RESUMEN
BACKGROUND AND STUDY AIMS: Growing evidence suggests that esophageal stricture frequently develops after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) in early esophageal cancer patients, with an incidence proportional to the greater extent of mucosal defects resulting from improved EMR/ESD techniques. There seems to be a potential risk of perforation during bougienage in such patients. PATIENTS AND METHODS: 648 stricture dilations for 78 lesions in 76 patients were consecutively included. The outcomes after combined use of Maloney and Savary wire-guided bougienage for esophageal strictures after EMR/ESD were analyzed in a single-institute retrospective case series study. The perforation rate was determined and risk factors for perforation were identified. RESULTS: Patients underwent a median of 5.0 dilation procedures performed over a median 3.0 months for post-EMR/ESD strictures. Initial dilation was done a median 14 days following endoscopic resection. Perforations developed in seven patients (7/648 dilation procedures, 1.1%), all in the lower esophagus, and bleeding occurred in one patient (0.1% dilations). Two independent risk factors for development of perforation during dilation therapy for post-EMR/ESD stricture were identified: multiple dilations (odds ratio [OR] 1.2; P=0.012), and lower site of stricture (OR 12.8; P=0.043). Dysphagia was ameliorated by the dilations, and no patient required surgery. CONCLUSIONS: A specific emerging risk of perforation in dilation therapy for post-EMR/ESD strictures was identified. Carefully planned treatment is necessary in patients with severe post-EMR/ESD strictures especially strictures requiring multiple dilations or located in the lower esophagus.
Asunto(s)
Carcinoma de Células Escamosas/cirugía , Dilatación/efectos adversos , Neoplasias Esofágicas/cirugía , Perforación del Esófago/epidemiología , Perforación del Esófago/etiología , Estenosis Esofágica/terapia , Esofagoscopía/efectos adversos , Esófago/cirugía , Membrana Mucosa/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Dilatación/instrumentación , Estenosis Esofágica/etiología , Esófago/patología , Humanos , Masculino , Persona de Mediana Edad , Membrana Mucosa/patología , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
We explored the origin of all-female broods resulting from male death in a Hokkaido population of Lymantria dispar through genetic crosses based on the earlier experiments done by Goldschmidt and by testing for the presence of endosymbionts that are known to cause male killing in some insect species. The mitochondrial DNA haplotypes of the all-female broods in Hokkaido were different from those of normal Hokkaido females and were the same as those widely distributed in Asia, including Tokyo (TK). Goldschmidt obtained all-female broods through backcrossing, that is, F1 females obtained by a cross between TK females (L. dispar japonica) and Hokkaido males (L. dispar praeterea) mated with Hokkaido males. He also obtained all-male broods by mating Hokkaido females with TK males. Goldschmidt inferred that female- and male-determining factors were weakest in the Hokkaido subspecies and stronger in the Honshu (TK) subspecies. According to his theory, the females of all-female broods mated with Honshu males should produce normal sex-ratio broods, whereas weaker Hokkaido sexes would be expected to disappear in F1 or F2 generations after crossing with the Honshu subspecies. We confirmed both of Goldschmidt's results: in the case of all-female broods mated with Honshu males, normal sex-ratio broods were produced, but we obtained only all-female broods in the Goldschmidt backcross and obtained an all-male brood in the F1 generation of a Hokkaido female crossed with a TK male. We found no endosymbionts in all-female broods by 4,'6-diamidino-2-phenylindole (DAPI) staining. Therefore, the all-female broods observed in L. dispar are caused by some incompatibilities between Honshu and Hokkaido subspecies.
Asunto(s)
Hibridación Genética , Mariposas Nocturnas/genética , Animales , Bacterias/genética , Secuencia de Bases , Femenino , Proteínas de Insectos/genética , Japón , Masculino , Datos de Secuencia Molecular , Mariposas Nocturnas/microbiología , Mariposas Nocturnas/fisiología , Razón de Masculinidad , Especificidad de la Especie , SimbiosisRESUMEN
Successful prosthodontic treatments for a patient with removable partial dentures including maxillofacial prostheses hopefully brings about psychological wellbeing as well as improved health. The purpose of this study was to investigate the relationship between quality of life (QOL) and the various aspects of denture function. At first, a questionnaire with a visual analog scale with 16 question items concerning denture and/or eating problems, the present state of health, psychological and physical wellbeing, life satisfaction, and QOL was developed. To discuss the validity and reliability of the questionnaire, 48 outpatients who wore a denture were asked to fill it out. Next, to discuss the difference in QOL of the patient with various kinds of dentures and conditions, 103 outpatients were asked to complete the newly developed questionnaire. The questionnaire which contained four factor areas with eight questions for denture patients was developed by factor analysis with Varimax rotation. The reliability of the QOL scale was confirmed by reliability analysis (Cronbach's alpha = 0.784). The QOL score of edentulous patients with a complete denture having some trouble chewing was significantly lower than that of other denture patients. It was suggested that the wearing of a denture significantly affected the QOL of elderly persons.
