RESUMEN
BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Ácido Oxónico/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Tegafur/administración & dosificación , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Administración Intravenosa , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Carcinoma Adenoescamoso/tratamiento farmacológico , Carcinoma Adenoescamoso/mortalidad , Carcinoma Adenoescamoso/patología , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Ácido Oxónico/efectos adversos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Tegafur/efectos adversos , Resultado del Tratamiento , GemcitabinaRESUMEN
AIMS: The adhesion ability of Lactobacillus gasseri SBT2055 was investigated in vitro by searching for its adhesion molecules. METHODS AND RESULTS: Lactobacillus gasseri SBT2055 showed adherence to host components, including two commercially available mucins, Caco-2 epithelial-like cells and the extracellular matrix molecule fibronectin (Fn). Its adhesion rates to host components were generally higher than those of other Lactobacillus strains. We examined sortase-dependent proteins (SDPs) anchored by a sortase enzyme encoded by srtA1. The adhesion rates of an srtA1 disruptant were lower than those of Lact. gasseri SBT2055, and the relative adherences were as follows: two mucins, 43 and 40%; Caco-2, 66% and Fn, 28%. Seven additional gene disruptants were generated to determine the precise SDPs that contribute to adhesion to each component. CONCLUSIONS: The adhesion ability of Lact. gasseri SBT2055 was superior to those of other Lactobacillus strains. Additionally, four adhesion molecules were newly identified from candidate SDPs. SIGNIFICANCE AND IMPACT OF THE STUDY: Although the contribution of SDPs to adhesion has been reported using sortase gene disruptants, this is the first report to identify the precise SDPs that act as adhesion molecules. Our results will contribute to achieving better understanding of probiotic bacterial adherence.
Asunto(s)
Adhesión Bacteriana , Intestinos/microbiología , Lactobacillus gasseri/fisiología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/metabolismo , Lactobacillus gasseri/genética , Mucinas/metabolismo , Probióticos/químicaRESUMEN
Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6.1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non-carriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low-frequency variants of MEFV gene may be one of the susceptibility factors of AOSD.
Asunto(s)
Proteínas del Citoesqueleto/genética , Mutación/genética , Enfermedad de Still del Adulto/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Pirina , Adulto JovenRESUMEN
Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4%. Of these patients, injection site reactions were observed in 64.8%, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5%, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9%), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/mortalidad , Vacunas contra el Cáncer/administración & dosificación , Desoxicitidina/análogos & derivados , Fragmentos de Péptidos/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/efectos adversos , Análisis de Supervivencia , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/efectos adversos , GemcitabinaRESUMEN
The rostral nucleus of the solitary tract (rNST) is the first-order taste relay in rats. This study constructed topographical distributions of taste response characteristics (best-stimulus, response magnitude, and taste-tuning) from spike discharges of single neurons in the rNST. The rNST is divided into four subregions along the rostrocaudal (RC) axis, which include r1-r4. We explored single-neuron activity in r1-r3, using multibarreled glass microelectrodes. NaCl (N)-best neurons were localized to the rostral half of r1-r3, while HCl (H)-best and sucrose (S)-best neurons showed a tendency toward more caudal locations. NaCl and HCl (NH)-best neurons were distributed across r2-r3. The mean RC values and Mahalanobis distance indicated a significant difference between the distributions of N-best and NH-best neurons in which N-best neurons were located more rostrally. The region of large responses to NaCl (net response >5 spikes/s) overlapped with the distribution of N-best neurons. The region of large responses to HCl extended widely over r1-r3. The region of large responses to sucrose was in the medial part of r2. The excitatory region (>1 spike/s) for quinine overlapped with that for HCl. Neurons with sharp to moderate tuning were located primarily in r1-r2, while those with broad tuning were located in r2-r3. The robust responses to NaCl in r1-r2 primarily contributed to sharp to moderate taste-tuning. Neurons in r3 tended to have broad tuning, apparently due to small responses to both NaCl and HCl. Therefore, the rNST is spatially organized by neurons with distinct taste response characteristics, suggesting that these neurons serve different functional roles.
Asunto(s)
Potenciales de Acción , Neuronas/fisiología , Núcleo Solitario/fisiología , Percepción del Gusto , Animales , Mapeo Encefálico , Masculino , Ratas , Ratas Wistar , Olfato , Núcleo Solitario/citologíaRESUMEN
Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.
