCLUSION: Our findings suggest that Hh signaling is implicated in protecting beta-cells from cytokine-induced cytotoxicity.
Asunto(s)
Citocinas/inmunología , Proteínas Hedgehog/metabolismo , Células Secretoras de Insulina/metabolismo , Transducción de Señal/fisiología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Diabetes Mellitus Tipo 1/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Proteínas Hedgehog/genética , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Técnicas de Cultivo de Órganos , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Ratas , Transducción de Señal/efectos de los fármacos , Alcaloides de Veratrum/farmacologíaRESUMEN
BACKGROUND: Although it has been suggested that the use of tachykinin receptor antagonists might prove to be an effective treatment for allergic rhinitis (AR), they are not used clinically. Therefore, we decided to examine the effects of tachykinin receptor antagonists on AR symptoms in an appropriate experimental model. OBJECTIVE: To evaluate newly developed tachykinin receptor antagonists in a Japanese cedar pollen-induced AR model and to determine their effect on allergen-induced sneezing, nasal blockage, and nasal hyperresponsiveness (NHR). METHODS: Sensitized guinea-pigs were challenged by forced inhalation of pollen once every week. Sneezing and nasal blockage were observed after pollen challenges. NHR (nasal blockage) to an intranasal application of leukotriene D(4) was assessed 2 days after an antigen challenge. We also evaluated whether intranasal dosing with a tachykinin causes NHR. NK(1) and NK(2) receptor antagonists were administered before an intranasal treatment with antigen or tachykinin. Amounts of tachykinins present in nasal cavity lavage fluid were measured by an enzyme immunoassay. RESULTS: Although an NK(1) and NK(2) receptor dual antagonist showed no effect on pollen-induced sneezing and biphasic nasal blockage, it did completely suppress the development of NHR. Experiments using specific NK(1) or NK(2) receptor antagonists revealed that NK(2) receptor activation was preferentially involved in the development of hyperresponsiveness. Increases in the levels of substance P (SP) and neurokinin A (NKA) in the nasal tissue were noted 20 min-1 h after the challenge. Intranasal instillation of either SP or NKA-induced NHR, which was almost completely inhibited by NK(2) receptor antagonists and partially inhibited by NK(1) receptor antagonists. CONCLUSIONS: SP and NKA, which are released early after the challenge, mediate the development of NHR by preferentially activating NK(2) receptors. Therefore, NK(2) receptor antagonists might prove to be effective treatment of AR.
Asunto(s)
Alérgenos/inmunología , Modelos Animales de Enfermedad , Polen/inmunología , Rinitis Alérgica Estacional/fisiopatología , Taquicininas/metabolismo , Animales , Cobayas , Humanos , Líquido del Lavado Nasal/química , Obstrucción Nasal , Pruebas de Provocación Nasal , Neuroquinina A/metabolismo , Nariz , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-2/uso terapéutico , Receptores de Taquicininas/antagonistas & inhibidores , Receptores de Taquicininas/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/metabolismo , Estornudo , Sustancia P/metabolismoRESUMEN
OBJECTIVE AND DESIGN: KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge. METHODS: As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model). RESULTS: Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges. CONCLUSIONS: KP-496 may be clinically effective for nasal blockage in allergic rhinitis.