Asunto(s)
Dentaduras/efectos adversos , Masticación , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Dentadura Parcial Removible/efectos adversos , Dentadura Parcial Removible/psicología , Dentaduras/psicología , Ingestión de Alimentos , Análisis Factorial , Indicadores de Salud , Humanos , Prótesis Maxilofacial , Persona de Mediana Edad , Dolor/etiología , Satisfacción del Paciente , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND: Mast cells (MCs) arise from haematopoietic stem cells. We have recently reported that CD34(+) progenitors derived from human bone marrow (BM) develop into tryptase+, chymase+ MCs when cultured in the presence of recombinant human stem cell factor (rhSCF) and recombinant human IL-6 (rhIL-6). In an experiment for the expression of chymase during differentiation, chymase+ cells were detected in human BM, but tryptase+ cells were not found. OBJECTIVE: The purpose of this study was to show the appearance of chymase+ cells in CD34(+) cells with an origin different from MC differentiation. METHODS: CD34(+) cells from human BM were sorted with anti-CD117 monoclonal antibody (mAb), and cytospins of CD34(+), CD34(+)CD117(+), or CD34(+)CD117(-) were prepared. These cells were cultured with rhSCF+rhIL-6 for 12 weeks. Some of the cells were subjected to either histological stain with Wright-Giemsa or immunocytochemistry with anti-chymase mAb. Real-time RT-PCR was also performed to compare the transcriptional level of chymase from each cell preparation. RESULTS: Chymase was expressed in CD34(+) cells as well as human MCs by immunocytochemistry. Substantial CD34(+)CD117(-) cells, but not CD34(+)CD117(+) cells, were stained immunocytochemically with anti-chymase mAb. For 1 week culture with rhSCF+rhIL-6, no cells expressed chymase in any preparation. Real-time RT-PCR revealed positivity for chymase mRNA in CD34(+) cells, but it reduced at 1 week of culture, and increased as cells developed into MCs. Chymase mRNA in CD34(+)CD117(+) cells was negligible compared with that in CD34(+)CD117(-). Tryptase mRNA was below the detectable level in CD34(+) cells, and increased along with MC differentiation. After 12 weeks of culture, CD34(+)CD117(+) developed predominantly into MCs, whereas CD34(+)CD117(-) developed into monocytes/macrophages. CONCLUSION: Our findings suggested that chymase is present not only in MCs but also in CD34(+)CD117(-) BM progenitors, but that its origin is different from the MC lineage.
Asunto(s)
Antígenos CD34/análisis , Células Madre Hematopoyéticas/enzimología , Serina Endopeptidasas/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Separación Celular/métodos , Células Cultivadas , Quimasas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Interleucina-6/farmacología , Mastocitos/enzimología , Proteínas Proto-Oncogénicas c-kit/análisis , ARN Mensajero/genética , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Serina Endopeptidasas/genética , Factor de Células Madre/farmacología , TriptasasRESUMEN
BACKGROUND: CD34(+) progenitor cells develop into tryptase(+), CD117(+) mast cells when cultured in the presence of recombinant human stem cell factor (rhSCF). However, spontaneous IgE receptor (FcepsilonRI) expression during human mast cell development is not well examined. OBJECTIVE: Here, the expression and function of FcepsilonRI in and on human bone marrow-derived mast cells (HBMMCs) during development were investigated. METHODS AND RESULTS: At 4 weeks of culture, predominant cells expressed high-affinity IgE receptor alpha chain (FcepsilonRIalpha) on the cell surface determined by flow cytometry, but CD117 was less expressed. Immunocytochemistry with antitryptase mAb and anti-FcepsilonRIalpha mAb revealed intracellular and surface expression of FcepsilonRIalpha at 2 weeks of culture, but tryptase was less expressed. FcepsilonRIalpha mRNA transcript preceded that of tryptase mRNA at 2 weeks of culture determined by real-time RT-PCR, and FcepsilonRIalpha, FcepsilonRIbeta, FcepsilonRIgamma, and tryptase mRNA increased along with differentiation. FcepsilonRIalpha cross-link on HBMMC and 4-week-old mast cells/mast cell precursors induced the release of IL-5 and granulocyte macrophage-colony stimulating factor, which was enhanced by rhSCF. CONCLUSION: These data indicated that HBMMC constitutively and spontaneously expressed functional FcepsilonRI subunits at the early stage of differentiation, probably because of the differences in the ability and functional property of progenitors.