Asunto(s)
Proteínas del Citoesqueleto/genética , Macrófagos/inmunología , Mutación , Miositis/genética , Miositis/inmunología , Polimorfismo Genético , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Miositis/diagnóstico , Miositis/patología , PirinaRESUMEN
BACKGROUND: We wanted to demonstrate the feasibility of a novel computer-assisted ventilator alarm system, the support system for care of mechanically ventilated patients (SCMVP), to detect gas leaks and provide graphical information on the site of the leak in a manikin model. METHODS: We tested six leakage scenarios. Four scenarios were applied to both the respiratory circuits with the SCMVP and without the SCMVP (conventional system), and two scenarios were each specific to one of the systems. Fifteen registered nurses were asked to manage three scenarios each (two mutual and one system-specific scenario). Time to identify the site of the leak was measured and compared between the two systems. RESULTS: The SCMVP showed significantly shorter time for troubleshooting in one of the four mutual scenarios and shorter accumulated time for troubleshooting in the four mutual scenarios [18.0 (range, 14.5-19.5) and 48.5 (9.0-180.0) s, respectively] compared with the conventional system [76.0 (47.0-133.8) and 82.5 (16.0-180.0) s, respectively]. In the mutual scenarios, SCMVP resulted in significantly more frequent incidences of successful troubleshooting within 30 s and less frequent incidences of troubleshooting requiring >180 s [43.3% (13/30) and 6.7% (2/30), respectively] compared with the conventional system [13.3% (4/30) and 30% (9/30), respectively]. CONCLUSIONS: The SCMVP can facilitate rapid and successful recognition of the site of leak in a respiratory circuit in a simulation environment.
Asunto(s)
Alarmas Clínicas , Toma de Decisiones Asistida por Computador , Seguridad del Paciente , Respiración Artificial/instrumentación , Respiración Artificial/métodos , Simulación por Computador , Computadores , Presentación de Datos , Diseño de Equipo , Falla de Equipo , Estudios de Factibilidad , Humanos , Maniquíes , Modelos Organizacionales , Enfermeras y Enfermeros , Proyectos Piloto , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Factores de TiempoRESUMEN
BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.
Asunto(s)
Cisplatino/toxicidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Morfolinas/administración & dosificación , Náusea/tratamiento farmacológico , Vómitos/tratamiento farmacológico , Adulto , Anciano , Aprepitant , Cisplatino/administración & dosificación , Dexametasona/administración & dosificación , Método Doble Ciego , Femenino , Granisetrón/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Vómitos/inducido químicamenteRESUMEN
Janus kinase (JAK) inhibitors have been developed as anti-inflammatory agents and have demonstrated clinical efficacy in rheumatoid arthritis (RA). We investigated if JAK-3-selective inhibition alone could disrupt cytokine signalling in rheumatoid synovial fibroblasts. In-vitro studies were performed using synovial fibroblasts isolated from patients with RA. Levels of activated JAK and signal transducer and activator of transcription (STAT) proteins were detected by immunoblot analysis. Target-gene expression levels were measured by reverse transcription-polymerase chain reaction (RT-PCR) or real-time PCR. The JAK inhibitors CP-690,550 and INCB028050 both suppressed activation of JAK-1/-2/-3 and downstream STAT-1/-3/-5, as well as the expression levels of target proinflammatory genes (MCP-I, SAA1/2) in oncostatin-M (OSM)-stimulated rheumatoid synovial fibroblasts. In contrast, the JAK-3-selective inhibitor, PF-956980, suppressed STAT-1/-5 activation but did not affect STAT-3 activation in OSM-stimulated rheumatoid synovial fibroblasts. In addition, PF-956980 significantly suppressed MCP-1 gene expression, but did not block SAA1/2 gene expression in OSM-stimulated rheumatoid synovial fibroblasts. These data suggest that JAK-3-selective inhibition alone is insufficient to control STAT-3-dependent signalling in rheumatoid synovial fibroblasts, and inhibition of JAKs, including JAK-1/-2, is needed to control the proinflammatory cascade in RA.