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Benzoatos , Antagonistas de Leucotrieno , Mucosa Nasal/efectos de los fármacos , Receptores de Leucotrienos/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Rinitis Alérgica Perenne/tratamiento farmacológico , Tiazoles , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Área Bajo la Curva , Benzoatos/farmacología , Benzoatos/uso terapéutico , Modelos Animales de Enfermedad , Cobayas , Humanos , Antagonistas de Leucotrieno/farmacología , Antagonistas de Leucotrieno/uso terapéutico , Masculino , Obstrucción Nasal/inmunología , Ovalbúmina/inmunología , Polen/inmunología , Rinitis Alérgica Perenne/inmunología , Estornudo/efectos de los fármacos , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
Tranilast, N-(3,4-demethoxycinnamoyl)-anthranilic acid, is an anti-allergic agent identified as an inhibitor of mast cell degranulation. Recently, tranilast was shown to decrease albuminuria in a rat model of diabetic nephropathy and to ameliorate vascular hypertrophy in diabetic rats, suggesting that it may be clinically useful in the treatment of diabetic complications. However, the effects of tranilast on glucose tolerance have not been elucidated. Thus, the aim of this study is to investigate the effect of tranilast on insulin secretion in pancreatic beta-cells. Treatment with tranilast significantly suppressed insulin secretion in INS-1E cells and rat islets induced by 16.7 mmol/l glucose. Furthermore, tranilast inhibited tolbutamide-induced insulin secretion. Treatment with tranilast increased (86)Rb (+) efflux from COS-1 cells in which pancreatic beta-cell-type ATP-sensitive K (+) (K (ATP)) channels were reconstructed and suppressed the cytosolic ATP/ADP ratio in INS-1E cells. Interestingly, treatment with tranilast enhanced glucose uptake in INS-1E cells. In the present study, we demonstrated that tranilast inhibited glucose- and tolbutamide-induced insulin secretion through the activation of K (ATP) channels in pancreatic beta-cells.
Asunto(s)
Antialérgicos/farmacología , Glucosa/antagonistas & inhibidores , Glucosa/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , ortoaminobenzoatos/farmacología , Nucleótidos de Adenina/metabolismo , Animales , Transporte Biológico Activo , Western Blotting , Separación Celular , Células Cultivadas , Transportador de Glucosa de Tipo 2/metabolismo , Secreción de Insulina , Canales KATP/metabolismo , Masculino , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Radioisótopos de RubidioRESUMEN
The in-plane and out-of-plane ferroelectric instabilities in compressed (100)-epitaxial SrTiO3 films were examined by infrared reflection spectroscopy. The strongly stiffened in-plane soft mode frequency softened very slowly on cooling. On the other hand, the silent mode appeared at around 150 K, indicating an out-of-plane ferroelectric transition. This behavior points to a split of in-plane and out-of-plane ferroelectric instability temperatures due to the lowered symmetry of the SrTiO3 lattice caused by mechanical misfit strain. Infrared spectroscopy provides a possibility to detect such an effect in the strained epitaxial ferroelectric films.
RESUMEN
We describe a giant aneurysm of the anterior communicating artery (ACoA) which was treated with a STA-RA graft-A3 bonnet bypass and A3-A3 side-to-side anastomosis. A giant and partially thrombosed ACoA aneurysm was partially coated 3 years before his current presentation, its gradual increase producing visual field disturbances. An A3-A3 side-to-side anastomosis and STA-RA graft-A3 bonnet bypass were performed. The aneurysm was dissected, and the thrombus removed under transient parent-artery occlusion. The aneurysmal neck was successfully clipped without encountering ischemic changes. This strategy may be useful for treating giant or thrombosed aneurysms in the region of the ACoA.
Asunto(s)
Arteria Cerebral Anterior/patología , Arteria Cerebral Anterior/cirugía , Revascularización Cerebral/métodos , Aneurisma Intracraneal/cirugía , Procedimientos Neuroquirúrgicos/métodos , Adulto , Arteria Cerebral Anterior/diagnóstico por imagen , Angiografía Cerebral , Revascularización Cerebral/instrumentación , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/fisiopatología , Masculino , Procedimientos Neuroquirúrgicos/instrumentación , Quiasma Óptico/irrigación sanguínea , Quiasma Óptico/patología , Arteria Radial/cirugía , Instrumentos Quirúrgicos/normas , Arterias Temporales/anatomía & histología , Arterias Temporales/patología , Arterias Temporales/cirugía , Resultado del TratamientoRESUMEN
Two novel oral DNA-based vaccines provide immune protection against breast cancer in mouse model systems. These vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against novel targets such as transcription factor Fos-related antigen 1 (Fra-1) and endoglin (CD105). Both vaccines elicit suppression of angiogenesis in the breast tumor vasculature and break peripheral tolerance by eliciting potent cell-mediated protective immunity against these tumor self-antigens resulting in effective suppression of breast tumor growth and metastasis.
Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/secundario , Vacunas contra el Cáncer/inmunología , Neovascularización Patológica/inmunología , Vacunas de ADN/inmunología , Animales , Neoplasias de la Mama/terapia , Humanos , InmunoterapiaRESUMEN
Primary intracranial solitary leptomeningeal gliomas are exceedingly rare. We, therefore, performed a detailed clinical, radiological and pathological analysis to better characterize these tumors in 3 patients (33- and 72-year-old men and a 72-year-old woman). Two of the tumors were located in the frontal region and 1 in the temporal region. Magnetic resonance imaging revealed a well circumscribed large lesion (maximal diameter 4 - 6 cm) with peritumoral edema, mixed low- and isosignal intensity on T1-weighted images, hypersignal intensity on T2-weighted images and non-homogeneous contrast enhancement. External carotid angiography demonstrated a vascular supply to these tumors via branches of the middle meningeal artery. Gross total resection was achieved in all patients. The pathological diagnosis was glioblastoma in 2 patients and oligodendroglioma in 1. The MIB-1 nuclear labeling index ranged from 11.8% - 23.6% (mean 18.2%). Local tumor recurrence was documented in 2 patients after 8 and 11 months, respectively. The other patient with glioblastoma developed a metastasis to the femur 39 months after craniotomy. A definitive diagnosis can be made by careful radiological assessment and histopathological examination.
Asunto(s)
Glioma/diagnóstico por imagen , Glioma/patología , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Adulto , Anciano , Femenino , Glioma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/cirugía , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE AND DESIGN: We evaluated the effectiveness of oral treatment with Japanese cedar pollen on experimental allergic rhinitis in guinea pigs. SUBJECTS: Male Hartley guinea pigs. TREATMENT: From 16 days before the first sensitisation, 1 and 100 mg/time/animal pollen suspension was orally administered twice weekly. Animals were then sensitised and repeatedly challenged with the pollen. METHOD: Guinea pigs were sensitised by intranasal instillation of cedar pollen extracts adsorbed onto Al(OH)3 at a dose of 0.3 microg pollen protein/0.3 mg Al(OH)3/3 microl/nostril twice a day for 7 days. Then the animal was challenged by inhalation with cedar pollen (1.8 mg/nostril) once every week. We evaluated the effects of the oral treatment with antigen on: 1) sneezing frequency, 2) nasal blockage after antigen challenge, 3) nasal hyperresponsiveness to histamine and leukotriene D4, and 4) titres of anaphylactic antibodies. RESULTS: During the course of the high dose administration, several animals died from a possible cytotoxicity, whereas the low dose caused no discernible change. The oral administration of the pollen at both the doses significantly inhibited nasal blockage, and the hyperresponsiveness to the stimuli was also strongly suppressed by the oral treatment. Inhibitory effectiveness did not differ substantially between the 1 and 100 mg/animal-treated groups. In contrast, neither sneezing frequency nor the increasing level of anaphylactic antibodies was influenced by the oral administration. CONCLUSIONS: In this study, we found that the pollen-induced nasal blockage and hyperresponsiveness were suppressed by the oral administration of the pollen in the sensitised guinea pig.