Asunto(s)
Interleucina-6/farmacología , Mastocitos/inmunología , Receptores de IgE/metabolismo , Serina Endopeptidasas/metabolismo , Factor de Células Madre/farmacología , Células Madre/citología , Antígenos CD34/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Diferenciación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática/métodos , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Inmunohistoquímica/métodos , Interleucina-4/inmunología , Interleucina-5/inmunología , Proteínas Proto-Oncogénicas c-kit/inmunología , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/inmunología , TriptasasRESUMEN
We propose a probative approach for noninvasive evaluation of airway hyperresponsiveness (AHR) and remodeling to investigate their outcome in adult asthmatics treated according to the Global Initiative for Asthma (GINA) guideline. Pulmonary function and AHR to methacholine were measured twice with an interval of 24.3 +/- 3.4 months in 18 adult asthmatics during the ongoing treatments. Mathematical formulas previously used in an animal model were applied in human asthmatics to eliminate the effect of airway wall thickening on respiratory resistance (Rrs), calculating indices for the proportional changes with time in airway wall thickness (PW(1)/PW(0)) and airway smooth muscle shortening (PMS(1)/PMS(0)), respectively. The minimum cumulative dose of methacholine (Dmin), an ordinary index of AHR measured with the oscillometry Asthograph, correlated with the asthma severity. The disease periods significantly correlated with the indices of airflow limitation. While there was no change in PW(1)/PW(0) (1.00 +/- 0.07) during the assessment periods, methacholine-induced airway smooth muscle shortening was attenuated by 46% (PMS(1)/PMS(0)=0.54 +/- 0.16). Less improvement in PMS(1)/PMS(0) was seen with a correlation to the disease periods, but PMS(1)/PMS(0) improved correlating to the relative length of the assessment period with ongoing treatments in the disease period. In conclusion, this probative approach may be useful to investigate the outcome of AHR and remodeling in human asthmatics, and shows that remodeling may get worse with time or may halt and AHR may improve with a stepwise, early intervention and prolonged treatment given according to the GINA guideline.
Asunto(s)
Asma/fisiopatología , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/fisiopatología , Pruebas de Función Respiratoria/métodos , Administración por Inhalación , Corticoesteroides/administración & dosificación , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/fisiología , Animales , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/inducido químicamente , Broncoconstrictores , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Cloruro de Metacolina , Persona de Mediana Edad , Modelos Biológicos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiopatología , Evaluación de Procesos y Resultados en Atención de Salud/métodos , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND AND STUDY AIMS: It is well known that patients with head and neck cancer often have synchronous or metachronous squamous cell carcinoma of the esophagus. However, the prevalence of subsequent head and neck cancer in patients with early-stage esophageal cancer is still unknown. The aims of this study were to analyze the frequency of metachronous head and neck cancer after endoscopic mucosal resection (EMR) for esophageal cancer and to investigate whether minute iodine-unstained areas, often associated with squamous cell carcinomas, would be an index for metachronous head and neck cancer. PATIENTS AND METHODS: 99 patients with esophageal squamous cell carcinoma who underwent EMR were studied. Based on the iodine-staining pattern at initial EMR, they were categorized into those with uniform (group U) and scattered (group S) types of background mucosa. Patients were monitored endoscopically and otolaryngologically (group U, median 46 months, range 12-83 months; group S, median 44 months, range 13-80 months). RESULTS: In total, 5/99 patients (5.1 %) were found to have metachronous head and neck cancer during the follow-up, including 4/20 patients (20 %) in group S. In three cases laryngeal or hypopharyngeal cancer was found by endoscopic examination. The cumulative proportion of metachronous head and neck cancer-free subjects was significantly lower in group S than group U (P = 0.0007). CONCLUSIONS: Among patients who undergo EMR for esophageal carcinoma, those with scattered-type iodine staining of the background mucosa have an increased risk of metachronous head and neck cancer, and should therefore be closely observed. Careful endoscopic observation led to early detection of laryngeal and hypopharyngeal cancer.