Asunto(s)
Artritis Reumatoide/metabolismo , Quinasas Janus/antagonistas & inhibidores , Factores de Transcripción STAT/antagonistas & inhibidores , Líquido Sinovial/citología , Membrana Sinovial/citología , Artritis Reumatoide/tratamiento farmacológico , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Quinasas Janus/metabolismo , Oncostatina M , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Membrana Sinovial/metabolismoRESUMEN
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion from pancreatic ß-cells. Inflammatory cytokines, including tumour necrosis factor-α (TNF-α), have been shown to promote insulin resistance, and altered expression of cytokines (adipokines) in obese adipose tissue is thought to be an important link between obesity and insulin resistance. It is also becoming clear that inflammation plays a key role in the development of ß-cell dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in T2D islets. Moreover, therapeutic inhibition of interleukin-1ß (IL-1ß) ameliorates ß-cell dysfunction in humans. This review summarizes current understanding of the molecular mechanisms underlying inflammation within islets and its relation to ß-cell dysfunction in T2D. A particular focus is on the physiological and pathological functions of macrophages within islets.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Inflamación/complicaciones , Islotes Pancreáticos/patología , Macrófagos/patología , Animales , Polaridad Celular , Diabetes Mellitus Tipo 2/inmunología , Glucosa/farmacología , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/fisiología , Inflamación/patología , Interleucina-1beta/metabolismo , Islotes Pancreáticos/inmunología , Macrófagos/inmunologíaAsunto(s)
Artritis Reumatoide/inmunología , Citocinas/inmunología , Fiebre Mediterránea Familiar/inmunología , Adulto , Anciano , Sedimentación Sanguínea , Proteína C-Reactiva/inmunología , Quimiocina CX3CL1/inmunología , Quimiocina CXCL10/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos/inmunología , Humanos , Inflamación , Interleucina-10/inmunología , Interleucina-17/inmunología , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
BACKGROUND: Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted. METHODS: A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1-7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m(-2), respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD). RESULTS: In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m(-2)/S-1 80 mg m(-2). In the phase II study, 34 patients were treated with docetaxel 35 mg m(-2)/S-1 80 mg m(-2) for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6-50.0%) and 62.9% (95% CI, 46.8-72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects. CONCLUSION: Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Humanos , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Taxoides/administración & dosificación , Taxoides/efectos adversos , Tegafur/administración & dosificación , Tegafur/efectos adversosRESUMEN
OBJECTIVES: Bone oedema is a pathological change in rheumatoid arthritis (RA) that is detectable by magnetic resonance imaging (MRI). Recent histological analyses revealed that a prominent feature of bone oedema is the replacement of adipose tissue with inflammatory cells. Here, we demonstrate the possible roles of mesenchymal stromal cells (MSCs) in bone oedema formation and the pathogenic potential of the cells in RA. METHODS: Adipogenesis of bone marrow-derived human MSCs was induced by a standard adipogenic induction medium in the presence or absence of cytokines. The cytokine productions from MSCs were screened by an antibody array system and confirmed by ELISA. The migration assay was performed to determine the locomotive abilities of undifferentiated MSCs or MSCs after adipogenesis. The expression of α smooth muscle actin (SMA) and F-actin was examined by immunostaining and phalloidin staining, respectively. RESULTS: TNF-α, interleukin (IL)-1ß, IL-6, and TGF-ß clearly inhibited the adipogenesis of MSCs. Production of IL-6 was markedly reduced, and IL-8 secretion was augmented in MSCs after adipogenesis. The mobility of MSCs after adipogenesis was clearly reduced in migration assays compared to that of undifferentiated MSCs. Consistent with these findings, SMA and F-actin expressions were clearly suppressed in MSCs committed to adipogenesis. CONCLUSIONS: Our data suggest that the inflammatory milieu promotes bone oedema by blocking adipogenesis of MSCs. In bone oedema, the enhanced IL-6 production and the increased mobility of MSCs may contribute to the progression of RA. Therefore, bone oedema may be an important target lesion in the treatment of RA.
Asunto(s)
Adipocitos/citología , Adipogénesis/fisiología , Artritis Reumatoide/patología , Edema/patología , Células Madre Mesenquimatosas/citología , Adipogénesis/efectos de los fármacos , Artritis Reumatoide/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Progresión de la Enfermedad , Humanos , Interleucina-1beta/farmacología , Interleucina-6/metabolismo , Interleucina-6/farmacología , Interleucina-8/metabolismo , Imagen por Resonancia Magnética , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
In order to address how taste information is modulated by inhibitory neuronal interactions in the rat gustatory cortex, we examined putative pyramidal neurons (PY units) and putative inhibitory interneurons (fast spiking [FS] units) that were distinguished by their spike waveforms and discharge rates. FS units were strikingly different from PY units in that the majority of FS units were N- or NH-best neurons and narrowly tuned to 1 or 2 tastant(s), whereas PY units were broadly tuned to plural tastants. Compared with PY units, FS units were characterized by a shorter response latency and/or a longer response duration. These results suggest that inhibitory modulations in the gustatory cortex are carried out in a taste specific and tonic manner. Sensitivity to tastant concentrations in PY units was similar to that in FS units for NaCl but higher for HCl. FS units may act to enhance concentration sensitivity in PY units by reducing PY units' response activity. High density of FS and PY units was observed in the superficial and middle layers (mainly layers III and IV). Responses in N-best FS units in these layers were significantly larger than those in the deep layers, suggesting the existence of layer-specific inhibitory interactions.