Asunto(s)
Antígenos/farmacología , Obstrucción Nasal/fisiopatología , Rinitis Alérgica Estacional/fisiopatología , Administración Oral , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Antígenos/administración & dosificación , Cedrus , Cobayas , Histamina/farmacología , Hipersensibilidad/inmunología , Inmunoglobulina E/biosíntesis , Leucotrieno D4/farmacología , Masculino , Obstrucción Nasal/etiología , Anafilaxis Cutánea Pasiva , Polen/inmunología , Rinitis Alérgica Estacional/complicaciones , Estornudo/fisiologíaRESUMEN
OBJECTIVE AND DESIGN: We investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on antigen-induced sneezing, biphasic nasal blockage and nasal hyperresponsiveness to histamine using a guinea pig model of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Intranasally sensitized guinea pigs were challenged once every week for 13 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 4th, 6th and 13th challenge. METHODS: Sneezing frequency and the change in specific airway resistance (sRaw) were measured at these challenges. Two days after the 13th challenge, nasal responsiveness to histamine was evaluated by measuring sRaw after intranasal instillation of increasing doses of histamine. Moreover, the levels of TXB2, p-LTs and histamine were estimated in nasal cavity lavage fluid (NCLF) collected at the 13th challenge. RESULTS: Only terfenadine (10 mg/kg) significantly inhibited sneezing at any challenge time. Seratrodast (3 and 10 mg/ kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg), but not terfenadine, suppressed both the early and late phase elevation of sRaw (biphasic nasal blockage), although the degree of inhibition on the early phase response varied with the challenge time. In contrast, the development of nasal hyperresponsiveness to histamine was inhibited by only dexamethasone. Furthermore, biphasic increases in TXB2, p-LTs and histamine in NCLF were observed after the challenge in sensitized animals. CONCLUSIONS: These results suggest that TXA2 and p-LTs, but not histamine, play important roles in both the early and the late phase nasal blockage in this model of allergic rhinitis.
Asunto(s)
Leucotrienos/fisiología , Obstrucción Nasal/fisiopatología , Rinitis Alérgica Estacional/fisiopatología , Tromboxano A2/fisiología , Animales , Antialérgicos/farmacología , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Benzoquinonas/farmacología , Cromonas/farmacología , Dexametasona/farmacología , Cobayas , Ácidos Heptanoicos/farmacología , Histamina/farmacología , Liberación de Histamina/efectos de los fármacos , Masculino , Cavidad Nasal/patología , Obstrucción Nasal/tratamiento farmacológico , Obstrucción Nasal/etiología , Rinitis Alérgica Estacional/tratamiento farmacológico , Estornudo , Terfenadina/farmacología , Irrigación TerapéuticaRESUMEN
OBJECTIVE AND DESIGN: We characterized the leukocyte kinetics after antigen challenge, and investigated the effects of the thromboxane (TX) A2 antagonist seratrodast, the peptide leukotriene (p-LT) antagonist pranlukast, the antihistaminic drug terfenadine and the glucocorticoid dexamethasone on this leukocyte response in a guinea pig model of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Intranasally sensitized guinea pigs were challenged once every week for 15 weeks by inhalation of Japanese cedar pollen as the antigen. Dexamethasone and other agents were administered orally 3 and 1 h, respectively, before the 15th challenge. METHODS: The time-related changes in the numbers of differential leukocytes in nasal cavity lavage fluid (NCLF) and in peripheral blood after pollen inhalation challenge were investigated. The effects of the drugs on the antigen-induced changes in the leukocyte counts were evaluated. In addition, histopathological examination of the nasal mucosa was also performed 5 h after the challenge. RESULTS: There was a marked increase in the number of leukocytes in NCLF, especially of eosinophils, which peaked at 5 h, after antigen challenge in this model. This response was also accompanied by the peripheral blood eosinophilia and neutrophilia. Seratrodast (30 mg/kg), pranlukast (30 mg/kg) and dexamethasone (10 mg/kg) inhibited the eosinophilia in all of the blood, the nasal mucosa and NCLF seen 5 h after the antigen challenge. Terfenadine (10 mg/kg) had no apparent effect on the blood and the mucosal eosinophilia, although it tended to suppress the eosinophil accumulation in NCLF. CONCLUSIONS: These results suggest that the present model is useful for analyzing the mechanisms of antigen-induced eosinophilic inflammation in allergic rhinitis and that both TXA2 and p-LTs, but not histamine, contribute to the antigen-induced eosinophilia in this model of allergic rhinitis.