Asunto(s)
Carcinoma de Células Escamosas/epidemiología , Neoplasias Esofágicas/epidemiología , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Anciano , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Endoscopía , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Hipofaríngeas/epidemiología , Neoplasias Hipofaríngeas/patología , Neoplasias Laríngeas/epidemiología , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Primarias Secundarias/patologíaRESUMEN
In neuropathological studies it is important to detect both resting and reactive microglia in paraffin sections. We examined the usefulness of human (h) GLUT5, a glucose transporter, as a microglial marker. We produced an hGLUT5 antibody against its C-terminal sequence and stained human brain tissue sections. The hGLUT5 antibody consistently stained microglia in cryostat sections. In paraffin sections fixed with formalin, paraformaldehyde or ethanol, both resting and reactive microglia were stained; the latter were stained more intensely than the former. The hGLUT5 and glial fibrillary acidic protein labeling did not overlap each other in double immunofluorescence analyses. Oligodendrocytes, perivascular cells, choroid plexus epithelium and ependymal cell were negative for hGLUT5. Even after 1-month fixation in formalin, the hGLUT5 antibody stained microglia well. Microwave pretreatment enhanced the immunoreactivity of hGLUT5. As compared with other microglial markers, KP-1, KiM1p, CR3.43 and RCA-1, the hGLUT5 antibody could be considered good morphological marker. hGLUT5 immunolabeling clearly showed the detailed microglial processes, whereas immunolabeling with Ki-M1P and KP-1 showed cytoplasmic granules, and it was difficult to trace the microglial processes. The hGLUT5 antibody stained both resting and reactive microglia, whereas CR3.43 stained only reactive microglia, and RCA-1 labeled microvessels more intensely than microglia. Thus, hGLUT5 is a marker that is suitable for routine histopathological staining procedures.
Asunto(s)
Anticuerpos , Biomarcadores , Microglía/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Transportador de Glucosa de Tipo 5 , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Proteínas de Transporte de Monosacáridos/inmunología , Adhesión en ParafinaRESUMEN
BACKGROUND: In vitro-derived human mast cells exhibit different properties, depending in part on the source of progenitor cells. Most investigations have used fetal liver, cord blood or peripheral blood. Few have used adult bone marrow. OBJECTIVE: Human mast cells derived in vitro from the CD34(+) progenitors in bone marrow and cord blood that had been cultured with recombinant human stem cell factor (rhSCF) and recombinant human interleukin-6 (rhIL-6) were compared. METHODS AND RESULTS: After 12 weeks of culture, nearly all of the cells were mast cells, and nearly all of these had cytoplasmic granules containing both tryptase and chymase (MCTC type), stained metachromatically with acidic toluidine blue, and expressed CD117 on the cell surface. Both tryptase protein and mRNA were detected by two weeks of culture. Chymase mRNA and protein were detected at 4 weeks but not at 2 weeks of culture. By 12 weeks, chymase content per cell, measured by ELISA, was significantly higher (P < 0.05) in human bone marrow-derived mast cells (HBMMC) (5.6 +/- 0.9 pg) than in cord blood-derived mast cells (CBMC) (2.4 +/- 0.9 pg), whereas histamine and tryptase levels were not significantly different. Of the cluster designations tested, CD29, CD49d, CD51 and CD61 were strongly expressed on HBMMC. CD54 and Fc epsilon RI alpha also were expressed constitutively. Approximately half of CD34-sorted cells at day 0 were CD13(+) and this diminished as mast cell maturation occurred. Electron microscopy revealed that 12-week-old HBMMC had many secretory granules that contained spherical electron dense cores surrounded by electron lucent space, consistent with previous reports of immature MCTC cells developing in vivo. CONCLUSIONS: CD34(+) progenitors of human bone marrow are a rich source of mast cell progenitors capable of expressing granule and surface markers of mature mast cells in the presence of rhSCF and rhIL-6.
Asunto(s)
Antígenos CD/biosíntesis , Antígenos CD/efectos de los fármacos , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Interleucina-4/farmacología , Interleucina-6/farmacología , Mastocitos/clasificación , Mastocitos/citología , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/efectos de los fármacos , Factor de Células Madre/farmacología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Células Cultivadas , Quimasas , Humanos , Inmunohistoquímica , Mastocitos/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Serina Endopeptidasas/metabolismo , Células Madre/efectos de los fármacos , Células Madre/metabolismo , TriptasasRESUMEN
Although mast cells accumulate within the mucosal epithelial layer of patients with allergic rhinitis and bronchial asthma, the responsible chemotactic factors are undefined. We investigated whether mast cells sensitized with Ag-specific IgE migrate toward the Ag. MC/9 mast cells sensitized with anti-DNP IgE migrated toward DNP-conjugated human serum albumin. This migration was directional, and the degree was stronger than that induced by stem cell factor. IL-3 and stem cell factor-dependent cultured mast cells derived from mouse bone marrow also migrated toward the Ag. Subsequent migration mediated by the Fc(epsilon)RI was significantly inhibited by incubating the cells with Y-27632, a Rho-associated coiled-coil-forming protein kinase inhibitor, or with SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Both p38 MAPK and MAPK-activated protein kinase (MAPKAPK)2 were activated following Fc(epsilon)RI aggregation, and activation of MAPKAPK2 was almost completely inhibited by 10 microM SB203580. Wortmannin or a low concentration of SB203580 partially inhibited MAPKAPK2, but did not block mast cell migration. In contrast, Y-27632 did not affect the activation of MAPKAPK2. These results indicate that Ag works not only as a stimulant for allergic mediators from IgE-sensitized mast cells, but also as a chemotactic factor for mast cells. Both p38 MAPK activation and Rho-dependent activation of Rho-associated coiled-coil-forming protein kinase may be required for Fc(epsilon)RI-mediated cell migration.