Asunto(s)
Corteza Cerebral/fisiología , Interneuronas/fisiología , Neuronas/fisiología , Percepción del Gusto/fisiología , Potenciales de Acción/fisiología , Animales , Electrofisiología , Masculino , Ratas , Ratas WistarRESUMEN
C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated ß-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP-deficient non-obese diabetic (NOD.Chop (-/-)) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in ß-cells. Interestingly, NOD.Chop (-/-) mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8(+)-depleted splenocytes induced ß-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop (-/-) recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop (-/-) compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse.
Asunto(s)
Autoanticuerpos/biosíntesis , Eliminación de Gen , Insulina/inmunología , Estado Prediabético/inmunología , Estado Prediabético/patología , Factor de Transcripción CHOP/genética , Traslado Adoptivo , Animales , Apoptosis , Autoanticuerpos/inmunología , Linfocitos T CD8-positivos/inmunología , Retículo Endoplásmico/genética , Retículo Endoplásmico/patología , Regulación de la Expresión Génica , Etiquetado Corte-Fin in Situ , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Depleción Linfocítica , Ratones , Ratones Endogámicos NOD , Peroxidasa/metabolismo , Bazo/inmunología , Estrés Fisiológico/genética , Factor de Transcripción CHOP/metabolismoRESUMEN
Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 µg/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-γ, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody-producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Linfocitos B/efectos de los fármacos , Enfermedad de Graves/inmunología , Enfermedad de Graves/prevención & control , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Linfocitos B/citología , Linfocitos B/inmunología , Recuento de Células , Modelos Animales de Enfermedad , Femenino , Enfermedad de Graves/sangre , Enfermedad de Graves/terapia , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Depleción Linfocítica/métodos , Ratones , Ratones Endogámicos BALB C , Cavidad Peritoneal/citología , Receptores de Tirotropina/genética , Receptores de Tirotropina/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tiroxina/sangre , Vacunas de ADN/genética , Vacunas de ADN/inmunologíaRESUMEN
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serosal or synovial inflammation. We examined the utility of CD64 (FcγRI) expression in polymorphonuclear neutrophils (PMNs) as clinical and biological parameters in patients with FMF. We studied 12 Japanese FMF patients (mean age; 22·8 ± 15·5 years, male/female: 2/10), along with rheumatoid arthritis patients (RA, n = 38 male/female: 6/32, mean age; 52·2 ± 15·3 years), systemic lupus erythematosus (SLE, n = 15 male/female: 0/15, mean age; 38·5 ± 15·9 years) and 12 healthy subjects (male/female: 3/9, mean age; 37·9 ± 17·2 years). CD64 expression on PMNs was determined using flow cytometry. The quantitative expression of CD64 in patients with FMF (2439·6 ± 2215·8 molecules per PMN) was significantly higher than in healthy subjects (547·8 ± 229·5, P = 0·003) or in patients with RA (606·5 ± 228·2, P < 0·0001) and SLE (681·3 ± 281·1, P = 0·004). The increased CD64 expression on PMNs isolated from untreated FMF patients was down-regulated by colchicine treatment. NACHT-LRR-PYD-containing protein 3 (NLRP3) activation using MurNAc-L-Ala-D-isoGln (MDP) resulted in increased CD64 expression on PMNs from healthy subjects. Our results suggest that quantitative measurement of CD64 expression on PMNs can be a valuable tool to discriminate between FMF and autoimmune diseases.