Asunto(s)
Antialérgicos/farmacología , Antígenos/inmunología , Leucocitos/patología , Rinitis Alérgica Estacional/patología , Administración Intranasal , Animales , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Antígenos/administración & dosificación , Benzoquinonas/farmacología , Cromonas/farmacología , Dexametasona/farmacología , Cobayas , Ácidos Heptanoicos/farmacología , Cinética , Recuento de Leucocitos , Antagonistas de Leucotrieno , Masculino , Cavidad Nasal/patología , Terfenadina/farmacología , Irrigación Terapéutica , Tromboxano A2/antagonistas & inhibidoresRESUMEN
We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized-challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD4 (10 microl/nostril) at 10(-10) to 10(-6) M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dose-dependently suppressed by N(omega)-nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized-challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized-non-challenged group. The amount of NO2- and NO3- in nasal cavity lavage fluid after LTD4 instillation in the sensitized-challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.
Asunto(s)
Leucotrieno D4/efectos adversos , Mucosa Nasal/efectos de los fármacos , Obstrucción Nasal/inducido químicamente , Rinitis Alérgica Perenne/inducido químicamente , Vasodilatación/efectos de los fármacos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/inmunología , Alérgenos/efectos adversos , Animales , Modelos Animales de Enfermedad , Cobayas , Masculino , Mucosa Nasal/irrigación sanguínea , Obstrucción Nasal/inmunología , Polen/efectos adversos , Rinitis Alérgica Perenne/inmunología , Vasodilatación/inmunologíaRESUMEN
We have developed a reproducible allergic rhinitis model showing biphasic nasal blockage on repetitive inhalation challenge with Japanese cedar pollen in sensitised guinea pigs. The role of nitric oxide (NO) in inducing nasal blockage was evaluated with this model. N(omega)-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, intravenously administered before the challenge, significantly inhibited both early and late nasal blockage by approximately 80% and 50%, respectively. When L-NAME treatment was performed after the challenge, the late response was inhibited by approximately 70%. This inhibition was completely reversed by co-administration of L-arginine. However, aminoguanidine and L-N(6)-(1-iminoethyl)lysine, selective inhibitors of inducible NOS, negligibly influenced the degree of nasal blockage. Meanwhile, the alpha-adrenergic agonist, naphazoline, strongly suppressed both early and late nasal blockage. These results indicate that NO, likely produced by constitutive rather than inducible NOS, plays a major role in the occurrence of biphasic nasal blockage, primarily by inducing vasodilatation.
Asunto(s)
Obstrucción Nasal/inmunología , Óxido Nítrico/fisiología , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Administración Intranasal , Agonistas alfa-Adrenérgicos/farmacología , Alérgenos/inmunología , Animales , Arginina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Cobayas , Inyecciones Intravenosas , Lisina/análogos & derivados , Lisina/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Nafazolina/farmacología , Obstrucción Nasal/prevención & control , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Rinitis Alérgica Estacional/prevención & control , Estornudo/efectos de los fármacos , Factores de TiempoRESUMEN
We have developed an allergic rhinitis model in guinea pigs using Japanese cedar pollen as antigen. In the present study, we examined whether provocation by pollen induces similar magnitudes of rhinitis symptoms in passively and actively sensitized guinea pigs. One group of animals was actively sensitized by intranasal application of pollen extract, and another was passively sensitized by intraperitoneal injection with anti-pollen serum. Actively and passively sensitized groups were then challenged by repeated and a single pollen inhalation, respectively. In both groups, sneeze was induced immediately after the challenge. The actively sensitized animals developed not only early but also late nasal blockage, whereas the passively sensitized animals showed only early nasal blockage. In both groups, an H1 antagonist, mepyramine, inhibited the occurrence of sneezing but did not inhibit nasal blockage. Nasal hyperresponsiveness to intranasal instillation of leukotriene D4 was obvious only in the actively sensitized animals. We thus conclude that although early nasal blockage is induced by a single antigen-antibody reaction, repetitive anaphylactic reaction is required for occurrence of late nasal blockage and hyperresponsiveness to stimuli. Furthermore, histamine plays a central role in induction of sneezing but not in nasal blockage, irrespective of whether animals are actively or passively sensitized.