Asunto(s)
Movimiento Celular/inmunología , Haptenos/inmunología , Mastocitos/enzimología , Mastocitos/inmunología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Androstadienos/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Células Clonales , Dinitrofenoles/inmunología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Inhibidores Enzimáticos/farmacología , Femenino , Flavonoides/farmacología , Imidazoles/farmacología , Inmunización , Inmunoglobulina E/metabolismo , Péptidos y Proteínas de Señalización Intracelular , MAP Quinasa Quinasa 1 , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-kit/fisiología , Piridinas/farmacología , Receptores de IgE/antagonistas & inhibidores , Receptores de IgE/fisiología , Albúmina Sérica/inmunología , Wortmanina , Proteínas Quinasas p38 Activadas por Mitógenos , Quinasas Asociadas a rhoRESUMEN
We investigated whether the atrial natriuretic peptide (ANP) might have an inhibitory effect on inflammatory cells. Treatment of RAW264.7 macrophages with interferon-gamma (IFN- gamma) caused a significant increase in tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production. Activation of p38 mitogen-activated protein (MAP) kinase was observed 30 to 120 min after IFN-gamma, and transcription factor nuclear factor-kappa B (NF-kappaB) was activated about 7 to 9 times of the basal activity. Human ANP(99-126) and a specific p38 MAP kinase inhibitor SB203580 inhibited the IFN-gamma-induced TNF-alpha production in a dose-dependent manner without affecting NO production. ANP inhibited the IFN-gamma-induced p38 MAP kinase activation, and ANP and SB203580 inhibited NF-kappaB activation. To study the involvement of oxidative stress in this system, the effects of allopurinol and acetovanillone, inhibitors of xanthine oxidase and NADPH oxidase, respectively, were studied. Allopurinol or acetovanillone did not inhibit the IFN-gamma-induced production of TNF-alpha or NO, suggesting little involvement of oxidative stress in this system. This is the first evidence in vitro that ANP has an anti-inflammatory activity on IFN-gamma-activated macrophages by suppressing signal transduction pathway leading to p38 MAP kinase and NF-kappaB activation.
Asunto(s)
Factor Natriurético Atrial/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Línea Celular , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Interferón gamma/farmacología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Nitritos/metabolismo , Piridinas/farmacología , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
To evaluate (+)-(R)-trans-4-(l-Aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate (Y-27632), a selective Rho-kinase inhibitor, as a novel bronchodilator in vivo and in vitro, we investigated the effect of Y-27632 on the acetylcholine- or ovalbumin-induced increase in lung resistance (R(L)) in non-sensitized or passively sensitized guinea pigs, and the relaxant effects of salbutamol, Y-27632 and theophylline on acetylcholine- or ovalbumin-induced contraction of isolated trachea. Y-27632 inhalation (1 mM, 2 min) inhibited acetylcholine- or ovalbumin-induced increase in R(L) without changes in mean blood pressure, and the effect persisted for at least 3 h. Salbutamol, Y-27632 and theophylline each completely reversed the acetylcholine- or ovalbumin-induced contraction of isolated trachea with rank order of potency, salbutamol>Y-27632>theophylline. The relaxant effect of Y-27632 was not affected by propranolol. We conclude that, although Y-27632 is not as potent as a beta-adrenoceptor agonist, Y-27632 may become an alternative inhaled bronchodilator, because Y-27632 is more potent than theophylline, and the relaxant effect is independent of beta-adrenoceptors.