Asunto(s)
Artritis Reumatoide/inmunología , Fiebre Mediterránea Familiar/inmunología , Lupus Eritematoso Sistémico/inmunología , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Adulto , Anciano , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/fisiopatología , Separación Celular , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/fisiopatología , Femenino , Citometría de Flujo , Humanos , Japón , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/patología , Receptores de IgG/genética , Receptores de IgG/inmunologíaRESUMEN
The dynamic behavior and kinetics of the structural transformation of supported bimetallic nanoparticle catalysts with synergistic functions in the oxidation process are fundamental issues to understand their unique catalytic properties as well as to regulate the catalytic capability of alloy nanoparticles. The phase separation and structural transformation of Pt(3)Sn/C and PtSn/C catalysts during the oxidation process were characterized by in situ time-resolved energy-dispersive XAFS (DXAFS) and quick XAFS (QXAFS) techniques, which are element-selective spectroscopies, at the Pt L(III)-edge and the Sn K-edge. The time-resolved XAFS techniques provided the kinetics of the change in structures and oxidation states of the bimetallic nanoparticles on carbon surfaces. The kinetic parameters and mechanisms for the oxidation of the Pt(3)Sn/C and PtSn/C catalysts were determined by time-resolved XAFS techniques. The oxidation of Pt to PtO in Pt(3)Sn/C proceeded via two successive processes, while the oxidation of Sn to SnO(2) in Pt(3)Sn/C proceeded as a one step process. The rate constant for the fast Pt oxidation, which was completed in 3 s at 573 K, was the same as that for the Sn oxidation, and the following slow Pt oxidation rate was one fifth of that for the first Pt oxidation process. The rate constant and activation energy for the Sn oxidation in PtSn/C were similar to those for the Sn oxidation in Pt(3)Sn/C. In the PtSn/C, however, it was hard for Pt oxidation to PtO to proceed at 573 K, where Pt oxidation was strongly affected by the quantity of Sn in the alloy nanoparticles due to swift segregation of SnO(2) nanoparticles/layers on the Pt nanoparticles. The mechanisms for the phase separation and structure transformation in the Pt(3)Sn/C and PtSn/C catalysts are also discussed on the basis of the structural kinetics of the catalysts themselves determined by the in situ time-resolved DXAFS and QXAFS.
RESUMEN
INTRODUCTION: The shunt operation remains the standard procedure for the treatment of hydrocephalus. We describe a simple minilaparotomy method that involves perforation of the peritoneum with the surgeon's little finger. TECHNIQUE: After placing a small paraumbilical incision at the skin and fascia, the little finger is introduced through the incision to perforate the pre-peritoneal fat and peritoneum. The finger should be inserted at a 30-45° angle to the horizontal plane to avoid injuring the underlying viscera and major blood vessels and to put sufficient shear force on the peritoneum. A catheter is inserted into the abdominal cavity after visual confirmation of proper perforation. CONCLUSION: As the paraumbilical wound is not noticeable postoperatively due to the presence of the natural umbilical skin fold, this method yields a cosmetically appealing result.
Asunto(s)
Hidrocefalia/cirugía , Laparotomía/métodos , Peritoneo/cirugía , Derivación Ventriculoperitoneal/métodos , Anciano , Humanos , Laparotomía/instrumentación , Persona de Mediana EdadRESUMEN
OBJECTIVES: To determine which variables at baseline are predictive for the development of rheumatoid arthritis (RA) from palindromic rheumatism (PR) in a Japanese population. METHODS: Anti-cyclic citrullinated peptide (anti-CCP) antibodies, joint involvement pattern, genotypes of HLA-DRB1, peptidylarginine deiminase (PADI4), and protein tyrosine phosphatase (PTPN22) were examined in 28 patients with PR at baseline, and their clinical outcome was prospectively evaluated. The same variables were also investigated in 38 healthy controls. RESULTS: Eleven out of 28 patients with PR developed RA. The prevalence of anti-CCP antibodies in the PR patients who developed RA was significantly higher compared to the patients who did not. Proximal interphalangeal (PIP) joint involvement at baseline was also predictive towards the development of RA. Compared with the controls, differences in the frequency of single-nucleotide polymorphism (SNP) on padi4_104 [T(RA susceptible)-->C(RA non-susceptible)] and the presence of an RA susceptible homozygote of the PADI4 haplotype were detected in patients with PR whereas we could not find any further difference in PR patients who developed RA compared to PR patients who do not develop RA in PADI4. None of the subjects possessed the PTPN22 SNP (1858C-->T). Cox regression analysis revealed that anti-CCP antibodies as well as PIP involvement are the most relevant variables for the development of RA from PR. None of the PR patients with either HLA-DRB1*SE alleles (or the HLA-DRB1*0405 allele) or anti-CCP antibodies developed RA. CONCLUSIONS: Anti-CCP antibodies, in relation to HLA-DRB1*SE carriership, and PIP involvement are predictive for the development of RA from PR in the Japanese population.