Asunto(s)
Amidas/farmacología , Broncodilatadores/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Acetilcolina/farmacología , Administración por Inhalación , Animales , Presión Sanguínea/efectos de los fármacos , Cobayas , Péptidos y Proteínas de Señalización Intracelular , Pulmón/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Quinasas Asociadas a rhoRESUMEN
To evaluate the potential inhibitory effect of theophylline on the pulmonary oxidative stress in asthma and chronic obstructive pulmonary disease (COPD), we concomitantly measured the blood levels of theophylline, a non-selective phosphodiesterase (PDE) inhibitor and lipid peroxides as an index of oxidative stress. The plasma levels of lipid peroxides were significantly elevated in patients with asthma (3.48 +/- 0.11 nmol ml(-1); mean +/- SEM; n=21, P<0.01), non- or ex-smoking patients with COPD (3.55 +/- 0.11 nmol ml(-1); n = 20, P<0.01), and current-smoking patients with COPD (3.53 +/- 0.15 nmol ml(-1); n = 15, P<0.01), respectively, as compared to those of non-smoking controls (3.02 +/- 0.08 nmol ml(-1); n = 19). There was a significant negative correlation between the plasma level of lipid peroxides and the forced expiratory volume in 1 sec (FEV1)% of forced vital capacity in these subjects (r = -0.304; n = 75, P < 0.01). In asthmatics, there was a significant negative correlation between the plasma level of lipid peroxides and the serum level of theophylline (r = -0.495; n = 18, P<0.05). These results suggest that there may be increased oxidative stress in patients with asthma and COPD, and indicate that oxidative stress could possibly attribute to the pathophysiology of asthma and COPD in leading to airflow obstruction and that theophylline could potentially inhibit oxidative stress in the process of bronchopulmonary inflammation in asthmatics.
Asunto(s)
Asma/fisiopatología , Enfermedades Pulmonares Obstructivas/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Teofilina/uso terapéutico , Anciano , Asma/tratamiento farmacológico , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Peróxidos Lipídicos/sangre , Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/sangre , Teofilina/sangre , Capacidad Vital/efectos de los fármacosRESUMEN
OBJECTIVE: To determine the clinical characteristics of gait disorders in patients with pontine medial tegmental lesions. DESIGN: We compared features of gait disorders between patients with infarcts in the medial tegmentum and those with stroke in other areas of the pons (pathological control subjects) by measuring electromyographic results of lower limb muscles and several biomechanical parameters. PATIENTS: Two patients with infarcts in the rostral medial tegmentum and 4 control subjects. Two of the control patients had lesions in the pontine base, while the lesions in the other 2 were in the pontine tegmentum and base (combined lesions). RESULTS: Patients with rostral medial tegmental lesions and controls with pontine base lesions showed unstable walking characterized by irregular angular displacements and foot pressures. However, they differed by the following 3 features. (1) Rostral medial tegmental lesions elicited truncal ataxia without limb ataxia. In comparison, pontine base lesions elicited limb ataxia without truncal ataxia and caused hemiparesis. (2) Instability was more severe and persistent in patients with the former lesions than in those with the latter lesions. Slowness of walking speed and prolongation of the double-support period were clearly observed in the former group. (3) Electromyographic changes characteristic of cerebellar ataxia were clearly evident in patients with rostral medial tegmental lesions. The electromyographic amplitudes of the gastrocnemius and tibialis anterior muscles were almost constant throughout the gait cycle, resulting in the disappearance of the inherent periodic pattern of each muscle. CONCLUSION: Medial tegmental lesions in the rostral pons cause prolonged and severe unstable walking that resembles spinocerebellar ataxic pattern, and impairment of the spinocerebellar loop might be the pathomechanism underlying such a gait disturbance.
Asunto(s)
Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Puente/fisiopatología , Anciano , Fenómenos Biomecánicos , Ataxia Cerebelosa/etiología , Electromiografía , Femenino , Marcha , Trastornos Neurológicos de la Marcha/diagnóstico , Humanos , Pierna , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Puente/patología , Tiempo de Reacción , Accidente Cerebrovascular/complicacionesRESUMEN
PURPOSE: To determine the changes in gastric intramucosal pH (pHi) following coronary artery bypass grafting (CABG) in comparison with systemic hemodynamic variables and circulating blood volume (BVc). METHODS: Twenty patients who underwent CABG under mild hypothermic cardiopulmonary bypass (CPB) were included. Hemodynamic variables and the values of pHi were obtained at 3,6, 12 and 24 hr after admission to the intensive care unit (ICU). The pHi was measured by gastric tonometric catheter. The BVc was measured by carbon monoxide (CO)-labeled hemoglobin (CO-Hb) dilution method (CO method) at 6 and 24 hr after ICU admission. RESULTS: Systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) decreased with time. Systemic oxygen delivery index (DO2I) and systemic oxygen consumption index (VO2I) showed a gradual increase during the study period. By contrast, pHi decreased to the lowest value (7.26+/-0.05) at six hours and returned to normal levels (7.34+/-0.04) at 24 hr after ICU admission. Changes in BVc between six and 24 hr ranged from -242 ml to 978 ml (mean, 334+/-338 ml). The pHi increased in patients whose BVc increased by > 300 ml. Mean fluid balance was negative in this period (-386+/-667 ml; range, -1786 - + 423 ml). CONCLUSION: The pHi showed the lowest value at six hours and returned to normal at 24 hr after ICU admission. The pHi increased with the decrease in vascular resistance and with the increases in BVc in this period. The improvement of pHi, an indicator of splanchnic perfusion, appears to be related to systemic vasodilatation and an increase in BVc.
Asunto(s)
Volumen Sanguíneo , Puente de Arteria Coronaria , Mucosa Gástrica/metabolismo , Anciano , Dióxido de Carbono/metabolismo , Espacio Extracelular/metabolismo , Femenino , Determinación de la Acidez Gástrica , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We have investigated the effects of long-term treatment with clomipramine, a tricyclic antidepressant, on central muscarinic acetylcholine receptors (mAChR) in mice. Repeated clomipramine administration resulted in an increase in the forebrain receptor density value (Bmax) for [3H]quinuclidinyl benzilate, a muscarinic ligand (P < 0.05), that was dependent on dose per administration (saline or 5, 10, or 20 mg kg(-1) once a day for 7 days) and number of days treated (20 mg kg(-1) for 1, 3, 5, or 7 days). No change in apparent affinity (defined as the reciprocal of the dissociation constant) (KD) occurred. Seven daily treatments with clomipramine (saline or 5, 10, or 20 mg kg(-1)) reduced hyperlocomotion induced by scopolamine (0.5 mg kg(-1), s.c.) dose-dependently, and the effect of 20 mg kg(-1) clomipramine was significant (P < 0.05). These results suggest that an upregulation of mAChR is produced by repeated clomipramine administration, and such a change is responsible for the decreased sensitivity to the muscarinic antagonist scopolamine.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Clomipramina/uso terapéutico , Antagonistas Muscarínicos/farmacología , Prosencéfalo/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Escopolamina/antagonistas & inhibidores , Animales , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Prosencéfalo/metabolismo , Quinuclidinil Bencilato/metabolismo , Receptores Muscarínicos/metabolismo , Análisis de Regresión , Escopolamina/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
To clarify the characteristics of parkinsonian and ataxic gaits, we analyzed electromyograms (EMGs) of the thigh and leg muscles, angular displacements of the hip and leg joints, and floor reaction forces during free walking for each gait phase in 16 patients with Parkinson's disease (PD) and 14 ataxic patients with cerebellar degenerations. We studied 17 healthy elderly subjects whose walking speed was similar to that of patients with moderate disease. Free walking by PD patients was characterized by low maximum activity of the gastrocnemius/soleus (GC) and tibialis anterior (TA) muscles. Ataxic patients showed high activity of GC and TA during the period when these muscles were not active in normal walking. The ratio of changes of EMG of the distal muscles to changes in angular displacement of the ankle (DeltaEMG/Deltaangle) was reduced in GC of PD patients in ankle dorsiflexion, whereas it was high in GC and TA of ataxic patients in ankle dorsiflexion and plantarflexion, respectively. Changes in DeltaEMG/Deltaangle coincided with those in proprioceptive reflexes reported previously. Our results showed that measurement of EMG for each phase revealed disease-specific factors, and that of DeltaEMG/Deltaangle might be a conventional clue for estimation of reflexes for these gait disorders.
Asunto(s)
Ataxia/fisiopatología , Marcha , Enfermedad de Parkinson/fisiopatología , Anciano , Anciano de 80 o más Años , Articulación del Tobillo/fisiopatología , Electromiografía , Femenino , Cadera , Articulación de la Cadera/fisiopatología , Humanos , Articulaciones/fisiopatología , Pierna , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Valores de ReferenciaRESUMEN
We report a rare case of acute respiratory distress syndrome (ARDS) induced by Influenza A (H3 N2) without secondary microbiological infection. A 69-year-old woman was admitted to our hospital because of cough and severe dyspnea. We diagnosed ARDS, because of the severe respiratory failure resistant to high-dose oxygen, the diffuse bilateral infiltrates without cardiomegaly on chest radiography, and the normal pulmonary artery wedge pressure. This patient was treated with high doses of methylprednisolone, antibiotics, globulins, urinastatin, neutrophilic elastase inhibitor, nitric oxide inhalation, and extracorporeal membrane oxygenation, but died on the thirteenth hospital day. Our final diagnosis was ARDS induced by fulminant influenza (A/Hong Kong/68 (H3 N2)) virus pneumonia, because the antibody titers of H3 N2 influenza of paired sera showed a 128-fold increase.
Asunto(s)
Virus de la Influenza A , Gripe Humana/complicaciones , Síndrome de Dificultad Respiratoria/etiología , Enfermedad Aguda , Anciano , Anticuerpos Antivirales/sangre , Biomarcadores/sangre , Resultado Fatal , Femenino , Humanos , Virus de la Influenza A/inmunología , Gripe Humana/virologíaRESUMEN
1 G protein-mediated Ca2+ sensitization of airway smooth muscle contraction was investigated with respect to the relative importance of Rho-associated coiled coil forming protein kinase (ROCK) and protein kinase C (PKC). We examined the effects of Y-27632, a ROCK inhibitor, and GF 109203X, a PKC inhibitor, on guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)-induced contraction in alpha-toxin- or beta-escin-permeabilized rabbit trachea. 2 Although pre-treatment with Y-27632 dose-dependently inhibited GTPgammaS (10 microM)-induced Ca2+ sensitization of alpha-toxin-permeabilized trachea, a Y-27632-insensitive component (approximately 16% of the maximum contraction) was retained during the early phase of the GTPgammaS response in the presence of Y-27632 (100 microM). 3 GF 109203X (5 microM) abolished 1 microM 4beta-phorbol 12, 13-dibutyrate (PDBu)-induced, but only partially inhibited the GTPgammaS-induced Ca2+ sensitization. A combination of Y-27632 (100 microM) and GF 109203X (5 microM) totally abolished the GTPgammaS response. 4 GTPgammaS caused only a small contraction in the absence of Ca2+. Wortmannin (30 microM), a myosin light chain kinase (MLCK) inhibitor, completely inhibited Ca2+-induced contraction. ATP-triggered contraction of the strip which had been treated with calyculin A (1 microM), a phosphatase inhibitor, in rigor solutions was markedly slowed by worthmannin (30 microM), but not by Y-27632 (100 microM), in the presence of GTPgammaS and Ca2+. 5 GTPgammaS, but not PDBu, contracted the beta-escin-permeabilized trachea in the absence of Ca2+, but the presence of Ca2+-independent MLCK. 6 We conclude that ROCK plays a primary role in G-protein-mediated Ca2+ sensitization, which requires MLCK activity, with minor contribution of PKC to the early phase of contraction, and PDBu utilizes conventional PKC(s) in airway smooth muscle.
Asunto(s)
Calcio/metabolismo , Proteínas de Unión al GTP/fisiología , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/fisiología , Tráquea/metabolismo , Amidas/farmacología , Animales , Inhibidores Enzimáticos/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indoles/farmacología , Péptidos y Proteínas de Señalización Intracelular , Maleimidas/farmacología , Fosfatasa de Miosina de Cadena Ligera , Forbol 12,13-Dibutirato/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Conejos , Tráquea/efectos de los fármacos , Tráquea/enzimología , Quinasas Asociadas a rhoRESUMEN
BACKGROUND: Although systemic inflammation is believed to cause upregulation of nicotinic acetylcholine receptors (nAchRs) in muscle, chronic infections such as Chagas' disease occasionally are complicated by myasthenia gravis. The authors investigated how a nonlethal cecal ligation and puncture (CLP) peritonitis model in rats could affect muscle nAchR. METHODS: On day 1, 4, 7, 14, or 21 after CLP or sham operation, nAchR binding was assayed in the anterior tibial muscle and diaphragm using [125I]alpha-bungarotoxin. The presence or absence of weakness, in vivo dose-response relationships for d-tubocurarine, and serum anti-nAchR antibody titers were assayed in separate experiments. RESULTS: Systemic inflammation was most severe during the first 4 to 5 days. Numbers of nAchRs were decreased in anterior tibial muscle on days 7, 14, and 21 after CLP, and in the diaphragm on days 7 and 14 (P < 0.01). Both 50% and 90% blocking doses of d-tubocurarine) were lower in CLP rats than in sham-operated rats on days 7, 14, and 21 (P < .05). Weakness was overt in approximately half of CLP rats at these times. Serum anti-nAchR antibody (0.7-1.4 nM) was detectable beginning on day 4 and continuing throughout the 21-day observation period in 58-67% of CLP rats. CONCLUSIONS: During the recovery phase of injury, nonlethal CLP peritonitis resulted in downregulation of nAchR. However, further study is needed to determine the role of anti-nAchR antibodies in the development of decreased receptor numbers and impaired neuromuscular function.